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Transcript
Celebrate
the Past–
Invent
the Future
DIA 2014 50TH Annual Meeting
Professional Posters
June 15-19
San Diego, CA
Invent
the Future
Celebrate
the Past–
DIA 2014 50TH Annual Meeting
June 15-19 | San Diego, CA
On Tuesday, June 17 and Wednesday, June 18 in San Diego, CA, DIA recognized ninety-one (91) professional poster presenters who presented scientific
developments related to topics addressed in this year’s program. Presentations were made in conjunction with the DIA 2014 50th Annual Meeting “Celebrate the
Past - Invent the Future.”
Poster No. Author
Poster Title
Page
T 01
Barbara Hendrickson, MD
Development and Implementation of Product Safety Statistical Analysis Plans
6
T 02
Rachida Essalihi, PhD
Ensuring Patient Recruitment Success in Phase I Clinical Trials: The Important
Role of Investigators
6
T 03
Jonathan Seltzer, MD, MA, MBA, FACC
Good Clinical Practice (GCP) Training: Identifying Key Elements and Strategies
for Increasing Training Efficiency
6
T 04
Tracey Cannova
Evaluation of Current and Future Medical Information Services Offered to
Healthcare Providers by Pharmaceutical Companies
7
T 05
Nicole Turner, MBA
Evaluation of Site Enrollment Estimates Pre- and Post-initiation to Actual
Enrollment Performance: An Assessment of Accuracy
7
T 06
Marianne Pedersen, PhD
Country-Specific Clinical Data and Reporting Requirements in Support of
Marketing Applications To Key Rest-of-World Countries
7
T 07
Paul Sheehan
Effectiveness of REMS Patient Education: An Assessment of Patient
Comprehension and Knowledge Retention
8
T 08
Kelly Colletti, PhD, MBA
Development of an ELISA Method to Characterize C1q Binding Affinity
8
T 09
Catharine Provosty
Best Practices to Effectively Close a Complex, Global Study: Different
Stakeholder Perspectives
8
T 10
Niki Kutac
Using Gamification in the Life Science Industry
8
T 11
Elisa Cascade, MBA
Burden of Clinical Trial Operations and Value of Supporting Solutions: Results
from a Global Investigator Survey
9
T 12
Luann Van Campen, PhD, MA, MSc
The Role of Bioethics in the Pharmaceutical Industry: Informal Review of 5-Year
Trends and One Company’s Systematic Approach
9
T 13
Christine Cheng, PharmD
A Survey of Boxed Warning Adverse Reaction Content from US Prescription
Drug Labeling
10
T 14
Sandy Greene
Processes and Responsibilities within Bioanalytical and Clinical Operations to
Ensure PK Sample Management in Phase 1 Studies
10
T 15
Nicole Zandy, PhD
Choosing Your Investment: What’s the Right Data Quality Solution for You?
11
T 16
Dinah Duarte, PharmD, MSc
Global Regulatory View of Nonprescription Medicines Classification
11
T 17
Rachel Skelton
Validation of Next Generation Sequencing Panels for Targetable Mutations in
NSCLC and TNBC Using FFPEs and Liquid Biopsies.
11
T 18
Elizabeth Rach
A Regulatory Informatics Approach to Identifying Trends in Minimal Residual
Disease for the Hematologic Malignancies
12
T 19
Sarah White, PharmD
Characterizing Medical Information Requests from Payer Customers to Improve
Database Planning for Respiratory Assets
12
T 20
Penelope Manasco, MD, MS
Assessing Current Monitor Performance on Monitoring Competencies for Risk
Based Monitoring
13
T 21
Kelly Hageman, PharmD
Utilization of Cross-Pollination Meeting Series: A Potential Catalyst for
Innovation
13
T 22
Dena Cosgrove, RPh
Evolution of Pharmacovigilance Regulations in the US and Europe
13
T 23
Vinit Mehta, PharmD
Validation of an Internal Communications Streamlining Initiative Utilizing an
External Communications Benchmarking Study
13
T 24
Libby Cerullo, MSc
Electronic Investigator Site Files: The Hidden Gem that Completes Remote Risk
Based Monitoring
14
Poster Abstracts | diahome.org/DIA2014
2
Invent
the Future
Celebrate
the Past–
DIA 2014 50TH Annual Meeting
June 15-19 | San Diego, CA
Poster No. Author
Poster Title
Page
T 25
Michael Waddington, MS
Precision Laboratory Network (PLN): PBMC Processing and Nuclei Acid Isolation
Suitability Study
14
T 26
Laura Wallace, MPH
Use of Epidemiology Data to Inform Pediatric Clinical Trial Design and Execution
and Its Impacts on MSL Support
14
T 27
Libbie McKenzie, MD
A Strategic Approach to Portfolio Benefit-Risk Assessments (BRAs)
15
T 28
David Horsburgh
Avoid at Your Risk? The Potential for Naïve Sites to Rescue Failing Recruitment
and Study Under-Performance
15
T 29
Kai Yu Jen
The Role of Medical Writers in Preparing Responses to Post-Submission Queries
From FDA, PMDA, and EMA
16
T 30
Ben Dudley
The Evolution of an Enterprise Risk Based Monitoring Process
16
T 31
Dominique Johnson, PhD, MSc
A Multi-Modalities Medical Imaging Investigative Network for Clinical Trials in
Cardiovascular, Neurology and Oncology
16
T 32
Kim Le, PharmD
Analysis of Product Labeling Changes for Successful Prescription to Over-theCounter Switches
17
T 33
Nicole Griswold
Utilizing the MSL Role to Characterize the Transition of Care of Patients with
Attention Deficit Hyperactivity Disorder
17
T 34
Nazia Rashid, PharmD, MS
Descriptive Evaluation of REMS Knowledge in An Integrated Healthcare System
17
T 35
Kenichi Otani, PhD
International Comparison of Process and Procedures to Overcome Clinical Trial
Applications Placed on Clinical Hold
18
T 36
Regina Ballinger, BSN, MS, RN
Impact of FDA Advisory Committee Voting on FDA Approval Decisions for Drugs
and Biologics
18
T 37
Zsuzsanna Csutor
The Silver Lining of the PSMF: Flow Chart Displaying the Business and User
Requirements
19
T 38
Krista Payne, MEd
Rock and a Hard Place: Mandated Multi-National Drug Utilization Studies in the
Absence of Suitable Secondary Sources of Data
19
T 39
Kristin Palmsten, DrSc
Medication Use Among Pregnant Women Enrolled in Medicaid
19
T 40
E. Mitchell Seymour, PhD, RAC
eCTD Submission Capability to FDA for Academic Sponsor-Investigators:
Process, Problems, and Possibilities
20
T 41
Kathy Boardman, MS
Integrating ISO and Relevant Industry Standards to Improve Clinical Trial Project
Management Processes
20
T 42
NaRae Baek
Can Asia Help Expedite Cancer Drug Development? Analysis of Three North
Asian Countries’ Potential to do More Clinical Trials
20
T 43
Bhavini Srivastava, MS
Electronic Data Capture in Oncology: A Review of Electronic Collection of
Patient-Reported Outcomes
21
T 44
Sally Okun, RN
Patient-Informed Clinical Trials: Cross-Sectional Survey on a Patient Powered
Research Network
21
T 45
Craig Burnett
Delivering Quality Systems Globally
22
T 46
Karolyn Kracht, MS
Creating Standard Analyses and Displays for Common Safety Assessments in
Clinical Study Reports
22
W 01
Weining Robieson, PhD
Evaluation of Operating Characteristics of MMRM Analysis Using All Available
Longitudinal Data at Interim Compared to ANCOVA
22
W 02
Pascal Guibord, MSc
Recent Developments in Scaled Average Bioequivalence
22
Poster Abstracts | diahome.org/DIA2014
3
Invent
the Future
Celebrate
the Past–
DIA 2014 50TH Annual Meeting
June 15-19 | San Diego, CA
Poster No. Author
Poster Title
Page
W 03
Annette Williams, MBA, RPh
An Overview of Both Current Best Available and Next Generation of Drug
Therapies for the Treatment of Depression
23
W 04
Karen Lockwood
Health Literacy Assessment, Usability Testing, and Revision of a European Union
Risk Management Plan Public Summary
23
W 05
Bambi Grilley, RAC
Coordination of a Multi-site Cell and Gene Therapy Study in an Academic
Medical Center: A Success Story
23
W 06
Irene Sheng, PharmD
An Innovative Way of Providing Timely Responses to Questions Related to
Ingredients/Allergens
24
W 07
Esther Sadler-Williams, MPharm, MSc,
RPh
Evaluating and Supporting the Increasing Patient Need for Delivery of Clinical
Trial Supplies Direct to Their Homes
24
W 08
Ilyssa Levins
New Business Acumen Tool Guides Strategic Thinking: Learn How to Increase
Your Value to the Company and to the Industry
24
W 09
Rebecca Hummel
Complexity in Protocol Design: Does it Lead to Better Clinical Trial Outcomes?
25
W 10
Abhishek Harde
Corporate Integrity Agreement and Its Impact on Industry
25
W 11
Ben Quartley, PhD
Giving Clinical Trial Start Up A Project Management Make-Over: Reducing Cycle
Times Through Critical Path Focus
25
W 12
Raul Vinueza
The Impact of Regulatory Reform in Mexico on Pharmaceutical Product Approval 25
Rates
W 13
Ed Seguine, MBA
So How DO You implement eSource: Practical Tips for Enhancing Efficiency, Data
Visibility, and Site Interactions
26
W 14
Andrew Buchanan, RPh
Duloxetine Feeding Tube Study: Medical Information Example of Collaboration
with Laboratory Scientists to Deliver Answers.
26
W 15
Elizabeth Nielsen
Targeting the Best Sites with an Analytical Site Selection Model Using Multiple
Metrics
26
W 16
Allan Spera
Central Recruitment Methodologies in a Global Clinical Research Study of a
Pediatric Autism Spectrum Disorder (ASD) Program
27
W 17
Mona Vimal, MSc
Evaluation of Shipping Systems to Maintain Sample Integrity in Clinical Research
27
W 18
Christopher Bone
A Comparison of MedDRA SMQs Relative to Individual Preferred Terms for
Signal Detection on a Large Insurance Claims Database
27
W 19
John Li, MD, MBA
Introducing and Conducting Traditional Chinese Medicine Trials in the US:
Challenges, Obstacles, and Potential Solutions
28
W 20
Geoffrey Gipson
Coherence of Observed-to-Expected Disproportionality Methods Used for
Pharmacovigilance at a Critical Threshold
28
W 21
Tracey Miller
Enhancing Project Management Tracking to Facilitate the Protocol Development
Process
28
W 22
Christina Gallagher, PharmD
Continued Tradition of Success: Critical Components of the Genzyme/Sanofi
Oncology/MCPHS University Post-PharmD Fellowship
29
W 23
Phil Reveal
Assessment of Violations Cited by OPDP in Untitled and Warning Letters Issued
from 2004-2013
29
W 24
Jeff Jamer, MBA
Accelerating Patient Recruitment Using In-Depth Market Research Insights:
Collected via a 3rd Party - From Clinical Trial Site Staff
30
W 25
Penelope Manasco, MD, MS
Implementing a Standard Report Set for Risk Based Monitoring Domains
30
W 26
Ayako Takizawa, MS
Investigation of Association Between COPD Treatment and Cardiac Events With
or Without Treatment for Co-Existing Disease
30
Poster Abstracts | diahome.org/DIA2014
4
Invent
the Future
Celebrate
the Past–
DIA 2014 50TH Annual Meeting
June 15-19 | San Diego, CA
Poster No. Author
Poster Title
Page
W 27
Caroline Lin, MA
Reinventing the Study Build Process to Promote Consistency, Increase Build
Efficiencies, and Reduce Overall Timelines
31
W 28
Hanming Tu, MSc
Collaborative Development of an Open Source Repository for Standardized
Analysis Using Cloud Services
31
W 29
Toshiyoshi Tominaga
Quality of Japanese Clinical Trials and Proposed Strategy for the Trial Sites
31
W 30
Gary Noel, MD
A Collaboration to Facilitate the Development of Antibacterial Agents for Unmet
Need: Streamlining Clinical Trial Protocols
32
W 31
Holly Groelle, PhD
Global Regulatory Considerations for Biosimilar Approval
32
W 32
Alex Wei
Impact of FDA Breakthrough Therapy Designation on the Regulatory Timelines
of Chronic Lymphocytic Leukemia (CLL) Therapies
32
W 33
Yueqin Zhao, PhD
An Extension of Likelihood Ratio Test-Based Method for Signal Detection in a
Drug Class with Application to FDA’s AERS Database
33
W 34
Alun Tanner, PhD
Maintaining Effective Pharmacovigilance Oversight: The Role of Remote
Auditing
33
W 35
Mikhail Samsonov
Data Empowered Decision Making in a Pharmaceutical Company: Project
Libraries and Workflows - Real Life Experience
33
W 36
David Bristol, PhD
Sample Size Re-Estimation Can Be Very Inefficient
34
W 37
Jessica Kloda, PhD
So You Hired a CRO…Now What? Advancing Clinical Research by Leveraging
Government Sponsor Relationships with CROs
34
W 38
Cyril Carrere, MSc
Office of Prescription Drug Promotion (OPDP) Enforcement Overview From 1997
to 2013
35
W 39
Jennifer Zellner, PhD
Enrollment of Pregnant Women in Medication Safety Research: MotherToBaby
Pregnancy Studies
35
W 40
Badhri Srinivasan, PhD, MS
A Model for Centralized Monitoring: Reducing Costs While Ensuring Compliance,
Risk Mitigation and Quality
35
W 41
Barbara Del Curto
Customer Satisfaction and Communication Methods Used in Conducting Large
Multi-Center Clinical Trials
35
W 42
Rona Grunspan
Easy as A,B,C? Adapting Pediatric Protocol Designs from Existing Adult Data
and Study Templates
36
W 43
Tsung-Ta Wu
The Construction and Promotion of Medication-Used Safety Education for
Traditional Chinese Medicine in Taiwan
36
W 44
Jonathan Nguyen Diep
Patterns of Regulatory Approval for Targeted and Immunotherapeutic Compounds
Indicated for the Treatment of Metastatic Melanoma in the US and EU
36
W 45
Dara Stein, MSc
Retrospective Chart Review Studies: Key Considerations for Fullfilling Safety
Reporting Requirements
36
Poster Abstracts | diahome.org/DIA2014
5
DIA 2014 50TH Annual Meeting
June 15-19 | San Diego, CA
T 01
Development and Implementation of Product Safety Statistical Analysis Plans
Barbara Hendrickson, MD
AbbVie Inc.
Objective: The objective was to develop a
living document that specifies the approach
for integrating and analyzing safety data from
multiple clinical trials of a product to facilitate
decision making during clinical development
and to support safety discussions in regulatory
submissions.
Method: The creation of a standard operating
procedure (SOP) describing the development of a
Product Safety Statistical Analysis plan (PSSAP),
as well as a PSSAP template, was a cross
functional effort (Pharmacovigilance, Statistics,
Clinical, Project Management, Regulatory) at
AbbVie in 2013.
Results: The PSSAP initiative was launched at
AbbVie in 2012 with the formation of a crossfunctional working group and the initiation of
two pilot projects. In 2013, an SOP and PSSAP
template were implemented and trainings
regarding the PSSAP were conducted. The SOP
describes the procedure for developing and
approving a PSSAP and documentation of the
review of the PSSAP output. The PSSAP is to be
created for products by Phase 2b or earlier and
is the predecessor of the Integrated Summary
of Safety (ISS) Statistical Analysis Plan for new
product or indication filings. The PSSAP is a
reference document for ongoing safety analyses
throughout the product life-cycle, evolving over
time. The PSSAP provides detailed instructions
on how the safety data will be pooled and
analyzed for safety signals, adverse events of
special interest (AESI), and safety assessments
of special populations. The PSSAP helps ensure
the collection of appropriate data in ongoing
studies to analyze AESIs. The PSSAP output
supports consistent safety related discussions in
regulatory submissions including the Investigator
Brochure, Developmental Safety Update Report
(DSUR), and ad-hoc regulatory responses. The
Product Safety Teams review the PSSAP output
and document the clinical assessment of the data
analyses. The PSSAP is reviewed by the Product
Safety Teams on at least an annual basis and is
updated as needed.
Conclusion: Product level safety statistical
analysis plans promote proactive, systematic,
and thoughtful product level safety monitoring.
Aggregation of safety data from multiple studies
in the pre-ISS phase enhances the ability to
detect signals and make drug development
decisions. The standardized PSSAP template
also fosters cross-functional alignment to best
practices for safety analyses, including analyses
of AESI. Ongoing training regarding the value
of the PSSAP is important to ensure successful
implementation. Pilot projects provide useful
information to advise the PSSAP initiative,
as well as valuable examples for subsequent
education of the product safety teams. The
PSSAP is a living document that evolves over
the product life cycle and informs the planning
of safety data collection and consistency in
the execution and quality of data analyses.
Co-authors: Shihua Wen, Mondira Bhattacharya,
Karine Smith, John Schoenfelder
T 02 EEnsuring Patient Recruitment Success in Phase I Clinical Trials: The Important Role of Investigators
Rachida Essalihi, PhD
Algorithme Pharma Inc., Canada
Objective: To evaluate and compare the critical
involvement of different types of investigators on
recruitment, screening and enrollment power of
patients in early stage clinical trials.
Method: Compare the patient enrollment success
rate of two different physician involvment levels
in two Phase I trials. The study U24 was based
exclusively on patient referals while study
N25 implicated an active participation of the
investigator in the clinical study conduct.
Results: In study U24, 12 patients were to be
enrolled in the study. Although 54 patients were
refered by the offsite specialist to the clinical unit,
7 patients were finally enrolled and completed
the study. Additionally, 23 of the 54 patients
refered attended the screening visit, signed the
consent form and were subsequently screened.
Of those 23, twelve (12) patients were rejected at
screening and thus, 11 patients were eligible for
dosing (47.83% of the total patients screened).
Lastly, from the 11 eligible patients, 7 patients
were enrolled and completed the trial (63.64%
of the total eligible patients). As such, from the
initial step, more than 57% of the patients actively
interested in participating lost their interest in the
trial. Considering the initial number of patients
refered to the trial, 13% of the 54 patients were
enrolled. The duration from the First Patient
In (FPI) to Last Patient In (LPI) was 4 months,
resulting in approximately 17 days per patient
enrolled, although more than one subject was
enrolled within the same dosing group.
In study N25, 16 patients were to be enrolled. For
this study, the investigator recruited patients from
his own database. All interested patients were
screened by the Investigator on site. Of the 23
patients screened, 6 patients were rejected and
17 patients were eligible for dosing (73.91% of the
total patients screened). Sixteen (16) out of the 17
eligible patients were enrolled and completed the
trial (69.57% of the total patients screened). The
duration from FPI to LPI was 3 months, resulting
in approximately 6 days per patient enrolled.
As for study U24, more than one subject was
enrolled within the same dosing group.
Conclusion: Poor performance in patient
recruitment and retention is known as an
important reason for delays in clinical trials. Many
intrinsic and extrinsic factors could impact the
success of patient recruitment and enrollment.
In the present case study, the impact of the
motivation and involvement of an investigator
was evaluated on actively recruiting and enrolling
patients. As observed in study N25, from initial
discussions to the screening process, the actively
involved investigator was able to increase its own
screening power by over 50 % as compared to
the other one (study U24). Additionally, we also
observe a lower screening failure rate (about
25%) which could suggest a better understanding
of protocol requirements and potentially an
optimization in patient identification. In fact,
73.91% of screened patients in study N25 were
eligible compared to 47.83% for study U24.
Finally, in regards to improvements in timelines,
the actively involved investigator in study N25
had a FPI to LPI of about 3 times faster than
the U24 study enrollment, a difference of 11
days per patient, even though, in Canada, more
patients are affected by the disease targeted for
recruitment of study U24 (1 person over 7.6 as
compared to 1 person over 15 for N25).
This case study clearly illustrates the synergistic
impact that an actively involved investigator has
on a clinical trial timeframe. Multiple other factors
can be present which can also affect recruitment
and enrollment power as illustrated in a previous
poster presentation (Legault E., Essalihi R.,
Lahjou M., Paraskevopoulos H. & Lefebvre M. How
a Study Design could Impact on Recruitment
and Enrollment Success: A Case Study. ASCPT
2013 Annual Meeting, Indianapolis (IN , USA),
2013.)). However, an investigator’s motivation and
involvement is definitively a critical factor that
should not be under estimated. Co-Authors: Mira
Francis, Eric Legault, Nadine Al-Hage Ali, Marc
Lefebvre
T 03Good Clinical Practice (GCP) Training: Identifying Key Elements and Strategies for Increasing Training Efficiency
Jonathan Seltzer, MD, MA, MBA, FACC
Applied Clinical Intelligence, LLC
Objective: To develop recommendations to
ensure knowledge of GCP while facilitating a
more efficient GCP training process
Method: The Clinical Trials Transformation
Initiative (CTTI) convened a multidisciplinary
working group involving partners from
academia, industry, and government to develop
recommendations for streamlining current GCP
training efforts.
Results: The working group reviewed the
current literature and the content of public and
private initiatives related to GCP training, and
drafted recommendations to define the minimal
key elements required for GCP training. Draft
recommendations were presented to a broader
group of experts from the clinical research
enterprise to foster discussion on the issues, and
seek consensus on proposed solutions before
finalization.
The recommendations that define strategies
to providing more efficient training, including
a frequency for repeat training, the format
Poster Abstracts | diahome.org/DIA2014
6
DIA 2014 50TH Annual Meeting
June 15-19 | San Diego, CA
to deliver the training, and approaches for
competency assessment after the training is
complete will be discussed.
Additional strategies on designing training
programs that integrate GCP elements into
clinical research will also be discussed.
Conclusion: The recommendations for GCP
training requirements generated through this
effort may encourage organizations to adopt
similar training criteria, thereby allowing
cross-acceptance of training. This may serve
to reduce the burden of repeated training,
and improve the efficiency of clinical trials.
CTTI-GCP Training Working group: Jamie Arango,
Tina Chuck, Susan Ellenberg, Bridget Foltz,
Colleen Gorman, Heidi Hinrichs, Susan McHale,
Kunal Merchant, Stephanie Shapley, Jonathan
Seltzer, Gretchen Wild
T 04Evaluation of Current and Future Medical Information Services
Offered to Healthcare Providers by
Pharmaceutical Companies
Tracey Cannova
Rutgers, The State University of New Jersey
Objective: To evaluate the types of medical
information services offered to healthcare
providers through pharmaceutical company
medical information communication methods and
online resources as well as evolution of medical
information in the future.
Method: The Rutgers Pharmaceutical Industry
Medical Information fellows and fellowship
alumni as well as Drug Information Specialists
throughout the country were surveyed to evaluate
the medical information services provided to
healthcare providers, their value and thoughts of
evolution.
Results: The study is in progress but will be
completed in advance of the meeting. Over one
hundred Rutgers Pharmaceutical Industry Medical
Information fellows and fellowship alumni were
surveyed as well as approximately three hundred
Drug Information Specialists were surveyed.
Conclusion: The study is in progress but will be
completed in advance of the meeting.
T 05Evaluation of Site Enrollment
Estimates Pre- and Post-initiation to
Actual Enrollment Performance: An Assessment of Accuracy
Nicole Turner, MBA
Quintiles Inc.
Objective: Evaluate investigator enrollment
estimates made pre- and post-site initiation
against actual performance to determine whether
accuracy improves along the continuum of site
selection; review identified trends by region/
therapeutic area, and recommend a reduction
factor for use in strategic planning.
Method: The enrollment estimates given by
over 500 investigators globally during various
stages of site selection have been compared to
the actual enrollment performance of the same
investigators in 5 or more studies conducted
globally by Quintiles that are no longer enrolling
from years 2009 to 2011.
Results: The commonly held belief that
investigator enrollment estimates received
prior to site selection are generally optimistic in
comparison to actual enrollment performance in
a study is true based on our analysis; investigator
estimates received prior to site selection are,
on average, 75% higher than the investigators’
actual enrollment performance. Investigators
indicate that this can be attributed to lack of
protocol details being available, short timelines
for responding, and purposeful inflation of
enrollment estimates to ensure the site appears
favorable for study inclusion, among other
reasons.
However, investigator estimates made based on
full review of the protocol after the site has been
selected for the study may also be poor indicators
of actual performance on the study. We will
evaluate if the inaccuracy seen pre-initiation
persists, and if so, whether this inaccuracy is seen
across indications and countries analyzed. Trends
seen by indication, country and therapeutic area
will be presented.
Using these results, we have modeled begun
an analysis using linear regression of the data
overall, as well as by region and indication, in
order to make recommendations for reduction
factors to be applied to investigator estimates at
multiple points during study enrollment planning.
These reduction factors will vary based on the
stage in site selection that the investigator
enrollment rates were gathered.
Analysis is ongoing; we are systematically
reviewing recently completed studies for
potential inclusion in order to continually advance
our analysis and to further validate our findings.
Conclusion: Basing study enrollment projections
on investigator enrollment rate estimates will
likely result in an inaccurate prediction of last
patient in. Investigator estimates received
prior to site selection are significantly overly
optimistic; however, even after site selection,
when investigators begin planning to conduct the
study and have received a full protocol for review,
they may be unable to provide an accurate (+/10%) estimate of their site’s actual enrollment
performance on the study.
Applying a reduction factor to these data will
allow for investigator estimates to be more useful
indicators of potential study enrollment; the
reduced rate can be used in creating enrollment
projections for a study.
T 06
Country-Specific Clinical Data and Reporting Requirements in Support of Marketing Applications To Key Rest
of-World Countries
Marianne Pedersen, PhD
Bristol-Myers Squibb Company
Objective: To compare and contrast clinical
documentation requirements in key Rest-ofWorld (RoW) countries that require local patient
experience to inform on clinical effectiveness and
extrapolation to the overall global population in
support of marketing approval.
Method: Regulatory guidelines were reviewed
for China, Japan, Korea, Taiwan, Mexico, India,
and Russia. These countries have established
requirements for the inclusion of clinical data
reflective of the local population in order to
facilitate the review of a marketing application.
Results: Countries such as China and Japan
require local studies be conducted to obtain
patient experience reflective of the population
within those countries. These data not only
provide an assessment in a particular region or
ethnic population, but allow for extrapolation
(or bridging) of local findings to the overall
population in global studies. These data are
reported in country-specific clinical study reports
(CSRs) and in clinical summary documents
as part of the marketing application. Other
countries, such as Korea and Taiwan, require the
inclusion of their local population in registrational
global clinical studies for population-specific
analyses and extrapolation to the overall
global population. These countries require the
submission of specific bridging study evaluation
(BSE) reports prior to or together with the
submission of their marketing application. These
comprehensive BSE reports provide an overview
of the pharmacology of the drug and address
the potential for ethnic sensitivity of the drug
being evaluated according to ICH5 guidelines.
Furthermore, BSE reports provide PK/PD data
for the local population as well as a comparison
of efficacy and safety data between the local
and global populations. Both Korea and Taiwan
have specific sample size requirements of the
country-specific subpopulation, but differ in the
definitions of the population subsets that need
to be compared in side-by-side data displays.
Other countries such as Mexico, India, and
Russia, like Korea and Taiwan, also require the
inclusion of their local populations in key global
clinical studies, but limit analyses to efficacy and
safety in the local population without formal
comparative analyses to global data. These data
are presented in subpopulation reports submitted
as part of the marketing application and are
discussed within the context of findings from the
global population.
Conclusion: China, Japan, Korea, Taiwan, Mexico,
India, and Russia represent countries with
specific and different data presentation and
reporting requirements for their local populations.
Regulatory requirements drive the need for
country-specific clinical studies or inclusion of their
Poster Abstracts | diahome.org/DIA2014
7
DIA 2014 50TH Annual Meeting
June 15-19 | San Diego, CA
countries within key global registrational studies to
provide population-specific pharmacology, safety
and efficacy data. Operationally, local data to
support country-specific reporting requirements as
part of marketing approval in key RoW countries
require early planning as well as early crossfunctional team engagement.
T 07Effectiveness of REMS Patient Education: An Assessment of Patient Comprehension and Knowledge
Retention
Paul Sheehan
Celgene Corporation
Objective: To evaluate the effectiveness of
patient education activities conducted within the
Risk Evaluation and Mitigation Strategies (REMS)
programs for lenalidomide and thalidomide from
2012-2013.
Method: U.S. lenalidomide and thalidomide
patients receive mandatory education about
serious risks and safe-use conditions as part
of comprehensive REMS programs. This study
examines the execution and outcomes of these
programs, via results from knowledge and
behavior surveys conducted from 2012-2013.
Results: During the study time period 73,645
patients participated in a mandatory survey
executed just before they obtained a prescription,
and of these 3,981 responded to an additional
voluntary survey initiated several weeks
after they received their prescription. Both
surveys assessed patients understanding and
compliance with key pregnancy prevention
education messages delivered by their healthcare
professionals before they started therapy, and
repeated frequently throughout their treatment
duration.
Most patients were treated for Multiple Myeloma
(83%), and the average age was 66. Females
of reproductive potential comprised 3% of the
patient population, males 55%, and females not of
reproductive potential 42%.
Patients completed 264,417 mandatory surveys,
of which 14,848 (5%) indicated an inaccurate
or uncertain understanding of safe-use
messages (e.g. patient risk category assignment,
appropriate pregnancy prevention measures,
sharing of blood or sperm, and sharing of
product). These were investigated and resolved
prior to a dispense.
90% of the voluntary survey respondents
confirmed receiving REMS patient education
materials, and 86% having read them. Results
from the survey conducted within 14 days of first
dispense shows 98% understood the key safeuse messages, and the same number reported
retaining this knowledge in a follow-up survey
performed 3 months later.
During the study time period 396,761
prescriptions were written, 5% required
intervention to ensure they met REMS safe-use
requirements (of which 43% were for females
of reproductive potential), and 2% resulted in a
delay in treatment initiation or a gap in therapy.
Conclusion: Both surveys confirmed that patient
education activities conducted within the
lenalidomide and thalidomide REMS programs
were successful. Patients reported receiving
and reading the program education materials,
understood the serious risk and safe-use
conditions, retained this knowledge throughout
therapy, and were generally compliant with
safe-use conditions. The study results were
fairly consistent across patient age, gender and
risk category. The impact on therapy delivery
of confirming and investigating if patients have
received and understood key safe-use messages
is reasonable.
This study illustrates how safe-use educational
messages delivered to patients on a consistent
and repeated basis may form an important
element of successful comprehensive REMS
programs. Such an approach can achieve high
levels of patient understanding, knowledge
retention and compliance.
Additional authors include Nancy Brandenburg,
Dr. Robert Bwire, John Freeman, and Dr.
Florence Houn who are all employees of Celgene
Corporation.
T 08
Development of an ELISA Method to
Characterize C1q Binding Affinity
Kelly Colletti, PhD, MBA
Charles River Laboratories International, Inc.
Objective: To characterize the effector function
of monoclonal antibody biotherapeutics
through the development of an immunoassay to
measurethe C1q binding potential of a human IgG,
which is necessary for activation of complement
dependent cytotoxicity (CDC).
Method: We have developed an in vitro
immunoassay that characterizes the C1q binding
potential of human IgG. The development
involved optimizing the ELISA assay procedure
and conducting statistical analysis of the data in
order to determine if the assay could compare
relative C1q binding affinities.
Results: The basic design of the assay is to use
a solid microtiter plate to immobilize the human
IgG in order to allow the C1q molecule to bind
to the Fc portion of the antibody. The human
IgG is absorbed to the plate surface at various
concentrations to produce a standard curve.
The complex is then detected with an anti-C1q
antibody labeled with horse radish peroxidase
in a colorimetric reaction. This format allows for
the comparison of C1q binding potential between
similar IgG molecules with applications for in
vitro characterization of biosimilar and biobetter
biotherapeutics through the comparison of the
standard curves. The assay was optimized with
respect to coating buffer, incubation times,
human IgG concentrations, and detection reagent.
The optimized assay demonstrated precision as
evidenced by %CV values less than 15% between
curves when evaluating ED50 values.
Conclusion: The immunoassay is a robust assay
that is capable of comparing the C1q binding
potential of human IgG based biotherapeutics.
This assay could be used to compare relative
binding affinities through comparison of
ED50 values of various biotherapeutics with
specific applications in biosimilar and biobetter
biotherapeutic development programs.
T 09
Best Practices to Effectively Close a
Complex, Global Study: Different
Stakeholder Perspectives
Catharine Provosty
Covance Inc.
Objective: Data driven case study investigation of
proactive approaches to plan and stop screening
activities for a phase II complex, global study with
limited over enrollment.
Method: Starting in 2011, the objective was
to screen, enroll and randomize 200 breast
cancer patients in US, LA, EU and AP. Presenting
the process flow from screening through
randomization, the poster demonstrates how
close communication between all stakeholders
was critical to limit over enrollment.
Results: Screening was closed globally, across
26 countries and four regions, within 24 hours.
Site staff was very responsive to the closure as
they had been kept informed of the expectations
for a quick response. This poster will illustrate
the approaches to achieve this result, presenting
the process flow sites had to follow for screening
through randomization for their patients as well
as illustrate the various points a patient could
screen fail. Firsthand examples will illustrate
how close communication between the site staff,
patient, laboratory and project management team
embodied a critical best practice approach to
limit over enrollment.
Conclusion: A common goal in clinical trial
conduct is to complete enrollment as quickly as
possible, as well as minimize over enrollment to
limit exposure to the study drug, avoid waste and
use resources as efficiently as possible.
To achieve these objectives it is necessary to gain
alignment and buy in from all stakeholders from
the very start of the study. These stakeholders
range from staff at study sites, principal
investigators, clinical team members from various
organization as well as global regulatory agencies
who have reviewed and approved the study for
their country. Co-presenter: Annabel Vaghar,
Senior Clinical Trial Manager
T 10Using Gamification in the Life Science
Industry
Niki Kutac
DATATRAK
Objective: The objective of this study is to
analyze the usage of Gamification during a
clinical trial to incentives the clinical sites and
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study team to improve clinical trial data quality
and speed of data entry.
Method: For this study we reviewed the results of
using Gamification in other industries & success
rate of changing key behaviors & activities. We
simulated the use of Gamification during the testing
of a major release of an eClinical technology and the
rate of closing bugs identified during the testing.
Results: The results of implementing a game
environment and providing a price of being
“crowned” Data Hero, we experienced a
300% increase in the speed of bug closer
than experienced before the Gamification was
implemented. By simply implementing a game
environment and identifying a winner we
experienced increased at and even above what
other industries experience with implementing
Gamification techniques.
Conclusion: Gamification can be implemented
within a Life Science company in many ways
to improve performance and speed: Patient
Adherence, Education (from sites to CRAs),
Adherence to Timelines (data entry timelines,
data cleaning timelines, regulatory reporting,
etc.), or Quality of Work (queries generated).
Thus, it is important for an organization to
properly plan and understand what they are
trying to implement before undertaking a
Gamification project. With implementing
Gamification, organizations not only incentivize
their clinical sites to improve overall response
times but also provide visibility to data-driven
information through better reporting and
dashboards that allow sponsors to manage and
evaluate the site’s quality and timelines.
T 11
Burden of Clinical Trial Operations and
Value of Supporting Solutions: Results
from a Global Investigator Survey
Elisa Cascade, MBA
Drugdev.org
Objective: The objective of this poster is to
present the results of a global survey of 750
investigators related to the burden of clinical
trial operations and the value of various support
solutions.
Method: Between Oct 28 and Dec 3, 2013, we
emailed ~11,000 randomly selected members of
the DrugDev investigator network in Argentina,
Australia, Germany, India, South Africa, UK, and
the US to invite them to an on-line survey of 25
questions. Respondents were offered a chance to
win one of 5 ipads.
Results: 750 investigators located in a study
country completed the on-line survey: 98 in
Argentina, 61 in Australia, 60 in Germany, 81 in
India, 45 in South Africa, 66 in the UK, and 344
in the US. The overall response rate was 7%
with country level response ranging from 4%
(Germany) to 14% (Argentina). Of the physicians
surveyed, 8.1% had participated in 2 or fewer
trials, 37.7% had previously participated in 3 to
10 trials, and 54.1% had participated in more
than 10 trials. Most respondents had experience
in more than 1 therapy area (average of 3.5
per investigator) with the Top 4 as follows:
Cardiovascular (26.8%), Internal Medicine (25.3%),
Endocrinology/Diabetes (24.9%), and Pulmonary/
Respiratory (20.9%).
Globally, completing contractual and
regulatory documents was rated as the most
burdensome administrative activity with 46%
of investigators rating this as very or extremely
burdensome. Getting paid on time was the
second most burdensome issue (36% rated as
very or extremely burdensome). At least 30% of
investigators also rated the following as very or
extremely burdensome: recruiting patients (32%),
budgeting for clinical trials (32%), completing
feasibility surveys (31%), and reporting SAEs
(30%). Interacting with on-site monitors was
considered the least burdensome activity
evaluated in the survey (13% rated as very or
extremely burdensome). Interestingly, interacting
with remote monitors was relatively more
burdensome (21% rated as very or extremely
burdensome).
With respect to supportive solutions, over
70% of global investigators found five activites
extremely or very valuable: 1) Cross-pharma GCP
repository with training needed once every two
years (85%), 2) Ability to upload investigator
CVs to a cross-pharma repository (79%), 3)
Guaranteed investigator payment within 30 days
(78%), 4) Annual Master Service Agreement
(MSA) with cross-pharma repository of essential
documents (75%), and 5) Cross-sponsor sharing
of contractual preferences (73%).
Conclusion: According to analyses conducted by
CenterWatch, Tufts, and others using FDA 1572
data, the investigator landscape has shifted in ways
that challenge successful conduct of clinical trials
(e.g., fewer experienced sites; high turnover among
new PIs). The resulting impact for Sponsors is
higher operational costs, especially related to site
identification, qualification, and start-up.
The purpose of our investigator survey was to
better understand sources of investigator burden
in clinical trial operation and to determine the
value to investigators of potentially supportive
solutions. Although published literature on
investigator burden in clinical trials is limited, our
findings appear to be consistent with comments
made by industry experts who have suggested
study start-up and ethics as large sources of
difficulty for investigators as well as a trend
towards higher protocol complexity posing
challenges to patient recruitment.
Understanding the feedback on burden, it is
not surprising that the supportive activities that
offered the most value to investigators were items
that either guaranteed payment or streamlined
start-up such as GCP training, contracting, and
essential document collection. Although there is
no benchmark with which to compare, the level
of value assigned to these activities was high
in absolute terms (70%+ of the sample rated as
extremely or very valuable).
One additional conclusion that emerges from
the study is that the supportive activities with
the greatest investigator value are all operational
items under the control of the pharmaceutical
research sponsor. Several efforts underway have
begun to address some of these solutions (e.g.,
Transcelerate, Investigator Databank), but it will
be interesting to monitor the degree to which
the pharmaceutical company research sponsors
are able to change their processes to ultimately
achieve the goal of reducing investigator burden
while also realizing time and/or cost efficiencies.
T 12
The Role of Bioethics in the
Pharmaceutical Industry: Informal
Review of 5-Year Trends and One
Company’s Systematic Approach
Luann Van Campen, PhD, MA, MSc
Eli Lilly and Company
Objective: The goal of this project was to assess
the role of bioethics in the pharmaceutical
industry as evidenced by trends from an informal
review of industry practices as well as Eli Lilly
and Company’s systematic approach. Of specific
interest was what companies state publicly about
bioethics.
Method: An informal review of approximately 20
major pharmaceutical companies was conducted
recurrently since 2008. The cohort changed over
time as a result of mergers/acquisitions. Data
from corporate websites were supplemented by
other public search engine data. Results were
recorded in Excel.
Results: Both descriptive and qualitative initial
assessements are being completed. Bioethics
information assessed include: company website
content, committees, full-time effort, education,
projects, and publications. To date, data reveal
a 45% increase in the use of the word ‘bioethics’
on company websites from 2008 to 2014. In
2008, few companies had webpages dedicated
specifically to bioethics or research ethics. In
2014, there are 7. Some companies included
bioethics-related material in externally-facing
documents, such as corporate responsibility
or investor reports. The first mention of a
company bioethics committee occurred in the
mid-1990’s. From 2008 to 2014, there has been
approximately a 20% increase in the number
of company bioethics committees – with
quite varied purposes and structures. In 2008,
two companies had full-time effort (the first
established in 2001, the second in 2008). In 2014,
a third company has established full-time effort.
In 2014, 4 companies specifically mention internal
bioethics education but only one delineates
what is offered. Externally-facing projects have
ranged from monetary donations to collaborative
projects with academia and private institutions.
Peer-reviewed industry-authored bioethics
publications are few. In addition to the review
data, Eli Lilly and Company’s systematic approach
to bioethics will be shared—outlining the purpose
and composition of the Bioethics Program that
was established in 2008. Core activities include
position development, consultation service,
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education and training, collaborative projects
(both internal and external), and scholarship.
Based on 5-year metrics and experience, a
working definition of ‘pharmaceutical bioethics’
can be proposed, and implications for a
pharmaceutical company and the industry can be
discussed.
Conclusion: Bioethics is a discipline that
examines ethical issues of both healthcare and
biomedical research. To date, the pharmaceutical
industry has been criticized both for its lack of
bioethics involvement and conversely for its
funding (and presumed undue influence) of
bioethics initiatives. The current informal review
provides a perspective, albeit imperfect, on
the developing role of bioethics in the industry.
Since 2008, there is increasing pharmaceutical
company activity and investment in this
discipline, but the range of self-described activity
is still unchanged—ranging from no mention
of bioethics to full-time effort. Therefore, it is
reasonable to conclude the role of bioethics in
the pharmaceutical industry is yet undefined.
The lack of consensus is not overly suprising.
First, because the industry is highly regulated,
it is presumable that most companies rely on
regulations to provide adequate human subjects
protections, and rely on ethics and compliance
departments to provide ethical guardrails.
However, the systematic approach and experience
of one company indicate ‘pharmaceutical
bioethics’ should be considered complementary
to, but separate from, legal compliance.
Second, the lack of consensus is not surprising
because the bioethics field has yet to recognize
pharmaceutical bioethics as a sub-discipline—
with challenges unique to a corporate setting.
We propose that pharmaceutical bioethics can
and should be considered 1) a sub-discipline
of bioethics, 2) an integral component of
pharmaceutical R&D excellence, and 3) an integral
component of corporate integrity. While it is
admirable to strive for excellence and integrity,
it is not realistic to expect results unless there is
a more systematic approach to pharmaceutical
bioethics—both for a pharmaceutical company
and for the industry. Until there is such an
approach, the field of bioethics likely will
continue to view ‘pharmaceutical bioethics’ as an
experiment, at best, and an oxymoron, at worst.
Co-author: Donald G. Therasse, M.D., Eli Lilly &
Company (Retired).
T 13A Survey of Boxed Warning Adverse
Reaction Content from US Prescription
Drug Labeling
Christine Cheng, PharmD
First Databank, Inc
Objective: To review all boxed warning (BXW)
content within FDA-approved prescription drug
labeling available on the National Library of
Medicine Dailymed website and the FDA website
between July 2013 and February 2014 and report
on the categories of adverse reactions (ADRs)
described within the BXWs.
Method: We reviewed all prescription drug labels
with BXWs on DailyMed and the FDA websites.
We created drug group associations based on
ingredient and, if needed, dose form, strength or
drug class depending on the BXW content. We
then categorized the BXW ADRs with concepts
similar to SNOMED CT.
Results: Between July 2013 and March 2014
we created a total of 419 BXW flexible drug
groupings, of which 295 were ingredient-based,
93 were based on ingredient/dose form (e.g.,
testosterone transdermal gel) , 7 based on
ingredient/strength (e.g., mifepristone 200
mg) and 24 based on drug class (e.g., systemic
fluoroquinolones). Our hierarchical representation
of BXW ADRs included 25 main categories and
more than 150 subcategories.
Most (n=387/419, 92%) of the drug groups had
a BXW that described at least one ADR (range
1 to 10 ADR concept per drug group). Among
the main ADR categories, the most prevalent
was hematologic abnormalities (n=103/387,
27% of drug groups), which included toxicities
such as bone marrow suppression, thrombotic
disorders and hemolytic anemia. The next
most common ADR categories were psychiatric
disorders, e.g. suicidal ideation, abuse potential,
(n=72/387, 19% of drug groups); cardiovascular
disorders, e.g., congestive heart failure, capillary
leak syndrome, (n = 61/387, 16% of drug groups;
hepatic disorders, e.g., hepatomegaly with
steatosis, peliosis hepatis, (n=58/387, 15% of
drug groups); neoplasms (n=50/387, 13% of
drug groups); respiratory system disorders, e.g.,
interstitial pneumonitis, severe bronchospasm,
(n=42/387, 11% of drug groups); immune system
disorders, e.g., hypersensitivity reactions, infusion
reactions (n=41/387, 11%) and serious infection,
e.g. progressive multifocal leukoencephalopathy,
tuberculosis, (n=37/387, 10% of drug groups).
Additionally, the BXW for 33/387 (9%) of drug
groups referenced a restricted distribution
program for the drug (e.g., TOUCH prescribing
program for natalizumab).
For the remaining 32 BXW drug groups without
ADRs, the most prevalent clinical issues
described were the need for experienced
physician supervision during use of the drug
(n= 16/32, 50% of drug groups) and precautions
surrounding appropriate patient selection
criteria for use of the drug (n= 15/32, 47%of drug
groups).
Conclusion: The BXW is the strongest safetyrelated warning that can appear in a US
prescription drug label, and is generally reserved
for serious, life-threatening adverse reactions
associated with use of a particular drug. To
our knowledge, this is the first report of BXW
content derived from systematic review of
currently available prescription drug labeling
on the National Library of Medicines’ DailyMed
website and the FDA website (including sites for
the Center for Drug Evaluation and Research,
Center for Biologics Evaluation and Research, and
Medwatch).
Our study demonstrates that the majority of
BXWs describe at least one serious ADR, and that
BXW ADRs are diverse but can be organized into
a drug- and ADR classification schema. Knowing
what serious ADRs are associated with the use
of certain drugs is an important step toward
creating a safety plan for patients taking these
drugs. Hierarchical classification schema for BXW
ADRs may help facilitate appropriate clinical care
of an individual patient, as well as prospective
monitoring/surveillance programs for BXW drugs
within a health care system. Such a knowledge
base could also help with retrospective drug
utilization reviews and/or assessment of the
impact of safety-related interventions related to
a BXW drug.
We were surprised to find that a minority (less
than 10 %) of BXWs solely addressed non-ADRs.
However, this information may be important for
defining usage criteria for a given BXW drug.
Future studies should focus on the specific
actions clinicians can take at critical moments
in the medication use process to minimize risks
associated with a BXW ADR. Further studies
should also determine what actions can be taken
to ensure that criteria for proper patient selection,
clinician expertise and other administrative
requirements are met prior to use of a BXW drug.
T 14
Processes and Responsibilities within
Bioanalytical and Clinical Operations
to Ensure PK Sample Management in
Phase 1 Studies
Sandy Greene
Gilead Sciences, Inc
Objective: To determine the incidence of
compromised pharmacokinetic (PK) samples in
Phase 1clinical studies conducted in 2013 and
evaluate the processes associated with PK sample
management in Phase 1clinical studies
Method: Phase 1 studies conducted at Gilead
Sciences in 2013 were reviewed. For each study,
number of sites, types of samples, processing
and shipping requirements were reviewed. We
evaluated the processes and roles of Bioanalytical
and Clinical Operations throughout the life cycle
of sample management.
Results: Forty-three (43) Phase 1 studies were
conducted by Gilead Sciences in 2013 at 96 sites.
There were a total of 36 single site studies (Phase
1 units or investigative sites) and 7 multi-site
studies. The 7 multi-site studies were conducted
over 60 sites (US and international). A total of
97,678 primary (plasma and/or urine) PK samples
were collected. The overall reported incidence
of compromised samples was <2%. The main
reasons for compromised samples include:
samples received at Bioanalytical Lab (BAL)
at incorrect temperature (frozen vs. ambient),
mislabeling of tubes, BAL receiving empty
tubes, incorrect sample collection tube utilized,
and shipping logistics (e.g. package held at the
vendor’s warehouse).
Over all, the low incidence of compromised
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sample integrity in the studies conducted
in 2013 was due to a number of factors,
mainly, collaborative leadership of sample
management by the Clinical and Bioanalytical
leads; development of the Sample Management
Manual (Manuals were found to streamline
the process and communication between the
various stakeholders and were pertinent training
and reference points for the site personnel),
development of Communication and Risk
Mitigation Plans and training and timely follow up
of issues.
Conclusion: Clinical trials require a collaborative
effort between sponsors, vendors, sites, contract
research organizations and collaborators. Sample
integrity can be compromised at various points
of a sample life cycle: collection, processing,
shipping, analysis and storage. Therefore, it is
important to have clearly defined processes and
roles and responsibilities between Bioanalytical
and Clinical Operations to optimize PK sample
management.
The following strategies play an important role
towards successful sample management:
• Partnership: Clinical and Bioanalytical
Operations provide a unified view (tracking,
integration, reconciliation, and real time
reporting).
• Training: Structured information in the
form of Manuals and Plans is instrumental in
dissemination of accurate instructions.
• Oversight: Direct and frequent communication
between Site, Clinical and Bioanalytical
Operations and the Bioanalytical Laboratory
reduces variability.
• Risk Assessment and Management:
Identification of risks, setting up processes
before the start of the study; ensures efficiency
and performance predictions.
• Post Issue Action: Immediate management
and re-training of applicable team members in
response to any issues that develop increases
probability of success.
Authors: Mona Vimal*, Amanda Vu*, Diana
Chung*, and Sandy Greene* **Gilead Sciences, Inc
T 15
Choosing Your Investment: What’s the
Right Data Quality Solution for You?
Nicole Zandy, PhD
Quintiles Transnational Corporation
Objective: This project evaluates a novel
methodology for assessing the cost of poor
quality of operational data, taking into account
several factors including aging of data, potential
impact on decision-making and source of error
discovery (reactive vs. proactive.)
Method: A set of Data Quality Issues (DQIs)
identified in the past 3 years were used for
analysis. The DQIs were classified by factors (#
of data points involved, source system, age, and
method of discovery) and combined with a cost
model to evaluate the ROI of various approaches
to improving data quality.
Results: This project consisted of two phases. We
first leveraged historical data around Data Quality
Issues (DQIs) to develop an algorithm to estimate
the cost of a DQI over time. We then applied this
algorithm in a simulation that examined the use
of various approaches to resolving a set of DQIs
to develop recommendations on identifying the
appropriate solution to a new DQI that arises.
In the initial phase, we randomly selected a set
of DQIs with resolutions in place. We conducted
interviews with representatives from key
operational groups (e.g. Clinical Site Monitoring,
Data Management, Central Laboratory) to
identify factors that may modify the cost of
resolving a DQI. These included the overall
number of data points involved, error rate,
source system characteristics (number of end
users, other systems that use this data,) method
of discovery (reported by an end user in the
business or proactively identified as a potential
issue) and time. To determine cost, we used a
modified version of the 1-10-100 rule as stated by
SiriusDecisions: “It takes $1 to verify a record as
it’s entered, $10 to cleanse and de-dupe it and
$100 if nothing is done, as the ramifications of the
mistakes are felt over and over again.”
After refining the data quality cost algorithm, we
applied the algorithm to a second set of DQIs to
simulate the ROI of different approaches available
to resolve the issue and prevent its occurrence in
the future. These results were then extrapolated
to design a decision matrix that can be applied
to determine which approach to recommend
for a specific DQI. For example, in some cases,
requiring a field in CTMS is the best approach;
in other instances, mandatory field may prevent
a CRA from completing a site visit report and a
data alert is appropriate. In addition, this data
allowed us to extrapolate factors that can be
used to justify the business decision to invest in
technology to verify records in near real-time vs.
a process for data cleaning vs. inaction.
Conclusion: Transforming the way the health care
industry brings new medicines to the patients
who need them in the most cost-effective manner
requires us to harness the power of both patient
data and operational study management data. In
fact, the most recent FDA guidance on risk-based
monitoring (RBM) suggests that a well-designed,
clearly written protocol and the ability to leverage
technology to monitor site and data quality
are critical components for successful study
delivery using a RBM plan. However, technological
advances that offer the promise of data-driven
insights are only as good as the data feeding
those systems. As such, ensuring the quality of
that data is paramount to realizing the full value
of these systems. The perceived difficulty of
measuring the intrinsic value of high quality data
often prevents firms from attempting to do so.
This, in turn, often leads to inaction or misdirected
action to improve data quality because of the
inability to measure success or justify a business
investment in a data quality initiative.
Our empirical research demonstrates that
a relatively simple model can be derived to
monetize the value of data quality, which is
commonly thought of as a nebulous concept.
Further, we have identified a number of factors
that can be assessed to help guide decisionmaking with regard to implementing a proactive
solution to ensure data is clean upon entering a
system or taking a reactive solution to correct/
complete data after a lag period. On the other
hand, it may not always make sense to invest time
or technology in fixing the data, e.g. there is not
much value in correcting enrollment data from
RA studies conducted 10 years ago because the
standard of care has changed so dramatically.
Finally, this model can be used to evaluate the
ROI of investing in a technological solution to
automate the process of data correction.
T 16Global Regulatory View of
Nonprescription Medicines
Classification
Dinah Duarte, PharmD, MSc
INFARMED, Portugal
Objective: To address issues concerning the
legal status of medicines in a global way and the
switch strategy implemented in Portugal (The
Portuguese 3rd List)).
Method: We propose to cover the following areas:
• Legal status of medicinal products in the
marketing authorisation (MA)
• Assessing the reclassification procedures and
identifying potential areas for improvement
• Innovative non-prescription medicines in the
centralized procedure
Results: We intend to present the regulatory and
policy environment impacting self-care and the
critical role that healthcare professionals can play
in realising the self-care potential, by addressing
how to appropriately respond to the public health
and citizens’ needs for innovation and access to
effective and safe products of high quality.
Conclusion: This Portuguese exercise in switch
reveals that our country is a strong believer in
patient empowerment and a wider access to
healthcare and intends to facilitate high-quality,
effective and safe products reaching citizens.
T 17
Validation of Next Generation
Sequencing Panels for Targetable
Mutations in NSCLC and TNBC Using
FFPEs and Liquid Biopsies.
Rachel Skelton
Insight Genetics Inc.
Objective: To establish procedures to validate
Next Generation Sequencing assays for clinical
laboratory adoption using formalin fixed paraffin
embedded specimens and matched blood
samples focusing on a targeted NSCLC panel and
an algorithm-driven RNAseq-based TNBC assay.
Method: Validation was conducted using a
compartmentalized approach that validated
the instrument, nucleic acid extraction, assay
protocol, and bioinformatics as separate entities.
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NGS panels were run on the Illumina miSeq
instrument. A minimum of 32 specimens were
tested in replicate sequencing runs.
Results: Validation of the non-small cell lung
cancer (NSCLC) and triple-negative breast
cancer (TNBC) assays determined the accuracy,
precision, analytical sensitivity, analytical
specificity, reportable, and reference range of
each component of the NGS procedure. Validation
of the Illumina miSeq was performed using
the PhiX Control v3 library and analysis of the
base call accuracy, sequence read agreement,
and coverage depth. All assays were validated
for the corresponding nucleic acid extraction
protocol used i.e., DNA, RNA, or Circulating
Nucleic Acid. The targeted NSCLC panel utilizes
the Illumina TruSeq® Custom Amplicon design.
This comprehensive panel identifies the key
mechanisms of ALK inhibitor resistance. Samples
of known mutation status were run in replicate and
evaluated based on an average amplicon coverage
> 500X. The targeted NSCLC panel protocol was
adapted to survey circulating nucleic acids from
plasma or serum for efficient monitoring of ALKspecific or secondary drivers of drug resistance
from patient blood. Matched solid tumor samples
were utilized when available to confirm detection
of tumor-derived nucleic acid. The mean target
coverage across all exonic regions was between
4000X- 20,000X, significantly higher than the
generally accepted 500x coverage. Validation of
the bioinformatics pipeline established that the
targeted NSCLC panel showed a sensitivity of
94.3%; specificity of 100% and limit of detection of
> 6.5% mutant content.
The TNBC diagnostic assay is designed to target
a poor-prognosis population to provide guidance
for treatment with the most effective therapeutics
based on expression profiles. For this format of
assay, RNAseq validation was performed with
matched fresh-frozen and FFPE specimens.
RNAseq data was analyzed using a software
algorithm and compared to previously acquired
microarray data to classify TNBC patient samples
into subtypes responsive to targeted therapies.
Conclusion: The utility of Next Generation
Sequencing in clinical laboratories depends on
the development of sequencing panels that focus
on clinically actionable oncogenic drivers. Strict
procedural guidelines for clinical validation of
NGS assays are not currently in place; thus, it
is critical that clinical laboratories take care to
robustly validate lab-developed NGS tests. All
assays presented in this work have been validated
using guidance from CLIA, CAP, and New York
State certification bodies and show > 90%
sensitivity and specificity. Compartmentalized
validation simplifies future assay validation
in that validation is only required for process
components differing from currently validated
processes.
The targeted NSCLC panel allows for detection
of the precise resistance mechanism(s) operative
in an individual patient’s tumor which can guide
physicians in tailoring decisions for the selection
of second-line therapy or appropriate clinical
trials. Because second biopsies from diseaseprogressing patients is not standard practice,
the targeted NSCLC panel was validated for a
non-invasive method using blood samples to
allow for continuous monitoring of a patient’s
inhibitor resistance profile. Validation robustness
was ensured using patient specimens of known
mutations status or comparing matched solid
tumor and blood specimens. A second NGS
assay described in this work functions to better
characterize TNBC samples into clinically
targetable subtypes. RNAseq followed by a
software algorithm analysis provides physicians
with clinically relevant genetic information to help
improve treatment options and selection for this
group of cancer patients. Validation robustness
was accomplished by comparing data outputs
from the TNBC NGS assay to matched microarray
data. In summary, these NGS assays have been
robustly validated and are available for use in the
clinical setting.
T 18A Regulatory Informatics Approach to
Identifying Trends in Minimal Residual
Disease for the Hematologic
Malignancies
Elizabeth Rach
Janssen R&D, LLC
Objective: Minimal residual disease (MRD) holds
great potential to allow for earlier detection
of relapse, accelerated approval, and shorter
trial duration. We aim to assess utilization of
MRD across efficacy endpoints, hematologic
malignancies, technologies, and the development
of breakthrough therapy drugs.
Method: We performed advanced searches in
the Clinicaltrials.gov Registry (dated 30 January
2014) and analyzed the results using ActivePerl
(v5.12.2) and R (v2.13.0). The numbers of clinical
trials for efficacy endpoints, indications, and
technologies were assessed using trial start dates
or cumulative sums.
Results: There were 262 clinical trials returned
with the search terms “minimal residual disease”
or “major molecular response” in the Clinicaltrials.
gov Registry, each trial having 24 properties. The
growth in utilization of progression-free survival
(PFS), overall survival (OS), event-free survival
(EFS), and MRD showed that PFS and OS had the
highest growth rates, while EFS and PFS showed
similar profiles until they diverged in 2007. The
first trial reported in the registry using MRD
was recorded in 1995 and since then, a trend of
positive growth has been observed.
The utilization of MRD was evaluated across
hematologic malignancies and were classified
into 3 categories based on their prevalence in
the Clinicaltrials.gov Registry, as follows: MRD as
an established endpoint (ALL, CML), MRD as an
emerging endpoint (AML, CLL), and MRD as a
novel endpoint (DLBCL, FL, MCL, MM, WM).
Next, the prevalence of the technologies PCR, FISH,
flow cytometry, and sequencing was evaluated
for the hematologic malignancies and MRD, over
time and cumulatively. Both registry analyses
showed that PCR (114 cumulative trials) was the
most predominant technology, followed by flow
cytometry (31 cumulative trials), FISH (10 cumulative
trials), and sequencing (2 cumulative trials). This
reflects the overall trends observed for the usage
of technologies over time and cumulatively across
endpoints in the hematologic malignancies.
Lastly, investigational drug development
programs with breakthrough therapy designation
were evaluated for their incorporation of MRD. As
of 03 January 2014, Friends of Cancer Research
reported 28 drugs with public disclosure of
breakthrough therapy designation; 6 of which
were granted for hematologic malignancies.
Results showed that 4 (66.7%) out of the 6 had at
least one trial utilizing MRD and ofatumumab had
the highest number of trials using MRD (7 trials).
Conclusion: The application of regulatory
informatics to the Clinicaltrials.gov registry data
is a novel approach to identifying trends across
efficacy endpoints and characterizing utilization
of MRD. These results show that MRD is an
emerging efficacy endpoint in the evaluation
of hematologic malignancies. As technologies
continue to advance to enable more precise
detection, the role and context of MRD in
regulatory strategy will continue to evolve.
Elizabeth A Rach1*, Shruti Kalra1*, Hsiao-Ling
Hung*, Terri Williams*
1 These authors contributed equally to this work.
*Department of Oncology Global Regulatory
Affairs. Janssen Research & Development, LLC,
920 US Highway 202, Raritan, NJ 08869.
T 19
Characterizing Medical Information
Requests from Payer Customers to
Improve Database Planning for
Respiratory Assets
Sarah White, PharmD
GlaxoSmithKline
Objective: The primary objectives of this study
are to develop an understanding of medical
information (MI) requests from payer customers
beyond the AMCP Dossier and to improve the
ability of MI scientists and field liaisons to prepare
for and respond to payer inquiries.
Method: This retrospective database review
will focus on payer requests for information
submitted directly to Medical Information or via
scientific engagement request forms (SERFs)
between January 1 and December 31, 2013.
Results: In order to identify topics of frequent
interest to payers at various phases of a product
lifecycle, trends in the numbers and types of
requests for newly approved products, older
assets and above-brand topics within the
respiratory space will be documented. Fulfillment
modes for each request will be classified into
one or more of the following categories: verbal
response, MI response, publication, scientific
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presentation, literature search, and AMCP dossier.
Ultimately, this information will be used to
characterize MI resource utilization for frequently
asked questions and to create a process for
database planning in this space. Data have been
collected and final results are to be presented at
the conference.
Conclusion: Conclusions are pending analysis.
T 20Assessing Current Monitor
Performance on Monitoring
Competencies for Risk Based
Monitoring
Penelope Manasco, MD, MS
MANA Consulting
Objective: The objective of this abstract is to
provide monitoring competencies for Risk Based
Monitoring and the results of a national skills
assessment provided to current monitors.
Method: Risk Based Monitoring has significantly
changed the role of the monitor. We developed
a set of monitoring competencies through dialog
with experts in the industry. We developed a
skills assessment based on these competencies
and distributed it to staff performing monitoring
on clinical trials.
Results: A set of questions based on each
competency was used. These questions included
skills assessment for interpreting data from
graphs and tables and other report formats that
are part of risk based monitoring. Monitors were
asked multiple questions for each competency
and then a final score was provided for each
competency. This presentation will provide data
on which competencies had the most monitor
proficiency and those with the least proficiency.
The results will show the results for each
competency for monitors based on the number of
years they have been functioning as a monitor.
Conclusion: A thorough assessment of
current monitor training needs is required
to facilitate the transition from traditional
monitoring to risk based monitoring. This
poster provides monitoring competencies for
Risk Based Monitoring, examples of assessment
questionnaires, and highlights the areas
where most monitors will need additional
training.
T 21Utilization of Cross-Pollination Meeting
Series: A Potential Catalyst for
Innovation
Kelly Hageman, PharmD
MCPHS University School of Pharmacy
Objective: The MCPHS University Fellows’
Network (MFN, comprised of more than 40
fellows and alumni across 7 functional areas and
5 pharmaceutical companies) piloted a quarterly
cross-pollination meeting series in an effort to
capitalize on the potential benefits of crossfunctional collaboration.
Method: The meeting series was designed as
a quarterly 90-minute Industry Seminar, each
focusing on one functional area within the
pharmaceutical industry. Each seminar consisted
of formal presentations and two round-table
discussions. Surveys were used to measure the
value and utility of each meeting.
Results: To date, two Industry Seminar events
have been developed and executed with a total
of 46 participants (n=28 and n=18, respectively)
in attendance; 40 completed the post-meeting
survey (n=24 and n=16, respectively). The events
hosted participants from 5 functional areas
within the biopharmaceutical industry including:
clinical supplies, translational medicine/clinical
research, medical affairs, pharmacovigilance, and
regulatory affairs. Overall, 95% of fellows strongly
agreed (n=29) or agreed (n=9) that the seminar
series was educational and worthwhile. All fellows
strongly agreed (n=31) or agreed (n=9) that each
event was an excellent opportunity to learn about
co-fellows working in different departments.
Ninety percent of fellows strongly agreed (n=23)
or agreed (n=13) that the Industry Seminar
provided them with an in-depth understanding of
other functional areas in the biopharmaceutical
industry. Via free text on the surveys, fellows
expressed an appreciation for gaining an
enhanced understanding of the roles and
responsibilities beyond their own departments
as well as the differences between companies.
Overall, 97.5% of fellows strongly agreed (n=29)
or agreed (n=10) that they learned something
new about the biopharmaceutical industry during
these events.
Conclusion: MFN designed a cross-pollination
meeting series in an effort to utilize the functional
diversity present within the network, further
cultivate individuals’ knowledge of various roles
within the biopharmaceutical industry, and
capitalize on the potential future benefits of
cross-functional collaboration. Survey results
showed that the majority of fellows found the
MFN Industry Seminar series to be valuable and
beneficial in creating an opportunity to learn
about different functional areas. Although there
were a limited number of events, the program’s
aim of cross-pollination and enhancement of
understanding across departments was reached.
Through this seminar series, fellows gained
exposure to different viewpoints, which will likely
foster future collaboration and innovation within
participants’ own functional and cross-functional
teams.
T 22Evolution of Pharmacovigilance
Regulations in the US and Europe
Dena Cosgrove, RPh
Quintiles Transnational Corporation
Objective: This poster will examine the history of
pharmacovigilance, identifying key turning points
and likely future developments.
Method: Milestones in the evolution of
pharmacovigilance will be identified, with an
analysis of trends in adverse event reporting in
the United States and Europe.
Results: A review of legislation will be presented,
starting with the first UK law aimed at regulating
drugs, the Pharmacy Act of 1868, and the United
States’ 1902 Biologics Control Act and 1938
Federal Food, Drug and Cosmetic Act. Key
milestones such as the thalidomide tragedy
in the 1960s will be examined. The poster will
provide information on drug safety activities at
national and regional regulatory authorities, the
World Health Organization and the International
Conference on Harmonization. The author will
highlight the trend for safety monitoring to
move from passive approaches (spontaneous
adverse event reporting) to more reactive (action
in response to interventions by regulators) and
proactive methods (using electronic medical
records [EMRs] and risk management programs
such as Risk Evaluation and Mitigation Strategies
[REMS]).
The impact of the Prescription Drug User Fee Act
will also be discussed.
Conclusion: Pharmacovigilance remains a very
young science, at an early stage in its evolution.
Looking forward, increasingly proactive
approaches will be required, and in future these
will encompass the need to access EMR and other
large data sets to identify and validate safety
signals. Pharmacovigilance executives everywhere
need to prepare for this.
T 23
Validation of an Internal
Communications Streamlining
Initiative Utilizing an External
Communications Benchmarking Study
Vinit Mehta, PharmD
Novo Nordisk Inc.
Objective: The objective of this study is to
identify inefficiencies in standard communication
channels and methods used by pharmaceutical
companies and compare the data generated
against process improvements implemented in an
internal communications streamlining initiative.
Method: For this study, a web-based survey
was disseminated to US pharmaceutical industry
employees within Medical Affairs departments.
Concurrently, a centralized communications
solution was piloted to prioritize and distribute
information to the internal Medical Affairs team
during a six month period.
Results: The external survey generated 184 initial
responses, of which 138 met the qualification
criteria of being an employee of a Medical Affairs
department at their respective pharmaceutical
company. Of the eligible 138 responses, 119
completed the survey yielding an 86.2%
completion rate. Questions included in this survey
were based on factors such as unclear messaging
and prioritization, information overload,
actionable items, and time allocations. Similar
measurements were used in the internal pilot
that was conducted using roughly one-fourth
(36 members) of the Medical Affairs team. At
the conclusion of the six month pilot period, 80%
of participants reported that the pilot program
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addressed the underlying inefficiencies of
interdepartmental communications. Participants
reported a 29% decrease in individual email
volume and a 98% increase in centralized intranet
usage leading to an average of 18 hours saved
across the team per week on communication
channels. While time saved on communications
may seem minor, this pilot was only conducted
using a small subset of the department over
a short period of time. It did not take into
account information disseminated by members
outside of the pilot group. Furthermore, with the
centrallized communications solution relaying a
clear understanding of responsibilities and level
of prioritization, 100% of the participants met the
time-sensitive deadlines.
Conclusion: This study shows that across all
pharmaceutical companies, there are core
inefficiencies in communications that mirror what
is seen within our Medical Affairs department.
Factors such as repetition, redundancy, and
lack of prioritization all negatively impact
productivity. Our internal metrics showed that by
implementing a central communications solution,
improvements were made for not only one,
but all inefficiencies listed above. When these
improvements were taken into account, there was
a combined reduction in time spent managing
information. By prioritizing communications
and clarifying actionable items, users had more
guidance on short- and long-term deliverables,
which led to increased participation and
completion rates. Overall, this communication
streamlining project has allowed for strategic
alignment across a National field-based medical
team and a clear vision across the internal
and external medical affairs organization. The
outcomes of this pilot program have resulted in
the launch of national implementation internally.
The concept behind this initiative could be
applied to any company looking to increase
productivity and improve their communication
processes. I want to acknowledge my co-author
for this abstract, Samantha Yang.
T 24Electronic Investigator Site Files: The
Hidden Gem that Completes Remote
Risk Based Monitoring
Libby Cerullo, MSc
Pivotal Consulting LLC
Objective: The objective of this abstract is to
highlight the importance of transitioning site
document management from paper regulatory
binders to electronic Investigator Site Files to
enhance efficiency and to facilitate Risk Based
Monitoring.
Method: We implemented electronic Investigator
Site Files that were available electronically
to the Site, the Sponsor, and the CRO. This
enabled remote review and reconciliation of trial
documents independent of the site visit. There
was no paper maintained for the study at all.
Results: We will present data on the time
to review documents, elimination of onsite
monitoring visits, use as a component of Risk
Based Monitoring, the acceptance of the site(s)
to using electronic Investigator Site Files, and
time to close out for the eTMF and electronic
Investigator Site Files. We will show how we
used the DIA reference model for investigator Site
Files in our processes. We will also provide data
on the use of a dynamic site essential document
checklist to assure inclusion of all documents at
the Site and Sponsor Level.
Conclusion: The Electronic Investigator Site
File provides a key component of risk based
monitoring and is critical to remote oversight
of investigative sites. We provide examples of
how we developed our processes to take full
advantage of the electronic investigator site files.
We further provide actual implementation metrics
and practical aspects to enhance implementation.
T 25
Precision Laboratory Network (PLN):
PBMC Processing and Nuclei Acid
Isolation Suitability Study
Michael Waddington, MS
Precision Bioservices, Inc
Objective: The Precision Laboratory Network
provides an integrated network of global
laboratories following the same procedures with
demonstrated comparable results for PBMC
isolation and DNA and RNA extraction.
Method: Multiple laboratories in the PLN
processed fresh human blood to isolate PBMC
which were all tested for recovery, viability
and functionality. In addition, DNA and RNA
were isolated from PBMC and tested for yield
and quality. Procedures were performed using
reagents available to all laboratories.
Results: Matched fresh blood samples were
processed by different laboratories witihin
the PLN. All laboratories followed the same
procedures to isolate and cryopreserve the
PBMC. The post-thaw recovery and viability of
the cells from all laboratories was substantially
similar. In addition, functionality as measured by
IFN-g ELISpot assay revealed that cells from all
laboratories retained matching functionality after
isolation and cryopreservation.
DNA was isolated from matched fresh and frozen
PBMC at different laboratories. Both fresh and
frozen PBMC yield comparable amounts of DNA.
The purity was measured by OD260/280 and
all laboratories produced DNA that met our
acceptance criteria of 1.6-2.0.
RNA was isolated at multiple laboratories
from fresh PBMC or PBMC frozen in RNAlater
to preserve RNA activity during the freezing
process. The RNA was isolated following the
same procedure and using kits that are available
worldwide. The resulting RNA showed similar
yield and purity by 260/280, with all laboratories
providing RNA between 1.8 and 2.0. RNA
integrity, as measured using the RIN, was over 7
for all laboratories.
Conclusion: This Suitability Study demonstrates
that multiple laboratories, widely separated by
geography, can coordinate to provide matched
sample processing. By following identical
procedures, using reagents available in all locations,
and performing periodic suitability studies across
the network, the PLN provides worldwide assurance
that research or clinical trial samples from widely
separated locations are processed to produce
comparable data. This assurance allows sponsors to
have confidence in the utility and comparability of
results achieved from all sites in a multi-center trial,
accelerating drug and vaccine development.
T 26Use of Epidemiology Data to Inform
Pediatric Clinical Trial Design and
Execution and Its Impacts on MSL
Support
Laura Wallace, MPH
Purdue Pharma L.P.
Objective: Our objective was to demonstrate the
use of epidemiology studies to provide targeted,
population-specific data to enhance a pediatric
clinical trial (CT) program, with focused efforts for
CT site and investigator identification, feasibility
assessment, and Medical Science Liaison (MSL)
support.
Method: We conducted an epidemiology study
of pediatric pain patient characteristics and
treatment. These data informed CT design,
recruitment, and regulatory interactions. We
collected feedback on the data’s usefulness
for improving trial participation and subject
enrollment from MSLs and other CT staff.
Results: This study included data on 25.5 million
pediatric patients from throughout the US. Of
these children, 1% had orthopedic conditions
associated with pain, 1.8% malignancies, 0.3%
surgeries, 3.5% trauma, and 0.7% genetic
conditions associated with pain; 8.7% of all
pediatric patients had a specific pain diagnosis.
Diagnoses varied by age, with most showing
higher prevalence in older children (age 12-16).
Treatments evaluated included NSAIDS, COX-2
inhibitors, opioids (IR or ER), antidepressants,
topical analgesics, anticonvulsants, and other
therapies. Treatment varied substantially by
condition, and many children, particularly in
younger age groups (age 0-5 and 6-11), did not
receive any prescription pain treatments (>50%
for most of the conditions evaluated). Overall, IR
opioids were used in 17.7% of pediatric patients
with pain conditions, compared to ER opioids in
0.1%, NSAIDS in 7.5%, antidepressants in 4.0%,
anticonvulsants in 2.0%, topical treatments in 1.4%
and glucocorticoids in 4.9%. The types, doses,
and duration of treatments varied substantially
by condition and patient age, with the highest
prevalence of pharmaceutical use in older
children.
We used these data to inform decisions about
trial design, investigator and site selection,
and MSL support. Findings enhanced MSL/
investigator interaction through clinical
discussions of painful conditions and treatments.
A targeted initiative for surgical and orthopedic
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populations was implemented to expand subject
recruitment efforts, based on data showing the
relatively high prevalence of children requiring
pain treatment at study-relevant doses and
timeframes within these populations.
Activities to identify additional practitioners
involved in pain management were undertaken
based on study data. Study data contributed to
identification of specialty centers and physicians
for site selection. Epidemiology data combined
with existing CT enrollment data to further
understanding of site enrollment potential.
Conclusion: With a broad range of potential
investigators crossing multiple specialty areas
and practice settings, identification of clinical
trial sites for a study of pediatric pain can be
challenging. By targeting efforts based on
targeted prevalence and patient characterization
data from epidemiology studies, sites may
be evaluated in greater detail considering
physician’s specialty focus, areas of clinical
interest, and actual patient populations.
Feasibility assessments may be augmented
based by evaluating the site’s patient populations
compared to prevalence data and protocol
inclusion/exclusion criteria.
MSL support of clinical trials includes initial site
identification, as well as support of investigators
and site staff with protocol education and
discussion of potential patient populations. Data
collected from epidemiological studies provides
the MSL with clinically relevant evidence to
provide investigators with tools to enhance
subject recruitment or to engage in outreach
efforts to additional clinical specialties.
Overall, MSL support of clinical trial sites was
strengthened through education based on
study findings about pediatric conditions
associated with pain and treatments utilized for
such conditions. MSL education and targeted,
epidemiology-data-driven initiatives contributed
to improved site support and clinical discussions
with investigators.
Engaging patient advocacy organizations may
contribute to increased awareness and improved
patient recruitment efforts for pediatric clinical
trials. The prevalence data obtained in our study
provides a comprehensive list of conditions
that may include pain comorbidities. Many
of these conditions have associated patient
advocacy organizations, and outreach to these
organizations has shown to expand clinical trial
awareness.
T 27A Strategic Approach to Portfolio
Benefit-Risk Assessments (BRAs)
Libbie McKenzie, MD
Quintiles Inc.
Objective: Given that sometimes several hundreds
of products within a specific portfolio are selected
for a benefit risk assessment Quintiles objective
was to develop a streamlined approach on how to
achieve this goal within a short time frame.
Method: Quintiles leveraged the processes and
structures established by its Safety Aggregate
Reporting and Analysis group and other expertise
to develop a streamlined approach for clients.
Different models of delivery had been compared
and evaluated taking dependencies and
efficiencies into account.
Results: Key factors driving the success of this
project include:
• Selection and prioritization of molecules
The pre-selection of drugs for which the BRA is
desired resulted in >300 drugs to assess from a
benefit risk perspective in a six-month period. A
possible strategy to prioritize was to divide the
portfolio in therapeutic areas (TAs) and to assign
MDs and other specialists with experience in a
certain TA to the drugs concerned. This approach
created synergies for the various products within
a given TA.
• Depth of review
The review of documents which served as the
basis for each BRA started with the most recent
PSUR/PBRER, the CCSI, and the RMP if available.
For all active ingredients as a further prerequisite,
it was necessary to identify important risks and
to assess the status of signals for the evaluation
of potential risks. Furthermore, a literature search
focusing on systematic reviews and metaanalyses was performed. Clinical Guidelines for
respective indications were considered.
• Process for high through-put, short-term delivery
Logistics were critical for both an efficient and
reliable high quality delivery of a large volume
of documents and for economic reasons. All
contributing disciplines were clearly defined in
advance. The high level process of document
creation was specified in writing and the
individual workload for specific tasks was
estimated for each contributor. The resulting
working model in agreement with the client led to
an assembly line approach with high through-put
constant delivery of BRAs.
• Further considerations
A communication plan was established to
facilitate the process of constant delivery over
time with a built in process of continuous
improvement. A time table was necessary to
adhere to the processes defined and to ensure
complete exchange of documents and data within
specified intervals.
Conclusion: This was an innovative project and
one with multiple future implications with lessons
learned. For instance, it was considered essential
to first perform a pilot phase with each client who
is dealing with high volumes of BRAs to clarify
upfront potential challenges and to fine tune
processes with the aim to meet expectations from
both parties. Interdisciplinary contributions from
various functions were necessary to complete the
various BRAs in a timely manner, drawing upon
relevant expertise across Quintiles departments
and geographies. A categorization of complexity
of BRAs was undertaken, e.g., standard, medium
and complex, based on several factors including:
number of active ingredients, number of
indications, important risks etc., with the aim of
being able to estimate total working hours for a
given BRA. This would allow for capacity planning
in total (working hours and FTEs), but also to
decide what should be done by whom, and when
and how processes were intertwined. Process
adjustments or fine tuning were conducted
along the way. This approach provides a model
of how to deliver a large number of benefit risk
assessments in a short period of time and could
be replicated for clients in the future.
T 28Avoid at Your Risk? The Potential
for Naïve Sites to Rescue Failing
Recruitment and Study UnderPerformance
David Horsburgh
Quintiles East Asia Pte Ltd, Singapore
Objective: This investigation looked at
determining relative site performance across
different levels of site experience; with the main
aim being to assess the recruitment potential of
naïve sites against the often favored experienced
site pool.
Method: Enrollment performance on Asia studies
was assessed for this investigation. Asian sites
taking part in these studies were retrospectively
grouped (top, middle, low performers and naive)
as they would have been at the time of study
start; and median enrollment rates calculated for
each tier.
Results: Fourteen studies involving Asia Pacific
countries were identified from the internal
database with a start date between 2010-2013 All studies and included sites had at least 1 year of
recruitment performance recorded
• 5 therapeutic areas were covered including
oncology, rheumatology, endocrinology, CNS,
and cardiovascular.
• Site groups were calculated specifically for each
indication and was based on the following:
o Past enrollment performance
o Previous start-up timelines
o Number of previous protocols in that
indication (experience)
Site groups were also calculated retrospectively
to be correct at time of study start (i.e. pre-2010
data was used for 2010 studies, pre-2011 data
only was used for 2011 studies, and so on)
• Median rates across all studies indicated a 295%
increase in enrollment rate (patients per site per
month) for historically top performing sites over
historic under performers
• Naïve sites outperformed the historic
underperformers by a median value of 157%
Conclusion: Identifying high recruiting and
performing sites is one of the most crucial, yet
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also the most challenging stages of the clinical
trial process. Approximately 50% of initiated sites
globally fail to reach their enrollment targets,
with 11% failing to enroll a single patient, creating
a huge patient need on the few top performing
sites which becomes more and more difficult to
meet.
Reducing the risk of under-performers has
typically involved a focus on previously-utilized
sites over naïve sites with the assumption that
experience working with previous protocols
will reduce the chances of poor enrollment and
provide a better return on the heavy investment
for site start-up.
However, this data shows that not only do
inexperienced (naïve) sites recruit at a faster rate
than poorer performing experienced sites, but
they are often comparable in performance to
the mid-level sites that form the majority of the
experienced site pool.
Key to meeting enrollment targets is not only
identifying a number of key top performing sites,
but also minimizing the patient deficit caused
by non-enrollers or under-performers. Despite
current trends in site-selection, initiating the
right naïve sites to replace experienced underperformers could reduce this benefit and tip
the balance back in the favour of on-time study
delivery.
T 29
The Role of Medical Writers in
Preparing Responses to Post
Submission Queries From FDA, PMDA,
and EMA
Kai Yu Jen
Biogen Idec Inc.
Objective: The purpose of this presentation is to
describe the role of medical writers in preparing
responses to post-submission queries from the
United States Food and Drug Administration
(FDA), the Japanese Pharmaceuticals and Medical
Devices Agency (PMDA), and the European
Medicines Agency (EMA).
Method: Compare and contrast the medical
writer’s experience in preparing responses to
post submission queries from the FDA, PMDA,
and EMA. Different approaches and styles across
the regulatory agencies will be discussed in this
presentation.
Results: The medical writing role in preparing
responses to queries from regulators includes
establishing review timelines, drafting response
text and tracking the status of the responses
through the review process. Although the
application review process differs across the
FDA, PMDA, and EMA, the role of the medical
writer in preparing post-submission queries from
the 3 agencies is generally similar. A common
approach to facilitate preparing responses to
regulatory queries across the 3 agencies involves
the creation of a Response Team (RT), which
should include members from the following
departments: regulatory affairs, clinical, safety/
pharmacovigilance, biostatistics, programming,
preclinical, chemistry manufacturing and controls,
pharmacology, pharmacokinetics, labeling, and
medical writing. The goal of the RT is to reach
consensus across the functions on the strategy
for responding to the queries. For the FDA and
PMDA, queries can arrive at any time after the
marketing application is submitted. For both
of these agencies, the review timelines are
characteristically very tight (e.g., 14 to 21 days).
In contrast, the EMA follows a highly structured
process where regulatory queries are provided
to the sponsor and the sponsor’s responses are
submitted to the agency at pre-specified time
points. This structured process with the EMA
allows the RT to systematically plan out the
strategy for addressing the agency’s queries. For
all 3 agencies, the queries can range from simple
requests for clarification to complex questions
requiring additional analyses.
Conclusion: From the medical writing standpoint,
the main lessons that are relevant across all
regions are: establish review timelines; track
the status of the responses through the review
process; remain singularly focused on the specific
question; and ensure consistency across all
submission documents.
The main lessons that are specific to the regions
are: For the FDA, ensure adequate staff to
manage short turnaround timelines and never
submit new data not included in the original
application unless specifically requested by the
regulator; for the PMDA, pay strict attention to
the details of the content, always build extra time
in the review process for translation; and as with
FDA, ensure adequate resources to manage short
turnaround timelines; and for the EMA, use the
structured application review process to your
advantage in planning your responses; take time
to review the agency’s assessment reports, which
provide context for the questions and building
the responses.
Co-authors: Terry Martin, Elizabeth Miller
T 30
The Evolution of an Enterprise Risk
Based Monitoring Process
Ben Dudley
Covance Inc., United Kingdom
Objective: To describe the evolution of an
enterprise RBM process from the baseline
problem across clinical trial conduct, the
processes implemented, and the data-backed
outcomes achieved.
Method: Over the past 5 years a global crossfunctional group (including clinical study teams,
functional leaders, and expert working groups)
has collaborated to define and implement an
enterprise RBM process.
Results: This poster will provide real life evidence
data from the conduct of global clinical trials
using an enterprise risk based monitoring process
that has delivered quantifiable benefits in a range
of areas, including:
• Increased early identification of issues at the
highest risk sites
• Ability to provide qualitative assessment of site
compliance
• Increased efficiency resulting in reduced study
delivery costs
• Improved data flow cycle times while reducing
data cleaning resource requirements
Conclusion: Five years ago, there was absolute
reliance on individual monitor capability to
identify and resolve site issues in a find and fix
paradigm. This process was prone to individual
CRA failure and did not identify and manage
cross study risks and trends effectively.
It was hypothesized that designing and
implementing processes that would maximize
up-front risk identification, design monitoring
interventions, and track actual performance using
data and risk indicators would simultaneously
drive improvements in quality and deliver
efficiency benefits.
A sequence of improvements were designed –
implementation of a predictive, proactive and
preventative study delivery paradigm, designing
of site quality risk reports, an enhanced clinical
quality control program, and adaptive monitoring
designs all drove improvements. These formed
the cornerstone of an enterprise RBM approach
which was validated with the release of FDA Risk
Based Monitoring guidance.
T 31A Multi-Modalities Medical Imaging
Investigative Network for Clinical
Trials in Cardiovascular, Neurology
and Oncology
Dominique Johnson, PhD, MSc
Montreal Health Innovations Coordinating Centre
(MHICC), Canada
Objective: To link together hundreds of
worldwide vascular imaging experts and
clinical research infrastructure and allow for
unprecedented cross sectional and longitudinal
clinical studies in cardiovascular, neurology and
oncology.
Method: A unique repository of anonymized
multi-modalities medical images and medical
data dispatched in real time, to the appropriate
imaging core laboratory in several locations in
North America to be utilized both in clinical trials
and for training purposes.
Results: Two Canadian national clinical research
networks, CAIN (Canadian Atherosclerosis
Imaging Network) and MITNEC (Medical Imaging
Trial NEtwork of Canada), were created at the
Montreal Heart Institute and Montreal Health
Innovations Coordinating Centre (MHICC) to
address the objectives of moving innovations in
medical imaging toward their broad application
in clinical research and facilitating the uptake
of research outcomes into clinical practice and
improved patient care. The MHICC plays the role
of the sole coordinating centre and repository for
this network. The main result of putting together
these networks has been the launch of 8 major
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international multi center clinical trials with
medical imaging components. The electronic
exam transfer allowed by this infrastructure is
essential to some of the studies because of the
sensitive time component to confirm patients’
eligibility. Utilizing the CD/DVD method as was
current practice would have made it impossible
to get the images from recuiting clinical sites in
Asia, Europe, USA and Canada to confirm patient
eligibility in an acute study. Using this unique
imaging network and infrastructure, more than
500 clinical sites in more than 15 countries in
North America, Europe and Asia, were provided
secure and private image management that
included anonymization of image data and the
secure transfer of image and clinical data to the
data center and multi-modalities imaging core
laboratories from the recruiting hospitals. The
members of these networks are now engaged
on a long term basis with the MHICC since this
organisation is now the unique repository of
the clinical research data (medical images and
medical data) of the clinical trials conducted by
these networks.
Conclusion: Medical imaging is one of the
approaches that will contribute substantially to
the revolution in clinical trials leading to shorter,
less expensive trials and more predictive medical
benefits. Consequently, these two networks of
partners and collaborators are active members
of the research programs, in particular because
the MHICC has developed a unique expertise
in hosting significant imaging repository and
transfer for multi-imaging modalities. This
infrastructure allows professionals with simple,
yet comprehensive access to cutting-edge
research as well as providing research training
and mentorship. Medical imaging expertise and
infrastructure linked in this procedure allows
health professionals to form a core clinical
research network. Patients are recruited from
qualified sites across the country, in actual time,
to enable the progression of cross sectional
and longitudinal clinical studies. This unique
procedure assures secure image processing that
includes anonymization of image data and would
enable large population imaging studies. Its
broad application in clinical research allows to
facilitate the uptake of research outcomes into
clinical practice and improve patient care. Over
the last few years with the pan-Canadian CAIN
and MITNEC networks, the MHICC also developed
a unique expertise in hosting significant imaging
repository from multi-imaging modalities,
including the development and establishment of
an electronic images transfer through a secure
network connectivity from more than 500 remote
clinical sites located in 15 countries. Additional
author: Jean-Claude Tardif, MD.
T 32Analysis of Product Labeling Changes
for Successful Prescription to Over
the-Counter Switches
Kim Le, PharmD
Rutgers Pharmaceutical Industry Fellowship
Program
Objective: The objective of this study is to
identify labeling changes for medications
that have had marketing status changes from
prescription to over-the-counter, thereby
characterizing successful switches.
developed that are specifically geared toward
an individual with ADHD. Both groups offered
suggestions for opportunities to improve the
transition process.
Method: The Rx package inserts and OTC labels
for first-in-class switches will be compared based
on factors related to indications, dosage and
administration, and safety information. A series of
binary response questions will be generated for
each factor. A descriptive analysis of the data will
be reported
Conclusion: The MSL team was able to
characterize the state of transition of care for
ADHD patients moving from adolescence to
adulthood through in depth real time discussions
with various care providers. Overall these findings
highlight the need for additional education on
the importance of transition of care planning,
the timing and content of such discussions and
the need for associated resources designed
specifically for those with ADHD. Utilizing the
MSL team to conduct systematic interviews
resulted in the elucidation of an unmet patient
need to further direct medical strategy.
Additionally, these discussions have the potential
to stimulate the development of tools and/
or programs designed to empower patients,
caregivers and HCPs to take a proactive approach
to transition planning. While this process was
applied to a specific unmet need in ADHD, it has
the potential to be translated across multiple
therapeutic areas.
Second Author: Meena Ramachandra
T 33Utilizing the MSL Role to Characterize
the Transition of Care of Patients with
Attention Deficit Hyperactivity
Disorder
Nicole Griswold
Shire Pharmaceuticals
Objective: Transitioning care during the period
of adolescence to adulthood is challenging for
those with ADHD. This initiative maximized the
MSL function to obtain structured feedback to
identify barriers and potential best practices
for the transition of care of patients with ADHD
across the US.
Method: From July-October 2013, the MSLs
conducted interviews with health care
practitioners (HCPs) who treat ADHD and
with ADHD patient advocacy representatives.
Information collected included demographics,
knowledge of available services, barriers to
transition and recommendations for these
individuals.
Results: Forty-seven HCPs (Adult Psychiatry
=2, Child/ Adolescent Psychiatry= 16, General
Psychiatry= 12, Pediatricians=2, Developmental
Pediatricians = 3, Pediatric Neurologist=1, Nurse
Practitioner =1) and 10 Advocacy Representatives
(7 representing CHAAD) were interviewed across
twenty-four states. Results suggest that although
there is a lot of interest in proper transition of
care, there was a significant lack of consistency
in implementation of any approach. Forty-six
percent (11/24) of adolescent HCPs had a specific
plan or routine practice to approach transition
discussions, 25% (6/24) knew discussions were
necessary but did not have a plan and 29% (7/24)
approached the topic on a case by case basis. Of
the adult HCPs interviewed, 96% stated they were
not aware of specific transition plans available,
despite acknowledging the importance of these
discussions.
Barriers identified to the transition of care of
ADHD individuals included patient understanding
of the disorder, access to a health care provider
educated in the treatment of ADHD, insurance
issues, patients’ ability to identify support and
accommodations at colleges, as well as lack of
structure and caregiver support. Most HCPs
and advocacy representatives could not identify
specific transition of care tools or resources
and acknowledged that resources need to be
T 34
Descriptive Evaluation of REMS
Knowledge in An Integrated
Healthcare System
Nazia Rashid, PharmD, MS
Kaiser Permanente Southern California
Objective: To assess provider perceptions and
experience with REMS in an integrated healthcare
delivery system.
Method: Cross-sectional online survey link was
emailed to eligible healthcare providers. Providers
were eligible if they prescribed at least one
selected REMS-related medication from 1/1/2013 to
6/30/2013. Descriptive analysis was conducted for
the physicians whom completed the survey.
Results: The survey focused on provider opinions
about REMS, their interactions with patients,
and uses of REMS materials in their daily
practice. 364 respondents (34%) completed the
online survey. The majority were primary care
prescribers (65%), other respondents included
specialists (15%), oncologists (8%), surgeons
(7%) and pain management (6%). Overall, 21%
of physicians felt REMS was meaningful, 41%
felt it was somewhat meaningful, and 38% did
not find them meaningful. Similar responses
were found when providers were asked if REMS
improved patient safety. When asked about
providing REMS medication guides to patients,
only 15% of physicians responded affirmatively;
large differences were seen between the different
specialty groups from 0% of pain management
to 46% of oncology providers. A majority of
the physicians counseled their patients or had
another health care team member discuss the
risks and benefits of the medications. Lastly, 48
% of respondents felt that REMS had no impact
on their interactions with patients, while 39%
felt that REMS had moderate impact on their
interactions with patients.
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Conclusion: The results from the survey suggest
that small percentage of providers (21%) felt
REMS were meaningful, a small percentage (15%)
provided REMS medication guides to patients and
the majority (87%) felt it has little impact on their
interactions with patients.
T 35International Comparison of Process
and Procedures to Overcome Clinical
Trial Applications Placed on Clinical
Hold
Kenichi Otani, PhD
Sunovion Pharmaceiticals Inc.
Objective: The objective of this study is to
compare process and procedures to overcome
first-in-human clinical trial applications that
were placed on clinical hold or grounds for nonacceptance in the US and the UK, respectively, as
a case study.
Method: Clinical Trial Applications for firstin-human studies for two, orally administered
molecules were submitted (Compound A:
investigation new drug application(IND),
Compound B: clinical trial authorisation(CTA)).
Both were denied and the processes from denial
to the “may-proceed” status are compared.
Results: Compound A: The IND to the FDA
was placed on “clinical hold” 30 days after the
submission. The removal of the clinical hold was
contingent upon adopting a stopping criterion
based on one tenth of the plasma concentration
of the active substance and its metabolite at the
level of the no-effect dose from a nonclinical
study with the most sensitive species for a drug
plasma concentration in the first-in-human study.
Overall, the entire process (IND submission
to “may proceed letter”) required 97 days.
Subsequently, the stopping criterion was reached
and a meeting request was submitted to the FDA
to discuss removal of the cap and raising the
stopping criterion. The subsequent process to
escalate the dose required additional 205 days
from the first dose (hit the cap) to the agreement
with the FDA.
Compound B: The CTA to the Medicine and
Healthcare products Regulatory Agency (MHRA)
was placed on “notice of ground for nonacceptance and right to amend request” 10 days
after the submission. The removal of the notice of
ground was contingent upon adopting a stopping
criterion based on a no-observed-adverse-effect
level (NOAEL) of the active substance form a
nonclinical study with the most sensitive species
for a drug plasma concentration in the first-inhuman study. The stopping criterion was set up
to the same plasma concentration as the NOAEL.
Overall, the entire process (CTA submission
to “notice of acceptance”) required 30.
Subsequently, the stopping criterion was reached
and another meeting request was submitted
to the MHRA to discuss removal of the cap and
raising the stopping criterion. The subsequent
process to escalate the dose required additional
14 days from the first dose (hit the cap) to the
agreement with the MHRA.
Conclusion: While Compound A and B are
chemically distinct, the first-in-human studies
for these orally administered, small compounds
were not able to proceed following the initial
review of the clinical trial applications. In both
instances, the Health Authority required the
implementation of stopping criteria based on
plasma concentration from the most sensitive
species in non-clinical studies in order to proceed
with the clinical study.
These examples highlight the International
Health Authority procedural and process
differences associated with removing clinical
holds, specifically between the United States and
United Kingdom. The process in the United States
is more formal and time consuming, while the
process in the United Kingdom is more informal
and less time consuming.
Drug Regulatory Affairs managers can utilize
this information when advising teams on
country selection regarding a first-in-human
study, considering the difference between the
MHRA and the FDA regarding the process and
procedures related to clinical hold removal for an
initial clinical trial application.
T 36Impact of FDA Advisory Committee
Voting on FDA Approval Decisions for
Drugs and Biologics
Regina Ballinger, BSN, MS, RN
Thomson Reuters
Objective: To examine voting patterns of FDA
advisory committees charged with reviewing
drug and biologic products under consideration
by the FDA for marketing approval and relate the
outcomes of these reviews to FDA’s marketing
approval decisions.
Method: Using committee meeting reports from
2002 to 2013, and computer analysis, committee
voting was compared with FDA approval
decisions. Committee support was defined as a
majority vote of “Yes.” Committee rejection was
defined as a majority vote of “No” or an “Equal”
vote.
Results: Of the 307* products reviewed by 21
committees from 2002 to 2013, 74.6% (229/307)
received FDA marketing approval. Committee
votes were positive in 80.8% of the cases; of
the 78 products that were not approved, 64.1%
received negative committee votes. Original
new drug applications (NDAs) and biologics
license applications (BLAs) accounted for 77.3%
(177/229) and 76.9%% (60/78), respectively, of
approved and not-approved products. Committee
votes regarding original NDAs and BLAs were
measured in cases of FDA approval: 80.2% (142/
177) positive; 10.7% (19/ 177) negative; 9% (16/177)
had no approval-related vote.
Of all products* that received marketing approval
in the 10-year period, 54.1% (124/229) had
been granted expedited review by the FDA.
The advisory committees supported 84.2%
of products with priority review designation
(96/114) and 85.7% for those with orphan
designation (12/14). Of all products that were
denied marketing approval, 42.3% (33/78) had
been granted expedited review (26 priority
review designations, 7 orphan designations). The
committee did not offer support in 69.2% and
85.7% of the priority review and orphan cases,
respectively.
The 4 most active committees accounted for
43.6% (134/307) of all the products reviewed by
committees for which the FDA has communicated
an approval decision. Of the 229 products that
have received marketing approval, these 4
committees assessed the application in 41.5%
(95/229) of cases; their vote was positive 82.1%
of the time. Also, they accounted for 56.4%
(44/78) of products that were not approved,
voting negatively 70.5% of the time. The
busiest committee was the Oncologic Drugs
Advisory Committee (ODAC). In cases where
FDA marketing approval followed an advisory
committee review, ODAC voted in the positive
85.7% of the time; when approval was denied by
the FDA, ODAC had rejected support 94.4% of
the time (*186 NDAs, 51 BLAs, 51 supplemental
NDAs (sNDAs), and 19 sBLAs).
Conclusion: Data regarding the 307 products
reviewed from 2002 to 2013 appear to show
a correlation between both the positive and
negative committee votes and a subsequent FDA
approval/non-approval. For products where the
FDA ultimately granted marketing approvals, the
committee had also expressed support in over
three-fourths of all cases. In cases where the FDA
issued a communication rejecting the application,
the committee had also rejected support in 64.1%
of cases. When assessed by review type (6-month
review clock), a similar percentage of products
that earned committee support also received FDA
marketing approval.
Expedited review accounts for a little more
than half of all products approved by the FDA
following an advisory committee meeting. For
products with an orphan designation, the FDA
agreed with the assessment by committees
supporting the application more than 85% of the
time. In cases where the FDA denied approval
for orphan products, the committees had also
rejected the product 85.7% of the time.
Voting trends of the 4 most active committees
were analyzed in more detail. About 19% of
the committees accounts for 44% of overall
meeting activity where product applications are
concerned. These results also reinforce the overall
conclusion that committee voting is predictive
of the FDA’s final decision on a marketing
application following an advisory committee
review. Assessment of the Oncologic Drugs
Advisory Committee (ODAC), the most active of
all the committees, provides a specific example
of the power of committee recommendations.
ODAC’s vote was positive in 85.7% of the cases
where the FDA granted marketing approval. This
is slightly higher than the agreement rate of all
committees.
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T 37
The Silver Lining of the PSMF:
Flow Chart Displaying the Business
and User Requirements
Zsuzsanna Csutor
B&C Consulting AG, Switzerland
Objective: Objective: Flow chart of the PSMF
processing displays the business and user
requirements in accordance with the new legal
requirement in EU (Dir.2010/84/EU), described
in Module II guideline for a Pharmacovigilance
System Master File (PSMF) since July 2012.
Method: Method: Mapping, the information
to be included in the PSMF per Module II in a
flow chart, gives an overview to the European
Medicines Agency (EMA), Competent Authorities
(CA), Market Authorization Holders (MAHs) of the
business and user requirement across functions
within Pharma Industry.
Results: Results: The primary benefit of the PSMF
concept over the Detailed Description of the
Pharmacovigilance System (DDPS) was seen as
the reduction in the burdensome and duplicative
work practices. In one glance, the flow chart of
the PSMF facilitates to comprehend the massive
impact of the new legislation on the working
environment of the Pharma Industry displaying
the potential benefits and the tremendous
opportunities for the various users.
Conclusion: Conclusion: The new legislation was
felt far beyond the boundaries of the European
Economic Area and left many breathless and
weak. However the silver lining of the new
legislation for PSMF was a new tool ” check
my pulse” system that presented the Pharma
Industry with more transparency not only to the
EMA and other CAs but also positioned the MAH
and QPPV in the “full knowing”.
T 38
Rock and a Hard Place: Mandated
Multi-National Drug Utilization Studies
in the Absence of Suitable Secondary
Sources of Data
Krista Payne, MEd
UBC, Canada
Objective: Describe new evidence requirement
challenges imposed by regulators with respect to
evaluations of drug safety post-market;
Discuss logistical challenges and timeline
constraints associated with chart review DUS to
inform dialogue and negotiations with regulators.
Method: Increasingly, regulators are mandating
multi-national drug utilization studies (DUS)
to evaluate (in)appropriate use of medicines.
Frequently, however,databases are lacking for all
or some countries of interest. Retrospective chart
studies can fill these gaps but are associated with
significant operational and logistical challenges
resulting in higher study execution costs and
extended timelines for study sponsors.
Design and operational parameters of recent
chart review studies of drug utilization and safety
conducted in Canada, the United States and
Europe have been summarized. Opportunities,
challenges and lessons learned are delineated.
Results: All studies fulfilled post marketing
requirements. Sample sizes varied from 100
patients to more than 2000 and the number of
countries and sites varied from 1-5 and 12-375.
Across studies, key design challenges included
the delineation of eligibility and study periods
that permitted evaluations of recent care
patterns while maintaining sufficient follow-up
time; determination of site-specific sampling
frame methodologies to minimize selection
bias; methods to minimize Hawthorn Effect and
physician response bias; and safety reporting
in the context of retrospective chart data.
Operationally, challenges included the need for
rapid study start-up to achieve site and patient
enrollment, data collection and analytics within
the timelines mandated by regulators.
Conclusion: Sponsors must be prepared to
evaluate patterns of drug utilization and (in)
appropriate use even in the absence of health
care databases. Though challenging to
implement, retrospective chart reviews may
be employed to meet evidence requirements.
Knowledge of the significant design and
operational and timeline challenges associated
with chart review DUS is warranted to support
early and constructive dialogue with regulators
during study planning negotiations.
T 39
Medication Use Among Pregnant
Women Enrolled in Medicaid
Kristin Palmsten, DrSc
University of California San Diego
Objective: To compare prevalences of the most
commonly used or dispensed medications during
pregnancy, as described in the literature, with
prevalences of the same medications among
pregnant women enrolled in Medicaid, the health
insurance program for low-income individuals in
the US, during similar years.
Method: The study included 1,106,757 pregnant
women enrolled in Medicaid during 2000-2007.
We identified dispensing claims for medications
used by >1.5% of women in the 1st trimester or
by >3% during pregnancy in previous studies,
excluding estrogens, progesterone, and
progestins.
Results: Of the 17 selected medications,
nitrofurantoin 22%, amoxicillin 18%, azithromycin
17%, metronidazole-oral only 15%, promethazine
14%, cephalexin 13%, acetaminophen/codeine
11%, terconazole-topical/vaginal only 10%,
albuterol 8%, terbutaline 3%, ondansetron
3%, and erythromycin-oral only 2% were the
most commonly dispensed medications during
pregnancy, and promethazine 8%, amoxicillin 7%,
nitrofurantoin 7%, azithromycin 6%, cephalexin
4%, metronidazole-oral only 4%, albuterol 4%,
acetaminophen/codeine 3%, terconazole- topical/
vaginal only 2%, ondansetron 2%, loratadine
1%, and sertraline 1% were the most commonly
dispensed medications during the 1st trimester.
For comparison, Andrade et al* reported the
following prevalences for medication dispensings
anytime during pregnancy: nitrofurantoin 7%,
amoxicillin 18%, azithromycin 3%, metronidazole
6%, promethazine 4%, cephalexin 5%,
acetaminophen/codeine 5%, terconazole 4%,
albuterol 5%, terbutaline 4%, and erythromycin
5%. Mitchell et al** and Thorpe et al^ reported
the following prevalences for medication use in
the 1st trimester: promethazine 1-3%, amoxicillin
3-4%, nitrofurantoin 1%, azithromycin 1-2%,
cephalexin 1%, albuterol 2-5%, acetaminophen/
codeine 1%, ondansetron 1-3%, loratadine 1-2%,
and sertraline 1-2%. Levothyroxine (1% during
pregnancy and 0.8% during the 1st trimester)
was less commonly used than in previous studies
(2% during pregnancy and 1-4% during the 1st
trimester). Only 33 women had dispensings for
clomiphene in the 1st trimester and 1-2% reported
using the medication in the 1st trimester in
previous studies.
*Am J Obstet Gynecol. 2004; 191:398-407.
**Am J Obstet Gynecol. 2011;205:51.e1-8.
^Pharmacoepidemiol Drug Saf. 2013;22:1013-8.
Conclusion: This is the first description of
commonly used prescription medications during
pregnancy from nationwide Medicaid data.
Previous descriptions of the most commonly
used prescription medications (i.e., not focusing
on specific classes) among pregnant women
in the US were based on maternal self-report
after delivery from volunteer-based studies (The
National Birth Defects Prevention Study and The
Slone Epidemiology Center Birth Defects Study)
and on claims information from private insurance
databases (The HMO Research Network).
Medication use during pregnancy is common
in the Medicaid population and prevalences of
use differ from previous studies. Some of these
differences may be attributable to the younger
maternal age distribution in the Medicaid
population (median age is 23). Antibiotics,
promethazine, acetaminophen/codeine, and
terconazole were commonly used in the Medicaid
population and appeared to be more common
than in previous studies. Lower levothyroxine use
in this population may reflect under-diagnosis or
lower prevalence of hypothyroidism. Clomiphene
is not reimbursed by Medicaid, so use is likely
underestimated in this study. Differences in
prevalences may be partially attributed to the
inclusion of certain routes of administration
and drug combinations in some studies but
not others. On one hand, we relied on drug
dispensing records rather than actual use and
may overestimate use. On the other hand, studies
based on maternal recall may underestimate
use, especially for specific medications (e.g.,
unspecified antibiotics vs. amoxicillin). Despite
the differences, antimicrobial/antibiotic,
antiemetic, analgesic, asthma/allergy, and
antidepressant medication use was common
during pregnancy in this study and in previous
studies. Identification of medications that are
commonly used by pregnant women enrolled in
Medicaid but have not been identified in previous
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populations is warranted to inform priorities for
studies of medication safety during pregnancy.
T 40
eCTD Submission Capability to FDA
for Academic Sponsor-Investigators:
Process, Problems, and Possibilities
E. Mitchell Seymour, PhD, RAC
University of Michigan Medical School
Objective: We describe the acquisition of eCTD
capability within an academic medical center. We
present both pros and cons from the perspectives of
academia, FDA, and industry. Information includes
obstacles to eCTD adoption and operational metrics
to support a business case for eCTD transition.
Method: This project was conducted at a
regulatory unit with 30+ IND/IDE submissions and
over 150 lifecycle submissions per year. Metrics
include labor and/or materials costs for eSubrelated document formatting, PDF remediation,
publishing (printing vs. eCTD assembly), and
materials and shipping costs.
Results: Sage Templates were used for MS Word
document authoring, Adobe PDF Maker was used
for PDF rendering, ISI Toolbox Pharma and PDF
Studio 8 were used for PDF remediation, LORENZ
docuBridge ONE was used for eCTD assembly
and publishing, and LORENZ eValidator was
used for validation. Metrics compared the paper
vs. eSubmission cost of lifecycle maintenance
submissions - an IND Annual Report and an
IND Amendment. Results confirm that for IND
lifecyle maintenance submissions, both labor
and materials costs favor the adoption of eCTD
capability in an academic environment. The use
of MS Word templates to author eCTD-compliant
PDFs is a critical component of the efficiencies
gained by electronic submissions.
Conclusion: To our knowledge, our institution
is the first academic unit to establish internal
eCTD submission capability for all of their IND
Sponsor-Investigators. Electronic submissions
can improve resource utilization for academic
clinical research. However, given the wide range
in quality and content provided by academic
study teams, significant medical writing effort
is needed to unify document formatting and
to build eSubmission-compatible documents.
As such, eSubmission-compatible MS Word
templates formatted to create compliant PDF files
are critical for eSub-related efficiencies. One or
two staff should be designated as the regulatory
publishers to maintain the unique skill sets and
expertise. High-volume academic regulatory
units like the one described here are equivalent
to big pharma in submission activity; eSubs can
yield operational benefits for managing a large
portfolio and for advancing medical innovation. In
an academic environment, lower cost and scalable
eCTD publishing and validation solutions like
LORENZ docuBridge ONE and LORENZ eValidator
are required to justify the initial eSub transition,
which may be slow and of lower volume. These
tools are also ideal for small business, freelancers,
and consultants who need an affordable and
scalable publishing solution. Finally, we predict
that alignment with industry submission practices
will favorably impact our interactions with both
FDA and industry and will enhance academicindustry partnerships. Other authors: Antoinette
Azevedo, Bill Reisdorph, Jeanne Wright, Mona
Moore, and Kevin Weatherwax.
T 41Integrating ISO and Relevant Industry
Standards to Improve Clinical Trial
Project Management Processes
Kathy Boardman, MS
VA Cooperative Studies Program
Objective: The objective of this work is to
integrate ISO and relevant industry standards
to improve clinical trial project management
processes by developing a synergistic framework
that supports the demands of large multicenter
clinical trials research while aligning with quality
management processes.
Method: We evaluated the use of ISO and
relevant industry standards in our organization’s
project management and quality management
systems to improve upon our processes and
to harmonize multiple standards to create a
synergistic framework that improves our study
design and management processes.
Results: The results of the evaluation by the
VA Cooperative Studies Program Clinical
Research Pharmacy Coordinating Center on
how to harmonize ISO 21500:2012 project
management requirements with ISO 9001:2008
quality management requirements identified
two key elements needed for synergistic results:
(1) Increase visibility and alignment with the
organization’s Work Breakdown Structure (WBS)
used in project scheduling and cost management
processes and (2) Increased awareness of Clinical
Trial Pharmaceutical Project Management as a key
process in both project and quality management
systems along with the other key processes
essential for service/product delivery. The
synergistic results included a Quality Management
System based on multiple ISO standards that is
transparent to the user, an increased visibility
of using the Work Breakdown Structure as a
framework for project management and quality
management activities, and increased focused on
developing a project management competency
framework to assure consistency in processes and
services. The organization’s quality and project
management cultures now have synergistic rather
than competitive alignment, leading to an overall
improvement of the Pharmacy Coordinating
Center’s Clinical Trial Project Management
Processes.
Conclusion: The results of the evaluation by
the VA Cooperative Studies Program Clinical
Research Pharmacy Coordinating Center on
how to harmonize ISO 21500:2012 project
management requirements with ISO 9001:2008
quality management requirements identified
two key elements needed for synergistic results:
(1) Increase visibility and alignment with the
organization’s Work Breakdown Structure (WBS)
used in project scheduling and cost management
processes and (2) Increased awareness of Clinical
Trial Pharmaceutical Project Management as a key
process in both project and quality management
systems along with the other key processes
essential for service/product delivery. The
synergistic results included a Quality Management
System based on multiple ISO standards that is
transparent to the user, an increased visibility
of using the Work Breakdown Structure as a
framework for project management and quality
management activities, and increased focused on
developing a project management competency
framework to assure consistency in processes and
services. The organization’s quality and project
management cultures now have synergistic rather
than competitive alignment, leading to an overall
improvement of the Pharmacy Coordinating
Center’s Clinical Trial Project Management
Processes.
T 42
Can Asia Help Expedite Cancer Drug
Development? Analysis of Three North
Asian Countries’ Potential to do More
Clinical Trials
NaRae Baek
Quintiles Transnational Korea Co., Ltd, Republic of
Korea
Objective: To determine if there is a disparity
among the incidence of a cancer, clinical trials
being conducted and the drug pipeline
To assess the availability of clinical trial sites
for the cancers that show significant untapped
patient pool for clinical trials in Taiwan, South
Korea and Japan.
Method: Data mining: Clinical Trial Intelligence
Database, Quintiles internal and publically
available data.Analysis of Cancer incidence; no. of
recruiting clinical trials currently; no. of molecules
in the oncology drug pipeline; available clinical
trial site pool in the countries.
Results: Country: Cancer; Incidence rates(ASR);
No. of multi country clinical trials; No of single
country clinical trials:
Taiwan: Breast; 62.38; 30; 0/ Lung; 32.17;57;0/
Colorectal; 37.55; 6, 0
S. Korea: Breast; 52.1; 20; 26/ Lung; 47.1; 29; 37/
Colorectal; 69.5; 8, 34
Japan: Breast; 51.5; 12; 165/ Lung; 24.6; 30; 318/
Colorectal; 32.2; 8, 235
France: Breast; 104.5; 33; 17/ Lung; 63.1; 80; 27/
Colorectal; 64.3; 30; 25
U. S: Breast; 92.9; 56; 342/ Lung; 67.8; 101; 225/
Colorectal; 42.5; 45; 135
Incidence Number: Lung 1,824,224; Breast
1,676,332; Colorectal 1,360,056
Site approved for clinical trials; sites with
capability/experience in oncology trials; top sites
based on location and patient pool:
Taiwan:74;35;22
S.Korea:164;74;26
Japan:7,806;168;34
Conclusion: Colorectal, breast and lung cancer
are the leading cancers globally and also show
a significant presence in North Asia. When
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comparing incidence rate (Age Standardized
Rate -ASR) and the clinical trial landscape within
a country, the number of CRC studies in S. Korea
& Taiwan is very low even though the incidence
rate for CRC is either higher or relatively close to
other cancers. In Japan & S Korea, a significant
portion of the clinical trials seem to be single
country trials, most likely due to a large number of
local drugs being developed and in early testing
or the small number of global trials conducted in
these countries being seem as ‘insufficient global
experience’. When compared to a mature market
like the U.S, the US shows a lot of on-going clinical
trials, but mainly single country trials, which could
potentially mean a lot of early phase testing.
Assessment of the available site pool shows
more than 100 oncology sites with capabilities
across S Korea and Taiwan alone, 48 with ‘good’
capabilities based on location and large patient
pool.
Given the disparity in the incidence rate, no
of clinical trials and huge site pool to tap into,
South Korea can potentially triple the number of
clinical trials, Taiwan even quadruple and Japan
too can take on more trials in CRC and contribute
significantly to global CRC drug development.
The potential for Breast and Lung cancer trials to
grow also remains strong in the region.
Taiwan, South Korea and Japan can also play
a potentially big part in the new trials that will
emerge from the drugs currently in Phase 1 &
Phase 2 development within the 3 countries itself.
Given the similarities in the ethnicity and the
acceptability of data by regulators in the three
countries, they could play a bigger role in the
clinical development of each local drug pipelines.
T 43Electronic Data Capture in Oncology:
A Review of Electronic Collection of
Patient-Reported Outcomes
Bhavini Srivastava, MS
Novartis Pharmaceuticals Corporation
Objective: The objective of this review is to
describe the feasibility of electronic patient
reported outcomes (ePROs) in studies and in clinics
in oncology settings, as well as investigate potential
benefits and challenges of using ePROs in oncology
clinical trials, by reviewing published studies.
Method: A targeted literature review was
conducted in Medline using a combination of
the following keywords: ePROs, electronic PROs,
patient reported outcomes, EORTC, FACT, and
cancer, oncology, chemotherapy, and outcomes.
Search was restricted to full text articles
published in English, in 2000-2012.
Results: The search yielded a total of 90 hits,
out of which 19 abstracts were related to ePRO
use in oncology. A total of 9 full text articles
were included in the review, which described
benefits, as well as, challenges of using ePROs in
oncology trials. Seven publications described the
feasibility and acceptability, patient preferences
and advantages of ePROs in oncology settings.
Three of these studies compared the mode of
equivalence between ePRO and paper PROs,
where PRO measures such as the FACT-G, EQ5D,
and the MDASI were used. Results from these
studies showed that there was no significant
difference in patient scores between the two
modes of PRO data collection. Furthermore,
the studies demonstrated greater patient
acceptability, ease of administration, and ease
of response in cancer patients using ePROs.
One study showed that ePROs were useful in
post-operative at home symptom monitoring
settings. One publication demonstrated that
ePROs were feasible and acceptable to patients
in clinic settings. Another study demonstrated the
electronic data collection method of collecting
PROs as a feasible method in patients recovering
from surgery due to gynecologic cancer. One
study showed that ePROs are useful in collecting
symptom and quality of life data in breast
cancer patients. Devices used to capture data
electronically in these studies included tablets,
e-diaries and smart phones. Demonstrated
benefits of using ePROs (reported in 7 studies)
included reduction of missing or inaccurate
information, increased accuracy of data capture,
meeting regulatory recommendations for
obtaining label claims, allowing data to remain
confidential, and real time monitoring of patients
for safety. Challenges of using this technology,
according to study results reported in two
publications, included increased training efforts
for site personnel and patients, and higher system
set up costs compared to paper PROs.
Conclusion: The results of this review identified
the growing use of ePROs in a variety of
settings for oncology patients. The studies
identified in this review demonstrated that ePRO
technology offers distinct advantages, such as
meeting regulatory recommendations, ease of
administration, patient acceptability, increased
accuracy of data capture, and mitigation of
issues such as missing data, and concerns with
confidentiality, which are common with paper
based PRO collection/administration.
T 44
Patient-Informed Clinical Trials: Cross
Sectional Survey on a Patient Powered
Research Network
Sally Okun, RN
PatientsLikeMe Inc.
Objective: To understand motivations, barriers,
and opportunities to enhance clinical trial
recruitment for patients with chronic disease
through a patient powered research network.
Method: In February 2014, 6,819 recently active
patients on PatientsLikeMe were invited to
complete a survey. Over two weeks, complete
responses were obtained from 1,621 patients
with MS, Parkinson’s, fibromyalgia, ALS, type
2 diabetes, epilepsy, rheumatoid arthritis,
depression, and lupus.
Results: Only 496 (31%) could recall being invited
to take part in a trial of any kind. Of these, 222
(45%) enrolled, took part and completed the
study. 82 (17%) were enrolled and taking part at
the time of the survey. 93 (19%) were ineligible
and 57 (12%) declined to take part. About one
in six patients (16%) “trial completers” who
had either enrolled or were still in a trial had
considered dropping out at some point. Reasons
included burdensome protocols, side effects, time
commitments, and financial reasons. Using the
Net Promoter Score, amongst trial completers
only around 57% would recommend that trial to
another patient and 13% would actively dissuade
others from taking part.
Across all participants the major drivers of
interest in a given trial were the opportunity to
improve their own health (84% rated as very
important), having their medical bills covered
if injured (84%), the reputation of researchers
involved (76%), the potential to improve the
health of others (74%), and getting the results
back after the trial had ended (73%). Factors
listed as less important included issues that are
commonly held to be bigger concerns, such as
issues around privacy and confidentiality (50%),
friendliness of staff (47%), number of visits and
time needed to participate (46%), the possibility
of receiving a placebo (37%), and the potential
of being paid to take part (16%). Most patients
(93%) would offer to help researchers improve
trials, such as by giving feedback on protocols,
outcome measures, recruitment materials,
and providing ongoing feedback during trial
participation.
Conclusion: Patient engagement in research
has been increasing in recent years, enabled in
part by digital technology and online patient
communities. Patients have the opportunity not
just to be subjects in trials but true partners in
research. Some groups such as the I-SPY cancer
trial and the OMERACT group for rheumatoid
arthritis measurement have successfully
harnessed the power of informed advocates
to improve their processes, make trials more
patient-centered, and ultimately achieve better
outcomes. To scale the lessons learned from
these pioneers, new tools are required to enable
consistent patient input in ways that can lead to
better decision-making. Patient powered research
networks appear to be particularly enriched for
patients who have either been in clinical trials
or who have a high degree of interest in taking
part in them. Therefore they may serve as a
useful venue to explore ways to optimize trial
design and operations by enabling researchers to
listen to patients’ concerns in a way that is fast,
repeatable, and with results that can generalize
to a broader population easier than individual
advocates or small focus groups. We identified
trends for differences between demographic and
disease subgroups that will be explored with a
larger sample size to enable the construction of a
“Trials Experiences Database” that can be queried
across a range of conditions. Furthermore we
intend to upgrade functionality to PatientsLikeMe
that would allow patients to be made aware of
trials for which they might be eligible, gain their
feedback on the decision-making process they
go through when deciding to enroll, and once
enrolled receive ongoing feedback about their
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experiences of being a participant to help trial
sponsors and researchers to optimize their clinical
operations.
T 45
Delivering Quality Systems Globally
Craig Burnett
Hospira
Objective: A North Carolina Life Sciences
Manufacturing Plant was looking for a way to
innovate and improve their Quality Systems while
reducing the total cost of ownership and risk.
Implementation needed to include Mobile iPad
access, dynamic form and streamlined dynamic
workflow along with updated manufacturing
execution document composition and data tools.
Method: Project began in 2011 with
implementation of Alfresco. Incremental
additions to Alfresco’s open platform at a costeffective pace have included add-ons for dynamic
form and workflow for change control along
with iPad access. Latest efforts have included
dynamic creation and electronic completion of
manufacturing batch records.
Results: Company was able to substantially
streamline process and improve user experience
at a cost-effective pace. Platform allows company
to continue to innovate on user experience and
leverage additional capabilities within a validated,
compliant environment. Solution is expanding to
additional manufacturing plants.
Conclusion: As a world class life science
manufacturing plant, the company was looking
for innovative ways to implement new interfaces
and improved processes for typical Quality
System initiatives around Document control.
Rather than selecting an older, legacy, proprietary
platform and vendor, in 2011, the successful
implementation of Alfresco has led to additional
successes for an improved user experienced
while insuring compliance with company quality
standards. The incremental implementation
approach was able to significantly reduce the
overall risk of the project both in regards of
timing and cost.
T 46
Creating Standard Analyses and
Displays for Common Safety
Assessments in Clinical Study Reports
Karolyn Kracht, MS
AbbVie Inc.
Objective: The objective of the project is to
provide recommended analyses and displays
(with associated code) for common safety
assessments, with a focus on Phase 2-4 clinical
study reports and integrated submission
documents.
Method: A cross-industry working group,
primarily of statisticians from the pharmaceutical
industry, has been formed and is creating several
white papers outlining recommended analyses
and displays.
Results: The working group has finalized a white
paper titled “Analyses and Displays Associated
with Measures of Central Tendency – Focus on
Vital Sign, Electrocardiogram, and Laboratory
Analyte Measurements in Phase 2-4 Clinical
Trials and Integrated Submission Documents”
and a white paper titled “Analyses and
Displays Associated with Non-Compartmental
Pharmacokinetics – Focus on Clinical Trials”. The
following four additional white papers are in
progress: 1) Analyses and Displays Associated
with Outliers or Shifts from Normal to Abnormal
– Focus on Vital Sign, Electrocardiogram, and
Laboratory Analyte Measurements in Phase
2-4 Clinical Trials and Integrated Submission
Documents; 2) Analyses and Displays Associated
with Adverse Events –Focus on Phase 2-4 Clinical
Trials and Integrated Submission Documents;
3) Analyses and Displays Associated with
Demographics, Medications, and Disposition –
Focus on Phase 2-4 Clinical Trials and Integrated
Submission Documents; and 4) Analyses and
Displays Associated with Hepatotoxicity –Focus
on Phase 2-4 Clinical Trials and Integrated
Submission Documents. Review of these white
papers is open to anyone interested in providing
feedback. (See www.phusewiki.org). Some
of the recommendations will be covered in the
poster for specific feedback by DIA attendees.
Building the Script Repository to support the
recommended analyses and displays is also
in progress and open to anyone interested in
supporting the effort.
Conclusion: Industry standards have evolved
over time for data collection (CDASH), observed
data (SDTM), and analysis datasets (ADaM).
Although substantial progress has been made,
additional standardization can improve product
development. Development of standard tables
and figures with associated analyses will lead
to improved product life-cycle evaluation by
ensuring reviewers receive the desired analyses
for the evaluation of patient safety. More
importantly, having an organized process for
shared learning of improved methodologies
can lead to earlier safety signal detection and
better characterization of the safety profile of
our products. Special acknowledgement to
Mary Nilsson, project lead and co-author, and to
members of the PhUSE Computational Science
Symposium Standard Scripts for Analysis and
Programming Working Group, White Papers
Project Team who have contributed to the white
papers, and to those who have provided review
comments.
W 01Evaluation of Operating
Characteristics of MMRM Analysis
Using All Available Longitudinal Data
at Interim Compared to ANCOVA
Weining Robieson, PhD
AbbVie Inc.
Objective: The objective of this simulation study
is to understand the operating characteristics
of ANCOVA and MMRM models using all
available data at interim analysis. Four different
longitudinal response scenarios, 3 dropout
profiles and 3 enrollment rates are examined.
Method: ANCOVA and MMRM were used to
analyze simulated longitudinal data with and
without including ongoing subjects at interim.
Type 1 error rates were examined in null cases.
Probability of claiming success and bias of point
estimates were assessed in cases where there
were treatment effects at endpoint.
Results: At interim, MMRM analyses with or
without data from ongoing subjects provided
more robust results than ANCOVA analyses.
MMRM models utilizing data from completed
and ongoing subjects increased the information
fraction for the analysis at interim compared to
using completers’ data only. For both MMRM
models, the information fraction at interim
decreased with the increase of dropout rate,
while the effect of enrollment rate on the
information fraction appeared to be small. In
scenarios that there is no treatment effect at the
study endpoint, the probability of erroneously
rejecting H0 at interim was similar for MMRM
analyses without and with ongoing subjects. In
scenarios that there is a treatment effect at the
study endpoint, the probability of rejecting H0
at interim (claiming success) was higher for the
MMRM model with ongoing subjects than without
ongoing subjects. The biases of treatment effect
estimate were similar between MMRM models
with or without ongoing subjects. ANCOVA
models had bigger bias of the point estimate
compared to MMRM models, especially if all
available data were used for interim analysis.
Conclusion: Regardless of longitudinal treatment
response scenarios, dropout rate and enrolment
rate, MMRM model utilizing all available data at
interim analysis consistently improves efficiency
without increasing bias of point estimates for
treatment effect.
W 02
Recent Developments in Scaled
Average Bioequivalence
Pascal Guibord, MSc
Algorithme Pharma Inc., Canada
Objective: A review of the recent developments
and its impact on the sample size, statistical
analysis and interpretation of the study results
will be presented. The impact of the type of
implementation, the regulatory constraints, the
study design, and the selection of subjects will be
evaluated.
Method: The 2 implementations of the scaling
approach (FDA, EMA) will be described and
compared. Data collected at Algorithme Pharma
will then be used to illustrate the diffrences in the
2 implementations and to show the reduction in
sample size resulting from it.
Results: A total of 455 studies conducted at
Algorithme Pharma evaluated under FDA or EMA
regulation were reviewed. Studies included in this
analysis were grouped in 3 types of design: 2x2
crossover (N=399), partial-replicate (N=19) and
full-replicate (N=37).
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Reference-replicated designs (partial or fully
replicated) represent two main benefits when
compared to the standard 2-sequence 2-period
crossover design (2x2). They allow the use of
the scaling approach for the assessment of
bioequivalence of highly variable drugs and,
as the reference is replicated, they require less
subjects to be exposed to the drug being tested
in order to achieve bioequivalence.
Results show that the sample size required to
prove bioequivalence does not increase as much
in reference-replicated designs than in a 2x2
crossover when the test-to-reference intrasubject coefficient of variation (ISCV) increases.
Linear trend lines clearly showing the differences
between the design types will be presented for
Cmax and AUCT. The studies included in this
analysis represent a wide range of ratio and testto-reference ISCV that are representative of the
variety of studies that are conducted.
Conclusion: The use of reference-replicated
designs is a more effective design than the 2x2
design when the drug is sufficiently variable so
that the sample size required becomes large.
The use of the scaling approach proved to be
also effective when the reference intra-subject
variability is high (>30%).
W 03An Overview of Both Current Best
Available and Next Generation of Drug
Therapies for the Treatment of
Depression
Annette Williams, MBA, RPh
Quintiles Inc.
Objective: Understand current state of play
regarding antidepressant therapy. Appreciate
role of side effects in patient non-compliance
with anti-depressants. Have an overview of
novel therapeutics in pre-clinical and clinical trial
studies.
Method: The methodology employed for this
research included a literature search of PubMed
with the key words ‘Novel targets for the
treatment of depression’, compared with Up-ToDate monographs of marketed antidepressant
medications and ADIS safety profile search of
specific antidepressants
Results: Ever since the development of the first
drug therapy for the treatment of depression,
prescribers, caregivers and companies have
struggled with issues of patient non-compliance.
These issues are due to a number of factors,
including non-responsive treatment groups
and the varied range of adverse drug reactions
associated with antidepressant treatments.
This paper aims to provide an insight into the
current best available treatments for depression,
focussing on: targets in the body, efficacy profiles,
safety profiles and current problems and solutions
for patient non-compliance. Furthermore, this
review will examine possible future treatments
for depression by looking at novel therapeutics in
pre-clinical and clinical trial studies.
Conclusion: It will attempt to determine whether
novel targets of treatment or more specific
targets of treatment could have an impact on
the safety profiles of antidepressant medication
without reducing its efficacy.
Overall, we will assess whether the next
generation of antidepressant treatments
will demonstrate superior safety profiles in
concurrence with efficacy profiles of similar or
superior value leading to better compliance and
overall improving the health of people suffering
with depression worldwide.
W 04
Health Literacy Assessment, Usability
Testing, and Revision of a European
Union Risk Management Plan Public
Summary
Karen Lockwood
Eli Lilly and Company
Objective: The authors assessed and performed
consumer usability tests (UTs) on an original
and revised version of a European Union
Risk Management Plan (EU RMP) public
summary with the goal of improving document
understandability and usability using best
practices in health communication and health
literacy.
Method: This 2013 study was conducted by
Health Research for Action (University of
California, Berkeley) and Eli Lilly and Company.
Assessment was performed using the Suitability
Assessment of Materials (SAM) tool. UTs were
conducted with American adults who had low-toaverage education levels.
Results: The original EU RMP public summary
scored 10/34 points (unsuitable) on the SAM. The
SAM testing showed that the text was written at
a college level, the context and purpose of the
document were unclear, the format and language
were complex, and little information was focused
on actions that consumers could take. Results
from the first round of UTs were aligned with
the SAM findings, highlighting common health
literacy issues, including problems with the
participants’ understanding of risk information,
difficult concepts, statistics, words, and medical
terms; reading dense text blocks; selecting key
points from text blocks; understanding tables;
and getting tired when struggling to understand
information.
Revisions to the EU RMP public summary
were necessarily conservative, constrained by
regulatory requirements for the document.
Revisions that were made within the regulatory
constraints did increase the document’s SAM
to 20/34 points (adequate). The reading level
was improved to a 9th-grade level, descriptive
introductions to sections helped to clarify the
context and purpose of the document, much
technical language and jargon were eliminated or
explained, and usability was improved somewhat
by placing more emphasis on consumer actions
where possible. Most of the revisions made
after the first round of UTs were successful in
improving its understanding and ease of use
in the second round of UTs. However, despite
improvements, participants still struggled to
read and understand parts of the document. The
focus on risks was concerning to participants,
and some did not seem to understand that risk
is an unavoidable issue for all medications. Other
inherently difficult concepts included potential
risks, unknowns, randomized controlled studies,
and risk frequencies.
Conclusion: The complexity of drug/device
risk information is of global concern, often
exceeding patients’ abilities to understand and
effectively act on it. Some best practices in
health communication and health literacy can
be incorporated into EU RMP public summaries
in order to improve document understandability
and usability . Recommendations that are both
effective and achievable without major policy
changes regarding the document scope and
structure include: adding introductory text to
explain the purpose and focus of each section in
lay language; referring consumers to other easily
understood and more comprehensive information
on the drug/device; using bullets to make the
text/tables easier to read; using frequencies
(e.g. 1 of 100 patients) rather than percentages
to express data; using consistent formatting for
tables; avoiding Roman numerals; and putting
headings, subheadings, and table titles in lay
language. However, the EU RMP public summary
contains many inherently complex concepts,
which can lead to misunderstandings. An
important, but more difficult, improvement would
be to clarify the context of the document, in order
to provide consumers with more guidance on how
to read and use it. Such a change would require
policy decisions from stakeholders, including
European regulators. If stakeholders would
consider making major changes to the document,
key recommendations would be to reassess the
intended use of the document by consumers
and to rethink its scope and structure, with close
involvement of patients and caregivers. A further
recommendation would be for stakeholders to
develop a template with input from members of
the intended audience(s), using usability testing
in an iterative fashion to produce a document that
is satisfactory to participants and that objectively
shows their understanding of the content.
W 05
Coordination of a Multi-site Cell and
Gene Therapy Study in an Academic
Medical Center: A Success Story
Bambi Grilley, RAC
Baylor College of Medicine
Objective: This initiative was designed to provide
an infrastructure to support the development,
implementation and conduct of a multi-site cell
and gene therapy protocol utilizing a product
manufactured at an academic medical center
under a Sponsor-Investigator Investigational New
Drug application (IND).
Method: A Memorandum of Understanding(MOU)
was developed and signed that outlined
regulatory and data management responsibilities
of the Academic Medical Center(PI) and a
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CRO. The MOU was sent to the Food and
Drug Administration(FDA) as part of the IND
submission to codify the roles and responsibilities.
Results: The study was submitted to the Office
of Biosafety Activities, National Institutes of
Health (NIH OBA) and the FDA by the Sponsor
Investigator and was allowed to proceed. The
study was ultimately submitted to and approved
by IRBs and IBCs at eight academic medical
centers within the United States. Conduct of the
study was overseen by a fully constituted Data
Safety Monitoring Board (DSMB). The study was
successfully activated in 2008 and a total of fifty
(50) patients were treated. The study was closed
to new patient entry in 2012.
Conclusion: The results of the study were
adequate to support further use of the product
under an Expanded Access Protocol. In fact, of
the 50 patients with severe, refractory illness
due to infection with EBV, CMV, adenovirus or a
combination of those viruses, the cumulative rate
of complete or partial response at six (6) weeks
post-infusion was 74% (95% CI, 58.5% - 89.5%)
for the entire group. Only four (4) responders had
a recurrence or progression. The product proved
to be a meaningful treatment alternative for these
patients. This regulatory approach proved an
efficient and effective way to expand the use of a
cell and gene therapy product to more than one
institution.
W 06An Innovative Way of Providing Timely
Responses to Questions Related to
Ingredients/Allergens
Irene Sheng, PharmD
Bristol-Myers Squibb Company
Objective: Approximately 85% of inquiries
related pharmaceutical properties of a product
are not addressed at the time of request at
Bristol-Myers Squibb. The objective was to create
and implement a customer-focused solution to
provide timely responses to questions related to
ingredients/allergens of products.
Method: With the assembly of the appropriate
team members cross-functionally (Global
Medical Information, Global Regulatory and Legal
colleagues), team developed a robust ‘realtime’ repository along with approved response
templates and work instructions.
Results: As a result of this project, a global
ingredient database is now available that covers
approximately 50 global brands. The company
enhanced customer experience by reducing
fulfillment time from an average of 2 weeks to
real-time delivery of information on a specific
ingredient for a product. Approximately 90% of
ingredient-related product inquiries can now be
addressed in real-time compared to the 15% that
was identified previous to the development of the
repository.
Conclusion: This innovative and streamlined
process meets the company’s business needs as
well as supports the needs of their customers by
allowing them to make informed decisions on
their health at the time they need the information.
The successes of this project support the
exploration of gathering other pharmaceutical
property-related information on the company’s
medicines, and have built a lasting and strong
partnership across the matrix.
W 07Evaluating and Supporting the
Increasing Patient Need for Delivery
of Clinical Trial Supplies Direct to Their
Homes
Esther Sadler-Williams, MPharm, MSc, RPh
Catalent Pharma Solutions, Inc., United Kingdom
Objective: The increasing global nature of studies
can result in long travel times to clinical sites for
patients which can compromise compliance thus
the objective was to explore options to support
the site and improve patient compliance through
delivering clinical trial supplies direct to patient
homes.
Method: An evaluation of documented patient
experiences in the literature and of an UK NHS
(National Health Service) organisation was
undertaken. Together we were able to derive and
implement regulatory compliant processes to
deliver Clinical Materials to direct to patients.
Results: Review of the available literature
confirmed that the actual number of sites that
participate in more than one clinical study is
not increasing. To increase the likelihood that
they remain in the study, patients themselves
are requesting that clinical trial supplies are
delivered direct to their homes where possible,
as a minimum for re-supplies. Setting this
requirement against the current cGMP/ cGCP
regulations provides a challenge as this direct
delivery of clinical supply medication to patient
homes is not possible and nor does the capability
exist in all countries worldwide. Working with
an National Health Service provider in the UK,
as well as sponsors, regulators and other third
party providers, it was possible to identify
various regulatory compliant possible distribution
pathways for many key global regions, including
the US where the situation is further complicated
by individual state laws. This methodology
increased the probability of patients complying
with the clinical protocol and streamlined the
(re)supply process. In more traditional models,
transportation by the patient from the clinical site
to the patient home may not utilize processes
to prevent temperature excursions. This is
apparent in more products that have cold-chain
requirements after the point of dispensing,
without supply of, for example cool bags for
patient transport.
Conclusion: With an increase in the number
of worldwide studies and with more clinical
protocols involving biologics coupled with the
increased pressure to recruit and retain patients
as well as optimize patient compliance, new and
innovative ways need to be found to optimize
the delivery of clinical supplies to patients.
Review of the literature and regulatory data
suggests that in certain countries opportunity
exists to ship clinical materials direct to patient’s
homes. Different distribution models can and
are being derived and employed to support this
which improves the overall patient experience,
supports their work life balance, and increases
the likelihood of patient retention and compliance
with the drug regimen and clinical protocol.
Additional Author: Dr Samantha Carmichael
MRPharmS
W 08New Business Acumen Tool Guides
Strategic Thinking: Learn How to
Increase Your Value to the Company
and to the Industry
Ilyssa Levins
Center For Communication Compliance (CCC)
Objective: Improve leadership agility and
performance by learning how to: articulate your
value to business partners; move from tactical
to strategic thinking; share best practices to
accelerate career advancement/contribute to
business success; and utilize an HBA/DIA tool for
career development.
Method: Strategic acumen and innovative
thinking are as important as technical expertise
for product development/commercialization.
When Regulatory, Legal, Medical and
Development think like the business, solutions
resonate with a company’s mission/goals. The
Business Acumen Tool addresses this need.
Results: It’s no longer enough to get a drug or
device through the approval process. Product
success is now based on reimbursement and
how new influencers, like payers and patient
groups, identify product value. Regulatory
affairs, medical, legal and clinical development
functions can support a company’s business plan
and product differentiation if they understand
how their business partners think. This includes
honing business acumen and executive presence
skills. The Business Acumen Tool focuses on five
parameters designed to help these functions
recognize, package and communicate their
value to the business from development to
commercialization. 1. Optimize the label to make
the strongest, most critical claims. At least
five years pre-launch, these functions create
meaningful product differentiation from key
competitors and the best way to design the
research to secure that claim. They carefully
consider product life cycle management,
including ways to replenish the pipeline; help
determine which data can deliver regulatory
exclusivity and support the patent life of the
product; and maximize regulator interactions
to secure the targeted product profile. 2.
Make the case for reimbursement. It’s critical
to design studies that demonstrate to payers
how innovative products are more valuable to
patients than existing therapies based on data
and labeling; how future competitive products
could impact the reimbursement status of a
product; which claim(s) would be most effective
at earning, and keeping reimbursement status.
3. Ensure commercial advantage in the face of
regulatory climate and health policy changes.
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Insights and expertise of medical and regulatory
affairs can help companies plan and prepare for
regulatory outcomes. 4. Develop effective and
compliant selling materials. It’s key to focus on
assessment of competitor labeling and shorten
review cycle time for promotional materials. 5.
Engender trust among external stakeholders.
Without these, the business cannot grow.
Conclusion: The pharmaceutical industry is
facing new challenges that require bold thinking
at this time of change. Leadership in Regulatory,
Legal, Medical and Clinical Development play
critical roles at a time when both compliance and
commercial excellence need to be prioritized.
That’s why honing skills like business acumen and
executive presence are so important for these
professionals. In this way, they manage risk and
help drive the business, from R&D to registration,
and through product promotion. Specifically,
regulatory, legal, compliance and medical
functions help their companies:
1. Exceed business objectives and financial targets
with clinical studies that differentiate products,
replenish pipelines and establish higher bars of
entry for competitors.
2. Enjoy a competitive edge by paving the
approval pathway for new indications in the
shortest amount of time through new evidence
generation strategies that deliver required data
for payer reimbursement.
3. Expedite entry into key emerging markets
through an intimate understanding of global
registration guidelines, approval processes and
more cost-effective ways to register products
and protect patents Optimize competitive
claims compliant with government regulations
to make marketing campaigns more effective
and durable.
4. Engender trust among key opinion leaders
and global regulators through proactive and
transparent communication about product
effectiveness and safety enhancing corporate
reputation which impacts purchase intent and
brand loyalty.
W 09
Complexity in Protocol Design: Does it
Lead to Better Clinical Trial Outcomes?
Rebecca Hummel
CNS Healthcare
Objective: Protocol complexity has increased
over the last fifteen years; however, it is
unclear whether this trend has led to better
trial outcomes. This is a follow up to our 2013
poster, examining more data and increasing
statistical power to explore the effect of protocol
complexity on trial outcomes.
Method: Data were collected from 73, phase
2 through 4, double-blind, placebo-controlled
clinical trials from 2002 to 2011. The trials were
assessed as successful or failed based on whether
there was statistically significant separation of
treatment from placebo on the primary efficacy
measure.
Results: A one-sided t-test was used to assess
whether the 2 groups differed on 3 measures
of study complexity: 1) the number of eligibility
criteria, 2) the number of site visits in the trial,
and 3) the total number of unique protocol
procedures. In our sample, there was no
difference between successful and failed trials on
the 3 measures of trial complexity.
Conclusion: Clinical trial outcomes may not be
benefiting from more complex trial design. Datadriven, more efficient trial design may strike a
better balance between containing clinical trial
cost and achieving successful trial outcomes.
Experienced research sites are in a unique
position to work as partners with sponsors to
optimize clinical trial design and improve trial
outcomes.
W 10
Corporate Integrity Agreement and Its
Impact on Industry
Abhishek Harde
Cognizant Technology Solutions Corporation, India
Objective: Understand the importance of
Corporate Integrity Agreement (CIA) and its
impact on pharmaceutical industry
Method: The study includes an establishment of
division to comply with various pharmaceutical
regulatory acts, enabling through IT / Technologies.
This includes but not limited to Sunshine Act, Safe
Harbor Act, PhRMA and FDA enforced off label
marketing regulations, Sarbans Oxley Act, etc.
Results: Successful execution of CIA
division within pharmaceutical company.
Governments around the world have created
laws and regulations governing our industry’s
operations, including the research, development,
manufacturing, marketing, promotion, and
distribution of pharmaceutical products. These
laws have a direct impact on daily work, and they
govern our interactions with patients, healthcare
professionals, researchers, customers, purchasers,
governments, and others.
Establishment of the division helped to make
right, better and smart decisions, in compliance
with CIA and pharma laws. Some of the aspects
include: maintaining patient safety,protecting
patient and customer privacy,conducting clinical
research and trials, interacting with HCPs and
other customers.
Social Networking and media communication,
laws governing international trade,Sunshine
Act,etc. Covering all aspects within
pharmaceutical company to ensure prevention of
any type of lawsuit/ infringement/ violations of
laws , best of the breed technology architecture
is developed with 3.0 technologies. The
technologies includes matrix collaborations
,artificial intelligence, Analytics and Big Data
platform. This architecture is the backbone for
executing the CIA laws and empowering the
division within the company.
Conclusion: Setting up a division for CIA and
improving the effectiveness by implementing
corporate regulations at federal and state level is
the need of an hour.This gigantic task is next to
impossible without enabling and applying world
class technologies to the CIA division. The case
study helps identifying the IT approaches for CIA
enabled division to achieve 100% compliance
from FDA and various regulatory agencies.
W 11Giving Clinical Trial Start Up A Project
Management Make-Over: Reducing
Cycle Times Through Critical Path
Focus
Ben Quartley, PhD
Covance Inc., United Kingdom
Objective: Fast clinical trial start up is essential to
finishing trial enrollment early, and this poster will
demonstrate how it is possible to deliver faster
start up timelines by treating start up as a project
and applying project management methodology
and processes.
Method: Beginning in midyear 2011, project
management methodology and processes have
been applied to global study start up, resulting in
a clear understanding of the critical path of the
start up project, and the development of effective
processes to reduce the critical path duration.
Results: The poster will provide illustrative
firsthand examples of the impact of successfully/
unsuccessfully optimizing the start up critical
path, and the factors involved. It will also
compare the firsthand examples to industry
start up process capability data to show the
quantitative advantage to be gained from
optimizing the critical path. It will show that
for two large international cardiovascular/
cardiovascular outcomes studies, successful
optimization of the critical path produced
start up timing in the 25 percentile of industry
performance, whereas unsuccessful optimization
produced start up timing in the 75 percentile. In
absolute terms, the difference was remarkable: at
the point where 80% of the sites were activated,
there was an 8 month difference between the
successfully and unsuccessfully optimized cases.
Finally, the poster discusses how this approach
can be used to educate internal and external
stakeholders as to the impact of common critical
path delays and ways to redesign processes to
eliminate these delays.
Conclusion: It has been shown in the research
covered by this poster that well-coordinated
teams can successfully streamline critical path
activities during site selection (especially
selecting sites for PSVs and making decisions
post-PSV) and site activation (especially budget/
contract approval and pre-booking of SIVs),
resulting in significantly shorter start up and
enrollment cycle times.
W 12
The Impact of Regulatory Reform in
Mexico on Pharmaceutical Product
Approval Rates
Raul Vinueza
Data-Pharma LLC
Objective: The objective of this study is to
describe the impact of the 2004 amendments to
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Article 376 of the General Health Law in Mexico
on pharmaceutical product approval rates.
Method: We compiled and analyzed product
approval records from Mexico’s regulatory
authority (COFEPRIS) for the years 2001-2013.
Metrics of interest included product approvals per
year, total number of manufacturers obtaining at
least 1 approval, and central tendency values for
approvals per firm.
Results: The data shows a rapid decline in the
rate of product approvals from 2005 onwards.
From 650 products gaining approval in 2004,
the approval rate decreased by over 70% in the
following 6 years. The number of firms obtaining
approvals exhibits a similar pattern, declining
from 222 firms in 2004 to a low of 71 firms in
2010. Lastly, the data shows a consistent pattern
across time for the number of registrations
obtained by the typical firm. Over 75% of firms
obtained less than 6 approvals each year, and
about 50% of firms obtained less than 3 approvals
each year.
Conclusion: As Schmidt (2005) suggested,
the amendments in 2004 were designed in
part to address the problematic growth of the
pseudo-generics market in Mexico that had
resulted from a regulatory loophole that allowed
manufacturers to market off-patent products
without proving bioequivalence. Previously,
product registrations were valid indefinitely, but
with the new law in effect, firms are required
to renew their registrations every 5 years. The
costs and regulatory hurdles associated with
renewing product registrations every 5 years
under increasingly stricter requirements was
predicted to have a deterring effect on sub-par
manufacturers and pseudo-generic products
planning to enter the market. The results provide
evidence of a significant slowdown in the rate of
firms and products entering the market. Since
the product registration patterns for the typical
manufacturer did not change significantly over
time, the decrease in total approvals can be
largely attributed to more firms either failing
to meet requirements or opting to not register
more products. Presumably, the subset of firms
that are continuing to register products are the
ones that have robust quality systems in place to
continuously meet regulatory standards. Given
the evident decrease in approvals, further studies
are needed to ascertain how much of this trend
is the direct result of low-quality generics being
deterred from entering the market.
W 13
So How DO You implement eSource:
Practical Tips for Enhancing Efficiency,
Data Visibility, and Site Interactions
Ed Seguine, MBA
Clinical Ink
Objective: To provide practical tools for adopting
electronic Source as your method for collecting
clinical trial data.
Method: It is critical to re-evaluate current
processes that were developed based on using
paper in clinical trials. We have conducted
this evaluation and have developed specific
processes designed to conduct completely
paperless trials using electronic Source.
Results: We will provide examples of specific
process changes that are required to move from
paper or EDC to electronic source/ These include
changes in monitoring from administrative roles
to analysis and intervention. We will also show
how data management’s role also changes to
provide more comprehensive reporting of all Risk
Based Monitoring Domains. We will also provide
examples of changes in workflow for start up and
close out to shorten timelines.
Conclusion: Technology can provide tremendous
opportunities for enhancing trial efficiency but a
careful assessment and modification of current
processes is required to take full advantage of
new technology. A change management model
can assist in assuring that processes, training, and
role descriptions are aligned to result in optimal
technology utilization.
W 14
Duloxetine Feeding Tube Study:
Medical Information Example of
Collaboration with Laboratory
Scientists to Deliver Answers.
Andrew Buchanan, RPh
Eli Lilly and Company
Objective: To demonstrate Global Medical
Information (GMI) collaboration within GMI and
with laboratory scientists to investigate and
develop answers to frequently requested Health
Care Practitioner (HCP) questions.
Method: GMI identified a common HCP question
of duloxetine administration through feeding
tubes (>200 requests/year) with no optimal
answer. GMI partnered with laboratory scientists
to develop a protocol to mimic clinical practice
and record observations of duloxetine delivery
through feeding tubes.
Results: Although participation in the design/
implementation of a study is not typical for GMI,
a collaborative effort was helpful to design the
study taking into account typical clinical practice.
GMI wrote the study protocol, in accordance
with published literature and consultations with
experienced nurses and scientists, which was then
accepted by the laboratory scientists. The primary
study objective was to determine whether the
intact pellets from a duloxetine 60 mg capsule,
after being mixed in apple juice or water and
injected into feeding tubes, would visually adhere
to and/or physically obstruct nasogastric (NG)
tubes (14 French silicone and polyurethane) or
gastrostomy tubes (G-tubes) (20 French silicone).
Apple juice (pH ~3.5) was chosen as a vehicle
because previous data had demonstrated stability
in this acidic liquid, and sterile water for irrigation
was chosen because water is often used as a
vehicle for administration of medications through
feeding tubes in clinical practice.
Study results showed that the majority of
duloxetine pellets accumulated in the junction
between the tip of the administration syringe
and the entry point of the feeding tubes, and
remained there even after flushing. Similar
patterns were observed for each of 3 tube types,
and with both apple juice and sterile water for
irrigation. A summary of these study results was
summarized in a medical letter, which is now
provided to HCPs in response to unsolicited
questions which continue to present on this topic.
Conclusion: From the results of the laboratory
study, we concluded that administration of
duloxetine pellets through either NG tubes or
G-tubes was shown not to be a dependable
method for delivery of duloxetine. The
accumulation of pellets in the tubes prevents
accurate dosage of duloxetine to patients.
These in vitro study data complement published
literature on the administration of enteric-coated
medicinal products through feeding tubes, much
of which discourages this practice due in part to
risk of tube obstruction.
Overall, these results demonstrate the impact of
cross-functional collaboration to propose and
implement practical solutions in order to create
meaningful responses for HCPs. In this particular
example, by collaborating within GMI, we were
able to capture an unmet customer need with
potential significant patient impact. We were then
able to assimilate expertise and partner crossfunctionally to research and deliver an answer,
albeit with limitations, which is meaningful,
readily available, and helpful to HCPs for making
clinical decisions.
The initiative describ
ed here serves as an example of how important
customer needs can be captured and resolved
as a result of successful, non-traditional
collaborations, which can ultimately and most
importantly benefit patients.
W 15
Targeting the Best Sites with an
Analytical Site Selection Model Using
Multiple Metrics
Elizabeth Nielsen
Quintiles Inc.
Objective: We determine the best sites for a
clinical trial by creating a data-driven score based
on multiple site and investigator metrics and
analytically ranking each site compared to other
sites.
Method: Through collaboration with multiple
departments, we identify and gather metrics
from each site to define and explain positive site
characteristics and determine which metrics are
the most helpful in quantitatively explaining the
variations between sites.
Results: The best sites are those which have
the highest patient enrollment, the fastest
cycle times and the fewest quality issues. Site
metrics are grouped into three categories:
patient enrollment, cycle time metrics, and
protocol and GCP compliance. Each category is
analyzed using Principal Components Analysis
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(PCA) to determine the optimal weighing of
each metric. After the weights are determined,
a linear combination of site metrics is created
for each site and thereby establishing a specific
score in each of the three categories for each
site. Additionally, the three categories can be
weighted to put more emphasis on one or more
categories, perhaps at the request of the sponsor.
Scores for one site can be directly compared
to other site scores, where a higher score is
more positive. The site scores can be ranked to
delineate top, middle, and low tiers of ranked
sites and filtered to determine the best sites
within a country or region.
Conclusion: We can use this site selection model
to help determine the best sites for a specific study
within each country. A site can be analytically
chosen for a study based on known attributes.
This allows for a data-driven approach to site
selection established from multiple attributes of
a site and principle investigator, thus enabling
the CRO and sponsor to choose a site based on
more than one aspect of site performance. The
model quantifies these attributes and creates
a score and ranking for each site. This score
encompasses multiple attributes but condenses
the information into one quantifiable number.
The ensuing score is straight-forward and easily
understandable, allowing for direct comparison
of sites. The model results can be a strong guide
for an experienced user who is familiar with local
and regional differences. In this manner, optimal
sites are selected for a specific study to insure a
higher probability of successful study participation,
faster and higher enrollment, and robust study
completion.
W 16
Central Recruitment Methodologies in
a Global Clinical Research Study of
a Pediatric Autism Spectrum Disorder
(ASD) Program
Allan Spera
Forest Research Institute
Objective: To review the recruitment strategies
resulting in a rapid enrollment into a program
of global investigational drug trials of the core
symptoms of autism in children aged 6-12 years
old with ASD, and to examine the characteristics
of subjects identified through central patient
recruitment.
Method: Study-branded media and educational
outreach strategies were used. Patients were
referred to a study site after pre-qualifying via the
study website or call center. Patient sources and
their demographics were tracked and analyzed to
enable an effective execution of the outreach.
Results: From 2004-2013, the total number
of both Untitled Letters and Untitled Letter
Violations has exceeded the total number of
Warning Letters and Warning Letter Violations.
The average number of Violations/Warning Letter
slightly exceeds the average number of Violations
in Untitled Letters (2.9 vs. 2.5). In the first half of
the assessment (2004-2008), the ratio Untitled/
Warning Letters issued was relatively equal;
however, the Untitled/Warning Letter ratio has
significantly increased by a ratio of 4:1 in the
years 2009-2013.
Conclusion: The Office of Prescription Drug
Promotion is responsible for surveillance and
enforcement of the Code of Federal Regulations
in prescription drug promotion. Many factors
determine whether OPDP issues a company
in violation of these regulations an Untitled
or Warning Letter. Indeed, we know OPDP
utilizes a risk-based approach to help guide
them on the issuance the violation letters.
From 2004-2013, OPDP issued more than 250
different enforcement letters to industry. Our
assessment found most enforcement letters
issued to industry during this time period were
Untitled Letters. Moreover, the ratio of Untitled/
Warning Letters has increased significantly in
the last couple of years. This observance may be
attributable to: increased industry awareness/
education, an increased understanding by
industry of previous OPDP enforcement actions.
Additionally, we also observed a slightly greater
number of violations per Warning Letter vs.
Untitled Letter which was relatively consistent
over the studied period.
W 17Evaluation of Shipping Systems to
Maintain Sample Integrity in Clinical
Research
Mona Vimal, MSc
Gilead Sciences, Inc
Objective: Evaluate ambient and refrigerated
shipping systems which effectively maintain
biological integrity of human blood samples
during overnight shipments.
Method: Six shipping containers were evaluated.
Human blood from 5 healthy donors was
shipped within 24-48 hrs after draw in 5 separate
shipments. The performance of each shipping
container was evaluated by assessing the
temperature and status of biomarkers using an ex
vivo whole blood assay with ELISA
Results: Three ambient (Therapak Category B
Ambient; Thermosafe ambient; World Courier
ambient) and three refrigerated systems
(NanoCool™; Credo® by World courier; GTS-35 by
Cold Chain) were evaluated.
from -4°C to 34°C. The temperatures at high or
low extreme end lasted 5 minutes to 6 hours in
some containers. The results of the ELISA assay
indicated that the extreme temperatures in the
shipping containers had impact on the sensitivity
of the biomarker measurements. Compared
to the ambient systems, refrigerated systems,
mainly the Credo® container, was able to maintain
temperature from 2-8°C during shipping relatively
consistently. The results of the ELISA assay from
blood shipped within 24 hours showed that
the sensitivity of blood to ex vivo stimulation
was relatively well maintained in refrigerated
containers compared to ambient containers.
Conclusion: Clinical research samples play an
integral role in drug discovery and development
process. The stability and biological integrity
of clinical samples has a significant impact on
biomarker results. Therefore, the selection of
an effective and suitable shipping method is
critical. Based on the study conducted, we found
that performance of the shipping containers did
not always match the manufacturer’s validation
specifications. Prior to selecting a shipment
system for a clinical program, it is recommended
that a series of well-designed mock shipments
be conducted to validate the shipping system
against the documented performance. In
general, ambient shipping containers were
not found to hold temperature during the
24-48 hour shipment. Among the refrigerated
systems, temperature was consistently held per
manufacturer specifications in two of the three
shipping containers. Temperature excursions
affected assay results, which concurred that
sample integrity is crucial during shipment
process.
Depending on the scope of the clinical program,
shipping method selected should also take into
account the subsidiary factors like availability
of the courier service, laboratory requirements,
feasibility of scale up, cost, and site logistics,
such as convenience and storage space at clinics.
Authors: Hui Wang*, Anita Reddy*, Patti Butler**,
Olga Acosta**, Mischa Hepner* and Mona Vimal*
*Gilead Sciences, Inc., Foster city, CA **SeaView
Research, Inc., Miami, FL
Performance was evaluated by assessing
temperature during shipping and status of
biomarkers using an ex vivo whole blood
stimulation assay with a commercially available
ELISA. Study design accounted for variables
like sample donor, shipment hold time, and
ambient versus refrigerated shipping conditions.
Performance of each shipping container was
validated against temperature logs and assay
results.
W 18A Comparison of MedDRA SMQs
Relative to Individual Preferred Terms
for Signal Detection on a Large
Insurance Claims Database
Christopher Bone
GlaxoSmithKline, United Kingdom
Objective: The objective of this study is
to compare the signal detection ability of
Standardised MedDRA Queries (SMQ) against the
individual Preferred Terms (PT’s) contained within
the same SMQ in order to determine the potential
value and dangers of using aggregate terms.
The specified temperature range per
manufacture’s specifications in ambient
containers is 15-25°C and in refrigerated
containers is 2-8°C. Our study results indicate
that the temperature in ambient containers varied
Method: A large US administrative health claims
database (Commercial Claims and Medicare;
130 million records) was used to data mine four
previously identified drug-event pairs. Relevant
MedDRA SMQ’s were selected and the aggregate
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signal score (screening rate ratio) was compared
against individual PT’s.
Results: Four drug-event combinations for
three drugs that received either a black-box
warning or FDA alert were evaluated for signal
scores (screening rate ratio, lower bound 95%
confidence interval) using a commercially
available observational data source. The
preliminary results of the comparisons indicate
that an aggregate signal score as provided by
an SMQ generates a lower signal score than a
relevant preferred term. The signal score for
Varenicline and the preferred term ‘depression’
was 80% higher than the ‘depression and suicide/
self-injury’ SMQ. The signal score for Celecoxib
and the preferred term ‘myocardial infarction’
was 84% higher than the signal score for the
SMQ ‘myocardial infarction’. The signal score for
Celecoxib and ‘gastrointestinal haemorrhage’ was
8% higher when using the preferred term than the
‘gastrointestinal’ SMQ. Telithromycin had a 25%
higher signal score for the preferred term ‘liver
disorder’ as compared with the SMQ ‘drug related
hepatic disorders’.
Conclusion: This research sought to determine
the potential value of looking at aggregate terms
(MedDRA SMQ’s) as compared to individual PT’s
as well as identify potential dangers of using
aggregate terms. The results from this study
suggest that use of MedDRA SMQ’s in signal
detection potentially risks suppressing a signal
and delaying detection. MedDRA SMQ’s aim to
improve characterisation of a disease or area
of interest however their application in signal
detection may be limited as the aggregate SMQ
score is suppressed by other events in the SMQ
when the actual PT term for the event is elevated.
Due to the broad selection of PT’s in an SMQ it
is also possible that an artificial increase in SMQ
signal scores could occur if a less important term
significantly influences the signal score relative
to more relevant terms. Further research might
consider examining the threshold for SMQ signal
scores in light of the broad selection of terms and
the objective of characterising a disease area over
detection of a specific drug-event pair.
W 19Introducing and Conducting
Traditional Chinese Medicine Trials
in the US: Challenges, Obstacles, and
Potential Solutions
John Li, MD, MBA
ICON Clinical Research
Objective: To review the status, trend of TCM
related trials in Clinicaltrials. gov , their presence
in different countries and regions, and therapeutic
areas in US trials and identify common challenges
and obstacles in introducing, designing, and
conducting TCM trials in the US.
Method: Used Traditional Chinese Medicine
(TCM) as the search term to search clinicaltrials.
gov on two separate dates; 25-Jan-2013 and 22Aug-2013. The status of trials arereviewed. Based
on our experience and literature research, we
identified challenges in designing and conducting
TCM trials in the US.
Results: As of 25-Jan-2013, searched clinicaltrials.
gov with term of TCM, the authors identified 300
TCM related clinical trials; as of 22-Aug-2013, the
authors identified 341 TCM trials, which include
ongoing and completed trials. Among these
trials, top ten countries/regions of having TCM
trials are China, US, Taiwan, South Korea, Hong
Kong, Germany, Singapore, Brazil, Italy, and
Canada. The presence of TCM trials in country/
region are summarized Among the 300 trails
on 25-Jan-2013 and 341 trials on 22-Aug-2013,
China had 141, 168 trials, United States had 47, 47
trials, Taiwan had 27, 29 trials, South Korea had
22, 22 trials, Hong Kong had 15, 16 trials, Germany
had 6, 6 trials, Singapore had 4, 5 trials, Brazil
4, 5trials, Canada had 2, 3 trials, and Italy had 2,
2 trials respectively. Among the 47 trials in the
US, 16 (35%) trials are for oncology; 14 (29%)
trials are for neurology/pain/psychiatry; 8 (17%)
trials are for inflammation/infection; 5 (11%) trials
are for internal medicine; and 4 (8%) trials are
for others (allergy, obesity, and would healing).
According to our experience of designing and
conducting TCM trial in the US and literature
reviews, we identified and summarized the
common challenges/obstacles and appropriate
approaches to overcome these challenges/
obstacles. Challenges/obstacles are, 1) Individual
treatment as common practice for TCM therapy;
2) insufficient safety data for IRB approval; 3)
Cultures difference and communication barriers;
4) Limited acceptance of TCMs for subjects in
US. The potential solutions are 1) Standardize
the prescriptions in TCM development; 2)
Substantial mentoring the sponsor as early
as possible for IRB approval process and
requirement; 3) Identification and implementation
of ideal staffing and increased the face to face
meetings; and enhanced Technology for effective
communication and information sharing; 4)
Educate the target population through poster,
newspapers, advertisement, etc.
Conclusion: Collaborating with TCM companies
based in China to conduct clinical trials in the
US provides the unique opportunity for CRO to
obtain the valuable experience of developing
TCMs. Different practice for TCM therapy,
sponsor’s insufficient safety data, culture
difference and language barriers, and the
subject’s limited acceptance are the main critical
challenges for conducting TCM trials in the US.
Be aware of these challenges and implementing
appropriate approaches are imperative for the
success of TCM trials in the US.
W 20
Coherence of Observed-toExpected Disproportionality Methods
Used for Pharmacovigilance at a
Critical Threshold
Geoffrey Gipson
Janssen Pharmaceuticals, Inc.
Objective: The purpose of this research was
to demonstrate the insensitivity of signal
detection to the observed-to-expected (OE)
disproportionality method selected when the
often applied critical value of 1.0 is used.
Method: This work extends upon previous work
(Gipson 2012) which demonstrated that many
popular disproportionality methods can be
calculated from a common equation. Monte Carlo
methods for statistical distribution estimation
were performed to demonstrate the logical
consequences of the shared equation.
Results: Much attention and discussion in
the scientific literature has been focused on
the relative merits of individual calculations
belonging to a large class of methods
often referred to as observed-to-expected
disproportionality methods. Frequently debated
topics in the Pharmacovigilance (PV) community
include: confidence interval calculations;
selection of signaling criteria and method
performance; treatment of small observed case
counts; and stratification. Here, we demonstrate
a method of interpreting observed-to-expected
disproportionality statistics which synthesizes
findings across the various sub-methods.
Specifically, we estimated the distributions of the
disproportionality statistics through a Monte Carlo
simulation where each of the variables in the 2x2
contingency table was modeled as a Poisson
variable. The specific advantages of this method
are: simple method for calculating confidence
intervals; identical cumulative distributions at
the often used critical value of 1.0; a natural
handling of small case counts without additional
applied shrinkage; straightforward extension of
calculations for handling stratification.
Conclusion: There are many different methods
of calculating disproportionality available
for identifying drug-event pairs in safety
reporting databases. There are ongoing
discussions in the PV community about what
is the most appropriate method to measure
disproportionality. This research demonstrates
the insensitivity to method selection if a critical
value of 1.0 is selected for the lower bound of the
confidence interval. Effectively, this means that,
if we define a signal as a significant deviation
from and observed-to-expected ratio of 1.0, all OE
methods give you the same result. This greatly
simplifies the interpretation of the statistical
results across the various methods and should
provide PV practicioners with additional clarity
when considering method selection. This work
is an attempt to start building a framework
for the simultaneous interpretation of multiple
disproportionality statistics, instead of viewing
the various methods as “in competition.”
W 21Enhancing Project Management
Tracking to Facilitate the Protocol
Development Process
Tracey Miller
Leidos Biomedical, Frederick National Labs
Objective: Develop a project management
tracking tool for the National Institute of Allergy
and Infectious Diseases (NIAID) Protocol
Navigation/Protocol Development Program
(PN/PDP) to evaluate milestones and manage
project logistics throughout the research protocol
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development and approval phases.
Method: Process steps, milestones, and key
performance indicators were identified using the
Six Sigma approach. These were integrated into
a PN/PDP-specific workflow. Using the PN/PDP
workflow, milestones and steps were aligned to
create the PN/PDP-specific project management
tracking module.
Results: Logistics were initially tracked in
spreadsheets. The growth of the PN/PDP protocol
portfolio mandated a comprehensive, searchable
PN/PDP-specific tracking module that supports
the methodical documentation of activities. The
resulting module reflects the PN/PDP’s efforts to
efficiently and effectively manage the protocol
development process.
The module workflow has 9 milestones and
8 activities that a protocol may require as it
is developed from concept to approval. The
workflow is tailored to the projected services
needed per protocol. The protocol progresses
through the determined milestones as triggered
by the completion of specified activities.
The tracking module optimizes management of
each protocol in development and enables the
measurement of overall program performance.
Specifically, it allows the PN/PDP team and
management to:
• Identify operational needs, required resources,
and timelines at project initiation. Metrics can be
extracted, allowing for visual displays of protocol
status, staff assignments, and comprehensive,
detailed project overviews.
• Generate PN/PDP metric reports which display
current and planned activities needed for each
protocol and its current status in the workflow,
staffing assignments, and other program metrics
(e.g., NIAID scientific lab, protocol type). Reports
can be generated by protocol as well as by
overall PN/PDP protocol portfolio. The project
manager can quickly identify the protocol status
at any given time and the activities remaining
for project completion.
• Communicate with the NIAID intramural
Regulatory Compliance and Human Subjects
Protection Branch (RCHSPB) offices.
Notifications are distributed automatically to
applicable personnel when targeted milestones
have been achieved that may require action
within their departments. This streamlines the
development process by keeping all applicable
departmental requirements and deadlines
transparent throughout the project.
Conclusion: Preparing a compliant research
protocol can be daunting for investigators.
Regulatory review processes are often complex
and multi-departmental, and are perceived as
barriers by research staff. Furthermore, given
the current uncertainty of research budgets, it
is imperative that programs track milestones
and key performance indicators to streamline
processes and optimize program performance.
The PN/PDP, in support of NIAID, identified the
need for a project management tracking module
to facilitate its mandate of delivering early
interventions in protocol development, managing
administrative and regulatory requirements, and
providing writing support.
Integrating the PN/PDP module into the database
already in existence to track protocols under the
sponsor’s purview and personalizing it for the
PN/PDP represented a cost-savings approach.
The module is a valuable project management
tool that provides a dashboard of program
metrics that can be used for program reports,
planning, interdepartmental communication,
decision-making, and publications.
This research was supported [in part] by the
National Institute of Allergy and Infectious
Diseases. Funded by the NCI Contract No.
HHSN261200800001E.
W 22
Continued Tradition of Success: Critical
Components of the Genzyme/Sanofi
Oncology/MCPHS University Post
PharmD Fellowship
Christina Gallagher, PharmD
MCPHS University
Objective: To evaluate various components of
the Genzyme/Sanofi Oncology/MCPHS University
Post-PharmD Fellowship program and determine
which factors are essential to ensure postfellowship success.
Method: Electronic surveys were administered
to all current Genzyme/Sanofi Oncology/MCPHS
University Post-PharmD Fellowship program
leaders (n=8) and fellowship alumni (n=16);
participants were asked to identify factors that
they felt translated into success post-fellowship.
Results: Electronic survey results were collected
from 88% (14/16) of fellowship alumni (graduates
from 2005 – 2013) and 62% (5/8) of current
program leaders. Of the fellowship alumni who
completed the survey, 71% (n=10) received a
job offer from Genzyme or Sanofi Oncology
upon completion of their fellowship. Ninetythree percent (n=13) of alumni fellows surveyed
agreed or strongly agreed that the type of work/
projects completed during their fellowship were
critical to post-fellowship success and 43% (n=6)
identified this as the single most important
component. Other identified factors attributing
to post-fellowship success included professional
development training (n=12; 86%), networking
(n=11; 79%), mentorship (n=11; 79%), and the
program leader (n=10; 71%). Alumni reported that
the least important component for success was
the presence of PharmDs in their department
(n=3; 21%). Alumni also noted in the comments
section that experiences at scientific congresses,
direct communication with thought leaders,
and public speaking/presentation opportunities
contributed to post-graduate success. Program
leaders’ responses were similar: 60% (n=3)
felt that the type of work/projects fellows
completed was the most important indicator of
post-fellowship success, followed by rotational
structure and networking (n=1; 20% each). Forty
percent (n=2) of program leaders felt that the
presence of PharmDs within their department
contributed least to post-fellowship success.
Additionally, when asked for suggestions to
improve the program, program leaders indicated
that networking between co-fellows and greater
involvement from the academic affiliate, MCPHS
University, would provide more opportunities for
collaboration and learning for fellows.
Conclusion: The purpose of the Genzyme/
Sanofi Oncology/MCPHS University Post-PharmD
fellowship program is to provide a comprehensive
experience for Doctor of Pharmacy graduates
within the biopharmaceutical industry. Survey
responses were collected from fellowship
graduates and program leaders of the clinical
supplies/investigational products, global
pharmacovigilance and epidemiology, global
medical affairs, and regulatory affairs programs.
Alumni and program leaders of the fellowship
agree that the type of work/projects fellows
complete, professional development training,
networking opportunities and mentorship are
critical program components and important
factors for post-fellowship success. Although
most program leaders hold a PharmD, alumni
reported that the presence of PharmDs in their
respective departments was of little importance
to post-fellowship success. In an effort to provide
a well-rounded fellowship program and maintain
the tradition of success for post-fellowship
graduates, program leaders will continue to
strengthen the program by elevating the type of
work/projects offered to fellows and providing
additional networking opportunities and
heightened mentorship
W 23Assessment of Violations Cited by
OPDP in Untitled and Warning Letters
Issued from 2004-2013
Phil Reveal
Meda Pharmaceuticals, Inc
Objective: To assess the number of violations
cited by OPDP in Untitled Letters and Warning
Letters enforced from 2004-2013.
Method: We assessed enforcement letters found
on the FDA website from 2004-2013. From each
Untitled and Warning Letter, the following was
evaluated: number and types of enforcement
letters from OPDP/year, number of violations
cited in each enforcement letter, average number
violations/letter per year.
Results: From 2004-2013, the total number
of both Untitled Letters and Untitled Letter
Violations has exceeded the total number of
Warning Letters and Warning Letter Violations.
The average number of Violations/Warning Letter
slightly exceeds the average number of Violations
in Untitled Letters (2.9 vs. 2.5). In the first half of
the assessment (2004-2008), the ratio Untitled/
Warning Letters issued was relatively equal;
however, the Untitled/Warning Letter ratio has
significantly increased by a ratio of 4:1 in the
years 2009-2013.
Conclusion: The Office of Prescription Drug
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Promotion is responsible for surveillance and
enforcement of the Code of Federal Regulations
in prescription drug promotion. Many factors
determine whether OPDP issues a company
in violation of these regulations an Untitled or
Warning Letter. Indeed, we know OPDP utilizes
a risk-based approach to help guide them on
the issuance the violation letters. From 20042013, OPDP issued more than 250 different
enforcement letters to industry. Our assessment
found most enforcement letters issued to industry
during this time period were Untitled Letters.
Moreover, the ratio of Untitled/Warning Letters
has increased significantly in the last couple of
years. This observance may be attributable to:
increased industry awareness/education, an
increased understanding by industry of previous
OPDP enforcement actions. Additionally, we also
observed a slightly greater number of violations
per Warning Letter vs. Untitled Letter which was
relatively consistent over the studied period.
W 24Accelerating Patient Recruitment
Using In-Depth Market Research
Insights: Collected via a 3rd Party From Clinical Trial Site Staff
Jeff Jamer, MBA
Merck & Co., Inc.
Objective: This abstract demonstrates the power
and efficiency of in-depth market research
insights, implemented through partnering with
a third party, from investigators (PIs) and study
coordinators (SCs) to transform patient trial
enrollment in a severely delayed study.
Method: 2 phases of telephone interviews (TIs)
were conducted with PIs and SCs to i.d. barriers
to pt. recruitment and develop action plans to
implement. Phase 1, i.d. barriers by conducting
45-min TIs with PIs and 90-min TIs with groups of
3 SCs. Phase 2 conducted similar TIs to evaluate
possible actions.
Results: The number of patients screened and
randomized were collected weekly before, during
and after the interviews were conducted and
recommended actions implemented. Prior to
the commissioning of the work outlined, patient
recruitment for the clinical trial was projected to
require 3 ½ more years. Following completion
of the interviews and implementation of the
recommended actions, patient recruitment for
the clinical trial was projected to require only 1
¼ years, a savings of more than 2 years. Patient
screening and randomizing increased significantly,
starting when the interviews began. When the
recommended actions were implemented there
was an incremental increase in the number
of patients screened and randomized. There
has been a 104% increase in trial enrollment
since implementation of the market research
compared to the previous enrollment trend line.
No other activities occurred during this period
that improved patient recruitment. The study
resulted in four very specific recommended
tactical tools desired by SCs and PIs, that have
been implemented and have proven to have a
significant impact. The apriori hypotheses (e.g.
lack of patients) based on CRA feedback and site
feedback directly to the sponsor were proven false.
Additional survey results, administered to SCs
and CRAs, were collected after implementation
of the recommended tools. Results demonstrate
that the large majority of both CRAs and Site
Staff found each of the tools introduced based on
the market research as either ‘very valuable’ or
‘somewhat valuable’. For the most preferred tool,
81% rated it as ‘very valuable’.
Conclusion: PIs and SCs are often aware of
specific factors impeding patient recruitment.
However, they commonly communicate a limited
amount of information directly to sponsors.
Prior to the work outlined in this abstract, the
clinical research sponsor contacted PIs and
SCs directly to obtain input. However, these
efforts did not result in any discernible increase
in patient recruitment. The use of a third party
to obtain inputs is necessary because PIs and
SCs are reticent to communicate internal issues
to sponsors; site staff must be mindful of the
importance of sponsors for future trials. However,
when interviews were conducted anonymously,
PIs and SCs communicated the real barriers to
patient recruitment. This initiative also highlights
the opportunity to incorporate insights earlier
in the clinical trial process. Insights can be
leveraged in protocol design, recruitment strategy
development, and educational and promotional
communication testing. Additionally, this
initiative highlights the importance of monitoring
SC and PI feedback earlier in the execution of
the trial, to uncover and diagnose issues prior to
the trial experiencing a significant delay. There
appeared to be a Hawthorne effect to conducting
interviews anonymously with PIs and SCs. An
increase in patient recruitment began shortly
after the interviews were started and before any
of the recommended actions were implemented.
W 25Implementing a Standard Report Set
for Risk Based Monitoring Domains
Penelope Manasco, MD, MS
MANA Consulting
Objective: The objective of this abstract is to
present an example of a Risk Based Monitoring
Report Suite and how it can be used to assessed
study quality.
Method: We identified 11 domains that are
needed in each trial for Risk Based Monitoring.
Additional domains that are related to the
primary efficacy endpoint are designed
specifically for a trial or program. We developed
a set of reports that provide data for each
domain.
Results: We provide examples of the reports
that we use for each domain and examples of
how these data are used to support risk based
monitoring. We use the reports to guide weekly
remote discussions with the sites and to develop
and monitor user and site-based re-training or
intervention.
Conclusion: Risk Based Monitoring reports can be
standardize for most domains. The results of the
reports can then be used to guide the monitor’s
site interactions and discussions with the PI and
the Sponsor. Risk Based Monitoring reports do
not have to be used to determine onsite visits
exclusively, they can be a “report card” to help
ensure higher quality study conduct.
W 26Investigation of Association Between
COPD Treatment and Cardiac Events
With or Without Treatment for CoExisting Disease
Ayako Takizawa, MS
Nippon Boehringer Ingelheim Co., Ltd, Japan
Objective: To assess the frequency of cardiac events
reported in FAERS in patients who treated their
background disease, COPD, and evaluate the effect
of treatments for co-existing disease, Hypertension.
Method: Reports of cardiac events submitted
to US FDA’s adverse event reporting system
(FAERS) from 2009-2012 were retrieved and
analysed by reporting odds ratio (ROR) data
mining algorithm. The ROR of cardiac events for
used COPD medication were compared in class
with/without anti-hypertensive treatments.
Results: Adverse events were reported in
83586 patients treated with COPD medications
during 2009Q4-2012Q3. In this period, 12888
cardiac events were reported in this population,
corresponding to 3309 COPD medication-cardiac
events pairs (anti-cholinergics; 632, betaagonists; 2032, inhaled corticosteroids [iCS];
361, Methyl xanthines; 36, PDE4-inhibitors; 110).
ROR and its 95% confidential interval (CI) values
for anti-cholinergics, beta-agonists and iCS to
other medications in FAERS were 0.27(0.250.29), 0.57(0.54-0.60) and 0.35(0.32-0.40),
respectively. On the other hand, ROR for methyl
xanthines and PDE4-inhibitors were 2.60(1.753.87) and 1.47(1.90-1.81).
28722 out of 83586 patients were treated with
anti-hypertensive drugs. Hypertension is one of
comorbidity of COPD. In patients treated with
anti-hypertensive drugs, the risk of cardiac events
increased, corresponding to ROR for hypertension
treated population being 2.94 (2.83-3.05). ROR
for inhaled medications had a similar trend in
this population, whereas ROR and its 95% CIs for
anti-cholinergics, beta-agonists and iCS to other
medications were 0.45(0.40-0.52), 0.50( 0.450.55) and 0.38(0.30-0.48), respectively. ROR
for methyl xanthines and PDE4-inhibitors were
1.37(0.52-3.61) and 1.02(0.72-1.44), respectively,
including 1 in their 95% CIs. In this population,
the lower limit of 95% CI of ROR for hypertension
treatments except for ACE inhibitors, calcium
blockers and beta1-selective adrenoceptor
blockers was above 1 (ARBs; 1.23[1.00-1.52],
ACE inhibitors; 1.03[ 0.81-1.30], renin inhibitors;
2.41[1.57-3.69], calcium channel blockers; 1.29[
0.98-1.69], diuretic agents; 1.43[1.07-1.91],
beta1-selecitive adrenoceptor blocking agents;
1.37[0.98-1.91], and alpha/beta-adrenergic
blocking agents; 2.06[1.13-3.75]).
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Conclusion: Inhaled medications, which have
COPD indications, such as anti-cholinergics, betaagonists and iCS, are not associated with cardiac
events in FAERS, the spontaneous adverse event
reporting system in the US. The trend of low risk
of cardiac events shown in COPD treatment was
similar in the population treated not only for
COPD but also for hypertension.
W 27
Reinventing the Study Build Process to
Promote Consistency, Increase Build
Efficiencies, and Reduce Overall
Timelines
Caroline Lin, MA
Novella Clinical
Objective: This purpose of this project is to
reduce the amount of time devoted to developing
the eCRF with the ultimate goal of reducing the
development cost/time per eCRF by redesigning
the study design process.
Method: The traditional study build process
is problematic because the iterative nature of
the review and re-programming contributes
to protracted eCRF approval timelines, often
compromising later timelines or even delaying an
EDC system Go Live.
Results: In the redesigned process:
1. The DM creates the T&E prior to or just after
the Data Collection Requirements meeting and
provides it to the Study Designer.
2. The Study Designer programs the eCRFs in the
target EDC system.
3. The Novella team reviews the eCRFs.
4. Draft eCRFs are sent to the client 48 to 72
hours prior to the OLSR.
5. The Client reviews the eCRFs in the target EDC
system during the OLSR with the Study
Designer and Novella team.
6. The Study Designer makes changes resulting
from the OLSR (typically within a day or two).
7. The Client approves the eCRF after reviewing
the documented changes requested.
8. The Study Designer documents the trial design.
W 28
Collaborative Development of an Open
Source Repository for Standardized
Analysis Using Cloud Services
Hanming Tu, MSc
Accenture
Objective: The objective of this poster is to
describe the process, platform and progress of
implementing an open source repository for
the collaborative development of specialized
programs to be used as analytical tools for clinical
trial research, reporting, and analysis through
cloud services.
Method: PhUSE formed a standard script working
group two years ago, consisting members from
FDA and Industry. A script repository has been
created for the collaborative development and a
scriptathon event in March 2014 used to test out
the cloud implementation.
Results: Industry standards have evolved over
time for data collection (CDASH), observed
data (SDTM), and analysis datasets (ADaM). But
for the industry and the regulatory authorities
there are currently no standard tools available
for the analysis of the standardized clinical data.
The Pharmaceutical Users Software Exchange’s
(PhUSE) Computational Science Symposium
(CSS) formed a “Standard Script for Analysis
and Programming” group for two purposes: 1) to
create white papers outlining recommendations
for safety analysis and reporting for clinical
trial study reports and integrated safetyrelated submission documents, 2) to establish
a platform for sharing and developing standard
scripts collaboratively and for implementing the
recommendations through cloud services.
In the past two years, the group has accomplished
the following tasks:
Data was collected over twelve months (January
2013-December 2013). Over the course of the
year, the time spent to create one form decreased
from 10 hours to 3.63 hours. The duration of
the eCRF spec development to OLSR and the
duration of the eCRF spec development to client
approval of the eCRFs decreased by 10 days
each. The new redesigned process allowed us to
average a savings of $11,000 per study build. Our
savings for the year was $223,000.
• Selected Google Code as standard script
repository for development and storage of the
PhUSE standard scripts
o Some scripts exist in the repository
o MIT license chosen
o Process guidelines developed
o Established the basic structure and
process for managing the repository
including
o Folder structure and name conventions
o Roles and responsibilities for each role
o Tasks and duties
o Process of tracking issues
o Required metadata and
recommended programming style
for scripts
o Test data and validation
documentation
• White papers describing recommended
analyses, tables, figures, and listings
o One white paper is complete
o 5 others in progress
Conclusion: Due to the cost and time benefits
gained, Novella is proceeding forth with the new
redesigned process for all study builds.
Script-athon at PhUSE CSS 2014 is planned to
test out the implementation of the open source
repository with cloud services in R and SAS.
The redesigned process will allow the Client to
review the eCRFs at the OLSR in as little as one
to two weeks after the Study Designer begins
programming. The revised approach should
remove the iterative process of review, reprogramming, and re-review that inevitably leads
to prolonged eCRF approval timelines.
How can we maintain the openness of the tools
that we use and at the same time guarantees the
security of the data? What we have done shows
the possibility of leveraging the secure cloud
systems in R and/or SAS to use the open platform
to develop scripts and utilize the validated scripts
to process shared and secured data sources.
Conclusion: The goal of the standard script
working group is to produce recommendations
and establish a platform for the collaborative
development of specialized programs to be
used as analytical tools for clinical trial research,
reporting, and analysis. This platform includes:
• Identification of areas that can benefit from a
standard set of analyses
• Development of recommendations for analyses,
tables and figures within a topic area
• Creation of a process and guidelines for
documentation and management of scripts
• Incorporation of data standards whenever
feasible
From what we have experimented, we can
conclude:
• Google Code provides a scalable, reliable, and
fast collaborative development environment
for developing and sharing standard scripts and
documents for data transformations and
analyses.
• It is mutually beneficial to both the industry
and the regulatory authorities if an open source
repository is available for storing and
developing standard scripts
• It is a good practice to use the white papers
defining the cross-industry analysis and reports
based on CDISC standards.
• It is possible to implement the open source
repository through cloud services, as it is tested
in the Scriptathon event for utilizing the
standard scripts from the repository in the
secure cloud systems.
Work together openly and collaboratively and we
can achieve more than what we have hoped for!
W 29
Quality of Japanese Clinical Trials and
Proposed Strategy for the Trial Sites
Toshiyoshi Tominaga,
Osaka City University, Japan
Objective: To find survival strategies for Japanese
trial sites (institutions) in the current global drug
development scene, with the underlying issues
of greater role/responsibilities of trials sites in
Japan, and the emerging risk-based definition of
the clinical trial quality.
Method: Existing reports on (a) the characters
of Japanese clinical trials, (b) the current Japan’s
policies on clinical development, and (c) the
current risk-based approach to the quality of
clinical trials were studied. The author formulated
a strategy for Japanese trial sites based on the
findings.
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Results:
Characteristics of Japanese trials
• The following are among the objectively
observable traits of the Japanese clinical trials.
(a) fewer subjects per trial site, with, however,
difference between clinics and (large) hospitals
(b) relatively high cost per subject
(c) heavy dependence on monitors’ source data
verification (SDV) for data accuracy
approaches to design more efficient trials.
What constitutes “Quality” ?
• It has been found that the definition of “quality”
has plural elements ( (a)fundamental merits
ascribable to the populations, (b) compliance
to GCP and protocol, and (c) data accuracy).
The quality has been defined differently in the
traditional understanding (100% in everything)
and in the current risk-based approach (absence
of errors that matter).
Results: A working group consisting of
multidisciplinary partners from academia,
industry, patient groups, and government,
including the FDA/CDER’s Antibacterial Drug
Development Task Force was formed. The
working group identified and focused on critical
protocol elements where efficiencies leading
to high quality, more feasible trials that can
complete enrollment in a timely manner, could be
introduced.
Are Japanese clinical trials of high quality?
• There have been separate reports regarding
particular studies, in which such parameters
as the number of queries, days before EDC
inputs, responses to queries, number of
findings in regulatory inspection showed the
Japanese clinical trials’ quality being relatively
high. However the author has not found a report
showing a statistically significant difference in
parameters across trials.
The protocol elements of primary focus were:
1) patient population, 2) study design and
endpoints, 3) safety considerations, and 4)
operational issues.
Discussion on risk-based approach
• The discussion in Japan on the approach has
apparently just begun. The author found that
the discussion has been mainly on the sponsors’
conduct especially in monitoring and that there
has not been much discussion on the expected
role of institutions/investigators under the
paradigm.
Conclusion: This endeavor to improve protocol
design and introduce operational efficiencies may
help overcome obstacles for the conduct and
regulatory review of HABP/VABP trials, hence
addressing a critical unmet medical need.
Conclusion: Based on the findings, the author
proposes following strategies (or strengthening of
the existing strategies);
1. National Level
a) Further differentiation and cooperation
among clinics and hospitals (advanced and
others)
b) Further encouragement in early phase trials
2. Hospitals with integrated clinical trial offices;
a) Abandonment of 100% ism in every conduct
and data
b) Construction of in-house risk management
system to supplement the sponsors’
risk-management
W 30A Collaboration to Facilitate the
Development of Antibacterial Agents
for Unmet Need: Streamlining Clinical
Trial Protocols
Gary Noel, MD
Janssen Research and Development
Objective: This multidisciplinary effort aims to
identify challenges in clinical trials conduct of
antibacterial agents for the treatment of hospitalacquired or ventilator-associated bacterial
pneumonia (HABP/VABP), and propose alternate
Method: This collaboration includes the
participation of a multi-disciplinary working
group led by the Clinical Trial Transformation
Initiative (CTTI). Several meetings and workshops
were held to gain a wider understanding of
issues, several solutions using a Quality by Design
approach were proposed.
Recommendations of the working group,
including alternate approaches to design efficient
and clinically meaningful trials to establish the
safety and efficacy of new antibacterial agents for
the treatment of HABP/VABP, will be presented.
CTTI-HABP/VABP Protocol working group:
Mark Behm, Sabrina Comic-Savic, Vance Fowler,
David Friedland, Charles Knirsch, Martin Landray,
Gary Noel, Christina Reith, Jonas Santiago, Brad
Spellberg, Rosemary Tiernan
W 31Global Regulatory Considerations for
Biosimilar Approval
Holly Groelle, PhD
PPD
Objective: To present a global perspective of
biosimiar legislation, guidelines, and approvals in
key markets.
Method: A literature review and analysis of the
current state of biosimilar legislation, guidance,
and approvals. Published articles; competent
authoritiy guidance and/or approvals; WHO and
ICH Comparability Guidelines; and company
websites.
Results: Biologics have changed the practice
of medicine delivering innovative solutions via
antisense, cell, gene, monoclonal antibody,
recombinant protein, and vaccine therapy. Patent
expiry and high costs of reference biologics
promote interest in biosimilars. In the past
decade one-third of new medine approvals were
biologics. Biologicals are expected to dominate
small molecular entities as top sellers by 2018.
Unlike new chemical entities and generics,
biologics and biosimilars are not chemically
identical and often are characterized by the
manufacturing process. Developing a similar/
interchangeable to a reference biologic requires
demonstration of comparability in quality, safety,
and efficacy.
Conclusion: The global landscape of biosimilar
legislation, guidance, and approvals is presented
in the context of the international standard: World
Health Organization, European Medicines Agency,
and U.S Food and Drug Administration. Explored
is a comparison of the 12-year regulatory data
exclusivity period afforded to the applicant first
to establish its product as interchangeable with
the brand-biologic pursuant to the U.S. Biologics
Price Competition and Innovation Act (2009),
10-year new biologics (8-year data exclusivity and
2-year market exclusivity) and a 1-year extension
for new indication in Europe, with legislation
developing globally.
W 32Impact of FDA Breakthrough Therapy
Designation on the Regulatory
Timelines of Chronic Lymphocytic
Leukemia (CLL) Therapies
Alex Wei
Ernest Mario School of Pharmacy, Rutgers
University
Objective: The objective of the study is
to determine the impact of the FDA’s new
breakthrough therapy designation on the
time to approval compared to the standard of
care approved without breakthrough therapy
designation.
Method: The study utilized publicly accessible
NIH clinical trial registry for trial information
as well as the FDA and sponsor company
press releases for regulatory milestones and
pivotal trial data for the breakthrough therapies
obinutuzumab and ibrutinib, as well as the
standard-of-care, rituximab.
Results: Obintuzumab is the first drug approved
under breakthrough therapy designation. The
phase I trial was initiated in 9/2007. Its pivotal
phase III trial was initiated in 2010 and interim
efficacy data was released in 1/2013. The sponsor
submitted a regulatory application in 4/2013. One
month later, breakthrough therapy was granted
in 5/2013. The drug was approved in November,
ahead of its PDUFA date of 12/2013. The pivotal
phase III data had obintuzumab in combination
with chlorambucil with an overall response rate
(ORR) of 75.9%.
Ibrutinib’s phase Ib/II trial was initiated in 2/2009.
The phase III trial was launched in 10/2012 and it
received its fast track designation shortly after in
11/2012. Breakthrough therapy designation was
granted in 4/2013 based on phase II efficacy data.
In 6/2013, the sponsor submitted a regulatory
application and the FDA set a PDUFA date of
2/2014. In 12/2013, final adverse event and efficacy
data for the phase Ib/II trial were released and 2
months later in 2/2014, it was approved for CLL
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based on phase Ib/II data. Patients in the phase Ib/
II study had an ORR of 58.3%.
The IND application for rituximab was filed in 1992.
Phase III trials in CLL began in 08/2004. Efficacy
data from the Phase III CLL8 and REACH trials
were presented in 12/2008. In CLL8, a regimen
containing fludarabine, cyclophosphamide, and
rituximab had a significantly higher ORR of 95%
compared to a regimen containing only fludarabine
and cyclophosphamide, which had an ORR of
88%. On 2/18/2010, rituximab was launched in the
United States for both first-line and refractory CLL
therapy.
The total time from Phase I initiation to FDA
approval was 6 years for obinutuzumab and
only 5 years for ibrutinib. The time from
regulatory filing to FDA approval was 7 months
for obintuzumab and 8 months for ibrutinib.
Comparatively, rituximab, the first biologic
approved for CLL which now has a place in the
standard of care, took 18 years from its IND to
launch for CLL.
Conclusion: Breakthrough therapy designation
sets the precedent for a considerably accelerated
drug development process. Recently, the
increased focus on higher criteria for quality of
care, along with advances in drug development
technology, has necessitated the Breakthrough
Therapy designation. Ibrutinib was approved
solely on its robust phase Ib/II data and will
have its approval confirmed by the phase III trial
estimated for a 12/15 completion, leading to
increased patient access for potentially life-saving
drugs. Given CLL’s reputation as the second-most
common type of leukemia in adults, the addition
of two new agents, both approved within months
of their Breakthrough Therapy designation, will
allow physicians more options to treat their
patients, enhancing patient care.
Created in July 2012, The Breakthrough Therapy
Designation remains a relatively new concept
in the process of drug approval. The exact
implications that the designation will have on
the future of patient care are yet to be seen.
However, the current data available suggests
that breakthrough therapy designation can
significantly expedite the process of drug
development, allowing patients earlier access to
drugs that considerably improve quality of life.
W 33An Extension of Likelihood Ratio Test
Based Method for Signal Detection
in a Drug Class with Application to
FDA’s AERS Database
Yueqin Zhao, PhD
FDA
Objective: We extend the likelihood ratio test
(LRT), recently developed for the detection of
signals of adverse events (AEs) of a drug of
interest in FDA Adverse Events Reporting System
(FAERS), to detect signals of AEs for a class of
drugs.
Method: The performance of the proposed
method is evaluated using power, sensitivity and
false discovery rate through simulations. It is
then applied to Gadolinium drug class in FAERS
database.
Results: In both simulated data sets and real
Gadolinium drug data set, the extended LRT is
shown to control type-I error and false discovery
rate (FDR) while retaining good power and
sensitivity for detecting signals.
Conclusion: The extended LRT is shown,
analytically and through a simulation study, to
control type-I error and false discovery rate (FDR)
while retaining good power and sensitivity for
detecting signals.
W 34
Maintaining Effective Pharmacovigilance
Oversight: The Role of Remote Auditing
Alun Tanner, PhD
Remedion Consulting LLC
Objective: Patient safety is a legislative
and corporate priority; our objective was to
understand the limitations, and quantify the
benefits of conducting pharmacovigilance
audits remotely in terms of maintaining effective
oversight while using resources more effectively
and reducing associated costs.
Method: Five remote audits were conducted.
Access to documentation was through webenabled document management systems, or by
scanning and email. Interviews were conducted
using remote-conferencing with screen-sharing
technologies. The facility inspection was managed
using digital photographs or video.
Results: It is common practice to allow up
to five days for the conduct of a routine
pharmacovigilance system audit, including
a nominal two days for travel to and from
the site. When compared to this standard, it
was determined that a routine audit of either
a corporate affiliate or a vendor could be
completed in three days using the remote
auditing process without any reduction in either
audit scope, or the quality of the oversight.
Without the need to travel, there was a saving of
ten days over the course of the five audits, which
could have been used, for example, to conduct
two or three further quality audits. Additional
benefits included a significant reduction in travel
related costs, and the ability to audit sites that
were not readily available due to factors such as
political unrest.
During the pre-audit stage, management at the
audit site were made aware of the differences
between a virtual and an actual site visit, and
any concerns raised were addressed. Using the
remote process, a greater number of documents
were requested in advance than would normally
occur so that the auditor could better understand
site processes and prepare a comprehensive list
of questions prior to conducting the interviews.
Secure access to documentation, either through
a web-based validated document management
system or through scanning, faxes or email,
was an essential component of this process;
comprehensive IT support, including adequate
bandwidth, was therefore crucial. Interviews were
conducted using tele- or video-conferencing;
answers were verified using screen-sharing
technologies allowing interviewees to effectively
demonstrate steps in the process.
Conclusion: Conducting pharmacovigilance
system audits remotely, using the process
developed during this pilot program, has proved
to be is a cost effective way of maintaining
oversight of on-site pharmacovigilance activities
irrespective of whether these are conducted
by a company affiliate or a vendor. These five
audits included both routine case processing
and the follow-up of remedial action plans. The
remote process also lends itself to other relevant
pharmacovigilance activities including regulatory
inspection preparedness. A key benefit was the
ability to maintain oversight of sites that might
not be readily accessible to a normal on-site visit
due to factors such as political unrest.
Since this process allows auditing resources to
be deployed more effectively, the number of
audits conducted can be increased without the
need for additional auditors or an increase in the
travel budget. Although feedback from those
participating in the remote audits was positive,
it should be noted that this process does not
replace the need for on-site audits but rather it
allows a more sustained degree of oversight when
integrated into a carefully planned, risk-based
pharmacovigilance system audit program.
W 35
Data Empowered Decision Making in
a Pharmaceutical Company: Project
Libraries and Workflows - Real Life
Experience
Mikhail Samsonov
R-Pharm, Russian Federation
Objective: This poster will justify the demand
for, explain the capability and summarise results
achieved from implementation of an innovative
enterprise web-based platform designed to
define projects and run business processes across
a pharmaceutical business.
Method: In August 2012 R-Pharm conducted
business process review and mapping and started
implementation of an enterprise wide platform
to support activities across all key functions:
regulatory, pharmacovigilance and product
development. This was achieved by implementing
two key technological solutions.
Results: Gathering management data across
a complex business such as a pharmaceutical
company is a problem which has long been
recognised. Pharmaceutical companies are
increasingly faced with the complex task of
becoming leaner and more efficient. This is down
to both strategic and operational decisions –
“doing the right things vs doing things right”.
A system of interconnected project libraries was
introduced in order to formalise project records
and enable analysis across the pipeline of the
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projects. The structure adopted was Molecule,
Drug, Non-clinical and Clinical projects. The
project records in these sub-libraries were linked
to each other, enabling to identify and analyse
interconnections between them.
In order to guide the activities on the projects,
automated workflow tool was introduced. The
system checks the entered data against predefined criteria. Once a task is completed, the
workflow engages the next person in the process,
moving the task from the Inbox of the current
executor to the next person in the process.
Implementation of the project library set up the
foundation for universal project management
activities across the projects. By capturing
key metrics, such as priority index, incentives
available from the government, contracting
information, etc, a mechanism was put in place
for quick prioritisation of activities in response
to external or internal demands ( such as,
for example, market changes and resource
shortages).
Implementation of the workflow platform allowed
accelerating problem identification from months
to days by providing real time data describing
the processes. The reporting has a built in tools
for identifying bottlenecks, by tracking duration
of tasks, number of outstanding tasks and each
user performance. A total of 15 processes have
been implemented within the platform to date,
ranging from Serious Adverse Event reporting to
preparation of a Clinical Development plan and
Due Diligence on in-licensing candidates.
Conclusion: The use of a single enterprise
platform brings a number of benefits, one of
the most important of which is the ability to
generate data to support decision making.
The structure presented allowed to streamline
project prioritisation by capturing project
information in a fluid interconnected system of
libraries and allowing to analyse the connections
between projects as well as their key metrics.
Implementation of workflow management
produced real time data on the project activities,
creating a data stream in support of optimising
project related processes. As a result, R-Pharm
obtained a complete management information
dashboard, providing all the necessary
information tools to optimise its portfolio and
efficiency/effectiveness of its processes.
W 36
Sample Size Re-Estimation Can Be
Very Inefficient
David Bristol, PhD
Statistical Consulting Services, Inc.
Objective: The objective is to present the
inefficiencies associated with sample size
re-estimation and to inform the users of such
characteristics.
Method: Simulations were performed for various
scenarios for the true known parameters and
assumed parameters used for initial sample size
determination, resulting in either an underestimate,
an overestimates, or the correct sample size.
Results: Sample size re-estimation is typically
inefficient and may be a major waste of resources,
with too few or too many patients enrolled.
This conclusion does not depend on whether
the assumed parameters result in either an
underestimate, an overestimates, or the correct
sample size.
Conclusion: The sample size for a clinical trial is
typically chosen to control the power of the test
corresponding to the primary efficacy comparison
of two treatments, using assumed values of the
true parameters, based on historical, clinical, and
financial considerations. These assumed values
may not be equal to the true values and thus the
sample size may be inappropriate. An interim
analysis can be used to check the appropriateness
of the assumed values and the required sample
size can be re-estimated using estimates from the
interim analysis. Such procedures have become
very popular in recent years and are often viewed
as a way to conserve resources; however, there
are inefficiencies that are rarely mentioned. The
results of several simulations are presented to
show that the re-estimated sample size may be
much larger or smaller than necessary. Resources
may be wasted because of these inefficiencies,
which may be extreme. It is important that users
are informed that such outcomes can occur.
W 37
So You Hired a CRO…Now What?
Advancing Clinical Research by
Leveraging Government Sponsor
Relationships with CROs
Jessica Kloda, PhD
Technical Resources International, Inc.
Objective: To share how a U.S. Government
Agency, serving as a sponsor for a large
global portfolio of HIV/AIDS clinical trials, has
successfully leveraged its relationship with a CRO
to optimize regulatory support for the sponsor
and its collaborators, in successfully conducting
complex clinical trials.
Method: Accountability and clearly defined
processes are vital to this Government-CRO
relationship, with quality metrics assessed
regularly. Clear communication of expectations
and continued outreach to stakeholders was
essential in building the trust that ensures a
successful clinical research structure.
Results: Engaging in quality planning and using
accountability metrics to assess performance
has been instrumental in the success of this
Government-CRO relationship. In addition,
applying project management principles
by designating leads for tasks has ensured
consistent strong communication and that high
quality work products are delivered on schedule.
To build efficiencies, technology has been
leveraged in data management and via electronic
communication tools. The Division of AIDS
Regulatory Support Center (DAIDS RSC), which
is run by the CRO, has been integral in optimizing
the use of the customized role-based Clinical Trial
Management System (CTMS) called the DAIDS
Enterprise System (DAIDS-ES), as the database
of record for DAIDS collaborators. Utilizing
a single CTMS across multiple collaborators
requires careful coordination and also ensures
consistency and accuracy in data reporting.
Electronic communications are used across all
DAIDS RSC tasks. Notably, e-Learning modules
were developed to optimize the launch of new
government policy manuals on safety reporting
and essential document submissions, which
are key in facilitating clinical trial site protocol
operations. Similar strategies were used to
deliver training to remote international locations
in planning for audits and helped to ensure a
cost-effective approach to promote compliance
with regulations throughout protocol lifecycles.
The trust established in this Government-CRO
relationship has allowed the DAIDS RSC to pursue
equally important collaborator coordination via
face-to-face outreach. The DAIDS RSC holds
Information Booths and supports consultative
sessions at collaborator meetings in addition
to providing presentations and conducting
meetings with clinical trial Network Operations
Centers. These efforts have helped to proactively
identify gaps in awareness about available clinical
research resources and in process inefficiencies
that the Government was able to address.
Conclusion: The experience with the DAIDS
RSC shows that the Government can effectively
leverage its CRO relationships to support critical
research in advancing the fight against HIV/
AIDS. Effective sponsor oversight and improved
efficiencies through this partnership have helped
to enhance clinical research operations among
DAIDS, the DAIDS RSC and other collaborators.
As part of outreach to external collaborators,
a “DROP-IN” program was instituted for sites
whereby DAIDS and DAIDS RSC personnel meet
clinical trial site staff on location to assess needs,
discuss processes, and share resources and tools
that may facilitate appropriate implementation of
procedures and promote regulatory efficiencies
and compliance. Such resources and tools
developed included tutorials, checklists, and
how-to videos that have been made available
via the public and mobile-accessible DAIDS
RSC website. The CRO has been an integral part
of the Government’s efforts to maximize the
use of new technologies and implement more
efficient processes to advance the HIV/AIDS
clinical research being performed by hundreds of
DAIDS collaborators around the world, including
clinical trial sites in resource-limited settings
and diverse regions. The strong Government
CRO relationship has significantly contributed
to scientific achievements including studies that
supported the 2013 FDA approval of Merck’s
Isentress® in liquid form for use in pediatric HIV/
AIDS patients, the 2012 FDA approval of Gilead’s
Truvada® - the first antiretroviral to be approved
as prevention therapy for HIV, and the successful
clinical trial, HPTN 052, which examined the use of
antiretrovirals in serodiscordant couples to prevent
HIV transmission and was recognized as Science’s
“Breakthrough Study of the Year” in 2011.
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W 38Office of Prescription Drug Promotion
(OPDP) Enforcement Overview From
1997 to 2013
Cyril Carrere, MSc
Thomson Reuters (Scientific) LTD, France
Objective: Assess the impact of FDA regulation
on warning and untitled letters from OPDP
(formerly Division of Drug Marketing, Advertising
and Communications) and identify the most
frequent deviations from the Code of Federal
Regulations (CFR) for warning letters.
Method: Warning and untitled letters sent
(1997-2013) were analyzed. For warning letters,
deviations from 21 CFR were identified and
placed into 4 categories—Prescription Drug
Advertising, Labeling, New Drug Promotion, and
Investigational Drug Promotion—and within each,
the numbers of citations were ranked.
Results: From 1997 to 2013, the Office of
Prescription Drug Promotion (OPDP) issued
771 untitled letters and 130 warning letters.
On August 12, 1997, the FDA announced the
availability of the Draft Guidance for Industry:
Consumer-Directed Broadcast Advertisements
(Federal Register: Volume 62, Number 155,
[Docket No. 97D-0302]); this document had a
major impact on the number of letters (warning
and untitled) issued, at a time when companies
increased the number of promotional campaigns
on their products. Specifically, the large number
of letters issued to companies in 1997 (139)
and 1998 (156) was related to that upswing in
promotional activity. A steady decrease in letters
sent was observed from 1999 (121), the year in
which the Draft Guidance was finalized, to 2002
(27). Numbers then stabilized, with a mean of
23.7 letters published per year until 2008. The
increase observed in 2009 (39) and 2010 (51)
suggests an FDA enforcement focus on Internetrelated promotional media.
The analysis of OPDP warning letters confirmed
a strong focus on Prescription Drug Advertising,
representing 70.7% of all citations identified,
followed by Labeling (18.9%), New Drug
Promotion (9.9%), and Investigational Drug
Promotion (0.6%). Within Prescription Drug
Advertising, unsubstantiated claims (clinical,
non-clinical) accounted for 53.4% of citations
identified, followed by deviations linked
to misleading with respect to side effects,
contraindications, or effectiveness (19.5%), and to
an omission of information related to side effects,
contraindications, or effectiveness (15.3%).
For Labeling, failure to provide adequate
directions for use accounted for the wide majority
(82.5%) of the citations identified. New Drug
Promotion citations were related to a failure
to submit under Form FDA-2253, while the
promotion of unapproved uses was only observed
in two letters.
Conclusion: The OPDP enforcement activity
varied depending on historical FDA guidance
publications, internal reorganizations, and
companies’ evolution in their promotional activity.
This had an impact on the number of letters
sent per year, with a peak of activity observed
in 1997 and 1998, then again in 2009 and 2010.
The analysis of the OPDP warning letters showed
that the vast majority of deviations from 21 CFR
belonged to the Prescription Drug Advertising
category, in which unsubstantiated claims were
predominant. Labeling deviations essentially
highlighted failures to provide adequate
directions for use, and the New Drug Promotion
and Investigational Drug Promotion categories
represented only a minor amount of deviations.
W 39Enrollment of Pregnant Women in
Medication Safety Research:
MotherToBaby Pregnancy Studies
Jennifer Zellner, PhD
University of California San Diego
Objective: The objective of this study is to
examine enrollment in MotherToBaby (MTB)
Pregnancy Studies, a group of U.S. and Canadawide pregnancy registries designed to examine
medication and vaccine safety during pregnancy
across a variety of maternal health conditions.
Method: MTB studies conducted from 20002014 have focused on influenza and meningitis
vaccines, antiviral medications, and medications
for asthma or autoimmune diseases. Women
are followed in pregnancy and at least 1 year
postpartum. Data are collected from interviews,
medical records, and infant exams.
Results: MTB participants are recruited through
physicians, direct to consumer marketing, and
Teratogen Information Services throughout
North America. Between 2000 and 2014, a
total of 3,886 pregnant women enrolled in
MTB pregnancy studies. Outcomes for exposed
women are compared with a disease-matched
group of women without medication exposure
during their pregnancy and/or a control group
of healthy pregnant women recruited using
the same sources and followed using the same
methods. Vaccine Studies enrolled 1,744 exposed
women and 483 non-exposed controls; Asthma
Medication Studies enrolled 247 exposed women
and 244 healthy controls; and Autoimmune
Disease Medication Studies enrolled 740 exposed
women who met strict study eligibility criteria,
435 exposed women who did not meet eligibility
criteria but whose pregnancies were followed,
487 disease-matched controls, and 420 healthy
controls. Overall, retention in MTB studies has
been high (lost-to-follow-up rate across studies is
2%), supporting internal validity of study results.
Conclusion: One in six women in the U.S. receives
a prescription drug for which there is limited
or no information on human teratogenicity
(Schwartz et al. 2005, 2007). Medication use
during pregnancy continues to increase; in
addition, some vaccines (e.g., influenza) are
specifically targeted to pregnant women. Yet the
lack of clinical trials involving pregnant women
for most medications and vaccines means we
have a very limited understanding of the effects
of these exposures on the long-term health of
babies and mothers. Pregnancy registries are
one method for collecting this information,
but have often struggled with recruitment of
exposed pregnancies, high lost to follow-up
rates, and lack of appropriate internal or external
comparators. MTB studies demonstrate the
capacity to successfully identify medication and
vaccine-specific exposed pregnancies across a
wide variety of therapeutic areas and indications,
to recruit and retain women representing a broad
geographic area, to enroll appropriate comparator
pregnancies, and to conduct long-term followup of mothers and infants. Such information will
help women and health care professionals better
understand the effects these exposures have on
infant health and development, which will in turn
inform improved healthcare decision-making.
W 40A Model for Centralized Monitoring:
Reducing Costs While Ensuring
Compliance, Risk Mitigation and
Quality
Badhri Srinivasan, PhD, MS
Quintiles Inc.
Objective: The poster will examine the potential
benefits of Centralized Data and Operational
Surveillance (CDOS), a novel approach to
Centralized Monitoring.
Method: The poster will describe how the CDOS
model delivers value in four key areas: ability to
impact clinical monitoring costs; decreased time
to analysis-ready data; increased quality/reduced
risk; and ability to impact medical monitoring.
Results: CDOS can reduce clinical monitoring
costs by as much as 20% through targeted
monitoring, while ensuring site compliance, risk
mitigation, and quality.
Conclusion: CDOS fits well within the RiskBased Monitoring (RBM) model, which starts
with an in-depth assessment of the scientific
and operational risk of each protocol, followed
by dynamic monitoring (on-site, remote or
centralized) and focuses on those sites, data,
patients and events that require increased
attention. Data surveillance allows monitoring
to be optimized and adapted as necessary
throughout the trial, with ongoing reassessment
of risk and appropriately timed responses.
W 41
Customer Satisfaction and
Communication Methods Used in
Conducting Large Multi-Center
Clinical Trials
Barbara Del Curto
VA Cooperative Studies Program
Objective: The objective of this work is to
develop processes that effectively identify
customers, manage expectations and measure
customer satisfaction results in a complex
pharmaceutical project management environment
of large multicenter clinical trials.
Method: For this work we assessed and
integrated Baldrige criteria, a project
management maturity model assessments and
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DIA 2014 50TH Annual Meeting
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customer engagement measurement techniques
to clearly define customer’s requirements
throughout the clinical trial life cycle.
Results: In 2009 the VA Cooperative Studies
Program Clinical Research Pharmacy Coordinating
Center (PCC) received the Malcolm Baldrige
Presidential Award which has a focus on customer
satisfaction. The result of our work demonstrated
that having a consistent and standardized
communication approach that captures customer
requirements has a direct correlation to customer
satisfaction. The PCC has participated in design
and management of multicenter clinical trials
since 1976 and as the number of trials increased
standardized, communications tool providing
overall clinical trial information and design
requirements was developed. The tool has evolved
from being used only for budget development
into a comprehensive approach used to manage
customer and sponsor expectations in all phases
of a clinical trial and improved communications
across our internal cross-functional teams.
Through the integration of performance excellence
criteria and understanding our organizational
project management maturity, we identified and
developed the communication tool needed to
maintain and improve customer satisfaction.
Conclusion: Capturing and communicating
customer requirements is key to ensuring that
clinical trial design criteria are met. The following
assessments were instrumental in validating
the importance that is placed in meeting our
customers’ expectations: (1) External validation
from the Malcolm Baldrige audit team confirmed
that our pharmaceutical project management
processes fosters a culture that strives for
customer satisfaction. (2) Conducting the PMI’s
Organizational Project Management Maturity
Model assessments validated that the PCC follows
and utilizes standard practices and tools that
are key to leading and managing clinical trial
activities.
W 42Easy as A,B,C? Adapting Pediatric
Protocol Designs from Existing Adult
Data and Study Templates
Rona Grunspan
Premier Research Group Ltd.
Objective: Learn the main differences between
pediatric and adult study design that must be
addressed. Outline the medical considerations
that every pediatric protocol should include.
Breakdown protocol elements specific for children
and family participation that will permit a study
to succeed.
Method: Scientific methods used for protocol
design and observed in the authorship of clinical
study proposals may be similar across scientific
disciplines in human health research in which
patient safety and GCP are central goals. This
presentation will breakdown the key child-centric
considerations.
Results: Case studies to be attached to poster.
Conclusion: Concepts in pediatric research design
are unique and require special consideration by
those first venturing into the realm of conducting
clinical research with children as subjects or
facing their first pediatric protocol deliverable.
W 43
The Construction and Promotion of
Medication-Used Safety Education for
Traditional Chinese Medicine in Taiwan
Tsung-Ta Wu
Department of Chinese Medicine and Pharmacy,
Taiwan
Objective: The objective of this study is to
intensify the correct knowledge of medicationused safety for traditional Chinese medicine in
Taiwan
Method: For this study, ten resource centers of
medication-used safety for traditional Chinese
medicine were established in Taiwan. We invited
experts in various fields to develop five core
abilities, SLOWS (See, Listen, Obey, Withdraw,
and Select), for using medicine correctly
Results: In this study, we held various promotion
activities of medication-used safety education
for traditional Chinese medicine (TCM), and the
questionnaires were collected after medicationused safety educating. There are totally 1,284
questionnaires, and among them, there were
1,066 valid questionnaires. The result shows
that the incorrect cognition can be significantly
improved after educating. For example, the
resources of purchasing TCM have been
dramatically changed, and nearly 70% of people
will choose Chinese medicine clinic and Chinese
herbal pharmacy to buy Chinese herbal medicine
rather than looking for unidentified resources.
Furthermore, we also founded five classes of
digital learning course of TCM and put them in
website of National Academy of Civil Service for
reference last year. According to the data from
website, about 131,000 participants attended to
the learning classes until December 31, 2013.
Conclusion: The result from the questionnaires
reveals that the promotion of medication-used
safety education is successful to enhance the
correct cognition. We also believe that the
medication-used safety education is helpful
to clarify a part of people with myth and
misunderstanding of TCM. Therefore, we still
should make efforts to improve the level of
medical knowledge of TCM in Taiwan.
W 44
Patterns of Regulatory Approval for
Targeted and Immunotherapeutic
Compounds Indicated for the
Treatment of Metastatic Melanoma in
the US and EU
Jonathan Nguyen Diep
Rutgers, The State University of New Jersey
Objective: This study aims to track key primary
and secondary endpoints used to support
the filing of all approved compounds for the
treatment of metastatic melanoma. Analysis
of study endpoints will provide further
understanding for the regulatory requirements of
targeted and immunotherapeutic compounds.
Method: We identified the primary and
secondary endpoints of pivotal trials for approved
mono- and dual-therapeutic compounds for the
treatment of metastatic melanoma in the US and
EU. All data was collected via publicly available
regulatory resources such as clinicaltrials.gov and
ema.europa.edu.
Results: The preliminary results demonstrate that
the key primary and secondary endpoints include
overall response rate (ORR), duration of response
(DOR), relapse-free survival (RFS), progressionfree survival (PFS), and overall survival (OS).
Despite the unfavorable adverse effect profile
and dosing regimen, earlier compounds such
as dacarbazine were not required to meet the
robust endpoint of overall survival (OS) in order
to gain approval. However, as the standards for
evaluation have evolved, tumor response rates
(e.g. ORR) continue to be key endpoints, while
more robust endpoints such as overall survival
have emerged as important measures of efficacy.
As new immunotherapeutic modalities move into
the melanoma treatment landscape, regulatory
agencies will continue to require companies to
demonstrate increasing clinical and economic
benefit.
Conclusion: It is evident that over the years
that the FDA and EMA agencies have adjusted
preferred endpoints for the advanced or
metastatic melanoma indication. These changes
have become necessary as the standards
in measuring patient outcomes continue to
evolve. As a relatively new mode of treatment,
there is an incomplete understanding of many
immunotherapy compounds. As a result, the
various required and recommended endpoints
evaluated are utilized to identify further safety
and efficacy benefits, about a treatment
modality that is not thoroughly understood. To
be noted the study analysis primarily evaluated
FDA approval with minor evaluation of EMA
approvals, due to pending EMA reviews of several
compounds. Further, the results of these study
endpoints will provide additional understandings
of immunotherapy and provide precedence for
the future landscape of similar compounds.
W 45
Retrospective Chart Review Studies:
Key Considerations for Fullfilling
Safety Reporting Requirements
Dara Stein, MSc
UBC: An Express Scripts Company
Objective: To highlight main considerations when
reporting drug safety outcomes in national and
international retrospective chart review studies
and describe strategies for ensuring safety
reporting requirements are met.
Method: Critical review/qualitative analysis of
six chart review studies conducted in Canada,
the United States, and select European/ROW
countries that evaluated drug utilization and
clinical/safety outcomes was performed to
highlight challenges to safety reporting and
strategies for overcoming challenges.
Poster Abstracts | diahome.org/DIA2014
36
DIA 2014 50TH Annual Meeting
June 15-19 | San Diego, CA
Results: Two out of 6 case studies were post
authorization safety studies (PASS); one study
was mandated by the EMA and one study was
non-mandated (imposed by the sponsor).
Sample sizes ranged from 200-500 patients;
number of study centers ranged from 12-40.
Therapeutic areas included oncology, cardiology
and infectious diseases. Safety reporting
requirements varied across studies. Expedited
reporting of safety outcomes (within 24 hours
of notification) was required for all 6 studies.
Three studies reported non-serious and serious
adverse events (AEs/SAEs) documented as being
related to the sponsor products as assessed using
chart review explicit documentation. Reporting
requirements varied for the other three studies.
One study reported SAEs documented as being
related to the sponsor product; the other study
reported all SAEs that occurred while on the
sponsor product(s) regardless of documented
product relationship. The last study reported all
AEs/SAEs that occurred while on the sponsor
product(s) regardless of documented product
relationship. Reporting requirements were driven
by PASS indication, whether the studies were
mandated or non-mandated by regulatory bodies,
country specific regulations, data being collected
and research sponsor standard operating
procedure (SOP) safety reporting requirements.
European safety reporting directives for noninterventional studies collecting secondary use
data are more defined compared with other
countries. Expedited reporting posed challenges
for regulatory requirements since not all safety
data fields were generally completed within
24 hours of AE/SAE notification leaving the
safety reporting form incomplete. Safety data
discrepancies could not generally be resolved
prior to the safety reports being generated;
safety reconciliation was therefore challenging.
Participating physicians were sometimes
reluctant to safety reporting since the AEs/SAEs
should have been previously reported at time of
occurrence.
Conclusion: When safety data are collected in
chart review studies, the early delineation of a
safety reporting plan is paramount to address
ambiguity in guidelines as well as variability in
requirements across research sponsor SOPs.
More clarity regarding safety reporting directives
from regulatory bodies is warranted. DIA
2015
51 Annual Meeting
st
June 14-18 | Washington, DC
DIA 2015 Call for Abstracts Opening Soon!
General Call for Abstracts
Opens August 4, Closes September 16
Call for Student Poster Abstracts
Opens August 4, Closes March 31
New! Call for Hot Topics
Opens December 1, Closes January 21
Call for Professional Poster Abstracts
Opens January 26, Closes March 3
Visit diahome.org/dia2015
for more information.
Poster Abstracts | diahome.org/DIA2014
37