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Tufts Center for the Study of Drug Development
TUFTS UNIVERSITY
Outlook 2015
R&D Trends
Regulatory
Environment
Biotechnology
Sector Trends
Prescription
Drug Policy
R&D Management
and Operations
CONTACT THE TUFTS CENTER FOR THE STUDY OF DRUG DEVELOPMENT
Tufts CSDD’s multidisciplinary faculty conduct research, publish, and speak regularly on a wide variety of topics
related to pharmaceutical and biopharmaceutical development.
Contact
Expertise
Kenneth I Kaitin, PhD
n Economic and regulatory environment
n R&D and corporate strategy
n Academic-industry partnerships
n Emerging markets
n New business models
Professor and Director
Tel617-636-2181
[email protected]
Christopher-Paul Milne, DVM, MPH, JD
Research Associate Professor and Director of
Research
Tel617-636-2188
[email protected]
Joseph A. DiMasi, PhD
Research Associate Professor and Director of
Economic Analysis
Tel617-636-2116
[email protected]
Joshua P. Cohen, PhD
Research Associate Professor
Tel617-636-3412
[email protected]
Ken Getz, MBA
Research Associate Professor and Director of
Sponsored Research Program
Tel617-636-3487
[email protected]
Ronald Evens, PharmD, FCCP
Adjunct Research Professor
Tel707-317-3046
[email protected]
Richard I. Shader, MD
Senior Research Fellow & Medical Consultant;
Professor Emeritus, Pharmacology &
Experimental Therapeutics
Tel617-636-3856
[email protected]
n Impact of regulatory policy
n Orphan drug program
n Pediatric initiative
n Counter-bioterrorism initiatives
n Global R&D and innovation
n Cost of drug development
n R&D efficiency
n Clinical approval success rates
n Post-approval R&D
n Therapeutic class development trends
n Prescription drug policy
n Formulary trends
n Follow-on drug development trends
n Prescription-to-over-the-counter switching
n Drug development management trends
n Contract research organizations
n Investigative site landscape
n International clinical trials
n E-technologies in drug development
n Biotechnology product development
n Novel biotech research platforms
n Biosimilar development
n Biotech business models and financing
n Experimental design
n Clinical pharmacology and therapeutics
n Clinical research ethics
A
bout Tufts CSDD and this Report
Founded in 1976, the Tufts Center for the Study
of Drug Development at Tufts University School of
Medicine is a multidisciplinary, academic research
group that develops strategic information to help
all stakeholders in the life sciences enterprise—
including drug developers, regulators, policy makers,
payers, and investors—improve the quality and efficiency of biopharmaceutical discovery, development,
and review.
Kenneth I Kaitin, PhD, director of Tufts CSDD since
1998, leads a team of six research professionals and
11 research and administrative support staff who:
n Monitor and report on the development, regulation,
and utilization of new drugs and biopharmaceuticals.
n Explore the economic, legal, scientific, and public
policy issues affecting pharmaceutical and biopharmaceutical innovation worldwide.
n Analyze the development and review process for
new therapeutic agents.
n Sponsor conferences, roundtables, and public
forums that bring together the often diverse perspectives of government, industry, academia, and
public health advocacy.
n Raise the level of national and international debate
on issues related to new drug and biotechnology
product development and regulation.
Tufts CSDD Outlook, published each January, showcases Tufts CSDD’s views on near-term pharmaceutical
and biopharmaceutical development trends. Data
contained in Outlook 2015 are based on proprietary
research conducted by Tufts CSDD. Analyses are
from the ongoing work of Tufts CSDD’s research
staff, who confer regularly with a broad range of
pharmaceutical and biopharmaceutical industry
­leaders, as well as with regulators, policy makers,
academics, investors, service providers, and others
involved in biomedical innovation.
Outlook 2015 constitutes one element in a full range
of information and related services focused on the
research-based drug and biotechnology industry and
other stakeholders in pharmaceutical innovation.
Other Tufts CSDD offerings include professional
development programs, graduate level courses,
­workshops, and symposia. In addition, Tufts CSDD
publishes the Tufts CSDD Impact Report, a bi-monthly
newsletter providing analysis and insight into critical
drug development issues, and the Tufts CSDD R&D
Management Report, a quarterly review of strategic
issues in pharmaceutical R&D.
Research findings developed by Tufts CSDD are regularly published in peer-reviewed, trade, and business
publications, and Tufts CSDD faculty are quoted
frequently in the business, industry, scientific, and
general interest press worldwide.
For more information, call 617-636-2170 or click
on http://csdd.tufts.edu.
© 2015 Tufts University. All rights reserved. No part of Outlook 2015 may be reproduced, transmitted, or ­distributed by
any means, mechanical or electronic, in whole or in part, without written permission from the Tufts Center for the Study of Drug
Development.
1
G
lossary
Biosimilar — A follow-on, approved biopharmaceutical that is biologically similar to an existing medicine.
Clinical trial — A specific type of clinical study in which a medical intervention is tested against a placebo
or an active control in human subjects. Clinical study is a broader term that includes other forms of human
participatory research, such as pharmacokinetic, epidemiologic, and behavioral studies.
Companion diagnostic — A diagnostic test linked to a therapeutic drug, which serves to stratify populations
into responders and non-responders, as well as indicate likelihood of adverse events in particular patients.
CRO — Contract research organization. A business entity that manages one or more steps in the drug
development process, including conduct of preclinical studies, clinical study design and execution, data management, analysis, medical writing, and regulatory submission.
Neglected diseases — 13 diseases or disease categories defined by the G-FINDER (Global Funding of
Innovation for Neglected Diseases Report), published in 2009 by the George Institute for International Health,
which include malaria, kinetoplastids, diarrheal diseases, helminths, bacterial pneumonia and meningitis, and
typhoid fever.
Monoclonal antibody (mAb) types — Murine mAbs are derived from mouse genes; human mAbs are
derived from human genes; chimeric and humanized mAbs are each derived from varying amounts of mouse and
human genes, with the humanized products containing more human protein sequence than the chimeric versions.
Orphan drug — Drugs developed for rare diseases and conditions, which, in the United States, affect fewer
than 200,000 people, or, in the European Union, affect 5 per 10,000 people or fewer. Because sales of orphan
drugs are likely to be small compared to their development costs, pharmaceutical companies are awarded
exclusive rights to market these medicines for a period of time as an incentive to develop them.
Personalized medicine — The tailoring of medical treatment and delivery of health care based on the
individual characteristics of each patient, including genetic, molecular, imaging, and other personal determinants.
Phase I — Studies typically conducted in healthy volunteers to determine the pharmacokinetic and pharmacologic actions of a drug in humans, the side effects associated with increasing doses, and, in some cases,
early evidence of effectiveness.
Phase II — Studies designed to obtain data on the efficacy of a drug for a particular indication or indications in patients with the disease or condition.
Phase III — Expanded controlled and uncontrolled trials to gain additional data about efficacy and safety
needed to evaluate the benefits and risks of a drug.
Phase IV — Studies conducted after a drug is approved for marketing to provide expanded safety and
­efficacy data on the drug when used in the general patient population, and to generate information to improve
the prescribing, use, quality, or manufacture of the product.
Protocol — A plan detailing the methodology of a clinical study.
Recombinant protein — Protein produced through the combination of DNA fragments from different
sources.
Specialty pharmaceuticals — Drugs used to treat chronic, complex, or life threatening conditions, such
as cancer and autoimmune diseases. They are typically priced higher than traditional medicines.
2
OT
utlook2015
he essential challenge for drug sponsors,
­policy makers, and payers—today and for
the foreseeable future—is to balance the
need for new, innovative medicines with the
equally pressing need to bring health care spending
under control. New products that successfully treat
complex diseases, while positive in and of themselves,
are spurring demand for more—and usually more
expensive—medicines for unmet medical needs.
Success though, is not cheap – it now costs nearly
$2.6 billion to develop and gain marketing approval
for a new prescription drug. (See chart below.)
Sponsors looking for the most promising returns on
investment have been transitioning from a high-volume, low-margin business model to a low-volume,
high-margin model, directing a growing share of their
resources toward development of precision medicines, specialty pharmaceuticals, and orphan drugs.
However, in five years or so, when many of these
narrowly targeted products now in development
reach the market, they may encounter strong payer
resistance. Recent payer reluctance to reimburse for
Solvaldi, a hepatitis C cure that costs patients $1,000
a pill and $84,000 for a course of treatment, could
be a harbinger of a reimbursement brick wall. Payers
will need to make tough choices about what to cover
and what not to cover. Ultimately, payers and sponsors will have to jointly determine what evidence is
needed to demonstrate value, and what represents a
fair price.
Government and regulators have significant roles to
play in the unfolding health care cost drama. For example, in 2014, the Energy and Commerce Committee
in the U.S. House of Representa­tives launched the
21st Century Cures Initiative, which aims to accelerate the pace of discovery, streamline drug and device
development, and expand the use of digital medicine
and social media in delivering treatment. European
and Japanese authorities will likely explore similar
programs, as they increasingly find that cost controls
cannot rein in growing health care spending. A key
challenge for all governments is to maintain strong
incentives for sponsors to innovate, while finding
new approaches to ensure that healthcare remains
affordable.
Pressing ahead, all stakeholders—sponsors, payers,
­regulators, legislators, physicians, and patients—will
need objective, unbiased data for effective decision
making. Tufts CSDD, through its scholarly studies and
analyses, will continue to fulfill its mission of informing
this critical debate.
NEW DRUGS NOW COST NEARLY $2.6 BILLION, SHAPING DIRECTION OF SPONSORS’ R&D EFFORTS
Average Cost to Develop and Win Marketing Approval for a New Drug
1970s - early 1980s
1990s - mid 2000s
1980s - early 1990s
2000s - mid 2010s
3000
Rising R&D costs, driven mainly by increased out-ofpocket costs and higher failure rates for drugs tested
Millions of 2013$
2500
in human subjects, means the average cost to develop
and gain marketing approval for a new prescription
2000
medicine, a process often lasting longer than a
1500
decade, is now $2.56 billion dollars. Drug developers
continue to make efforts to rein in costs, but also have
1000
responded by focusing their R&D on products for
markets with more attractive investment returns.
500
0
Pre-clinical
Clinical
Source: Tufts Center for the Study of Drug Development
3
Total
R
&D
Trends
Oncology development activity will expand,
driven by advances in science, medical
need, and regulatory and market incentives.
Across all therapeutic areas, developers
will increasingly rely on risk-sharing and
collaborative relationships, from discovery
through development, to spur innovation
and reduce costs.
FIRMS WILL CONTINUE TO INVEST HEAVILY IN CANCER DRUG
DEVELOPMENT
Trends in New Drug and Biologics Approvals by Therapeutic Class (four largest
classes)
Antineoplastic
Anti-infective
CNS
Cardiovascular
2010-13
2000-09
n U.S. policymakers will continue to spur innovation
of drugs to treat resistant bacterial infections,
following the recent approval of antimicrobials that
were developed under the Generating Antibiotic
Incentives Now (GAIN) program, authorized as
part of the FDA Safety and Innovation Act of 2012.
n Drug developers will continue to participate in
risk-sharing relationships and other strategic
partnerships with academic institutions, patient
groups, contract research organizations, and
other developers to improve R&D productivity.
Pre-competitive consortia will grow as membership by developers expands.
n Clinical trial costs will continue to increase as
­payers demand more information on how new
drugs and biologics perform relative to products
already on the market. Increases in trial costs due
to comparator testing will be greater for new biologics than for small molecule drugs, because of
the high cost of acquiring comparator biologics.
n Pharmaceutical companies will increase their use
of outsourcing providers during the development
process, but will experiment with a number
of outsourcing models to improve quality and
reduce costs.
1990-99
1980-89
0%
n Drug and biologic developers will expand their
investment in new cancer therapies as a consequence of advances in the scientific understanding
of the molecular basis of human cancers, cancer
immunotherapy and its role in dealing with drug
resistance, and how cancer drug combinations can
best be utilized.
10%
20%
30%
40%
50%
60%
70%
Share of New Drug Approvals in U.S.
NOTE: Anti-infective excludes AIDS antivirals
Source: Tufts Center for the Study of Drug Development
Cancer (antineoplastic) compounds now account for about 30% of all U.S. approvals.
Interest in developing new cancer medicines has expanded, due in part to new approaches
to development, including greater focus on new targets within validated and new pathways, novel drug formats, and improved clinical study design.
4
R
egulatory Environment
Public demand for new and innovative
medicines to treat a wide range of diseases,
for broad as well as narrow populations,
will spur regulatory authorities to increase
engagement with stakeholders and
encourage sponsors to explore novel
development pathways.
n The U.S. Food and Drug Administration (FDA) will
respond to Congressional calls for improved clinical trial efficiency by supporting i­nitiatives, such
as the Lung Cancer Master Protocol, that create a
­single clinical trial infrastructure for testing several
drugs simultaneously, and evaluating the Special
Medical Use or Limited Population Pathway, that
encourages novel development programs for
­limited, well-defined subpopulations with unmet
medical needs.
n The FDA will expand stakeholder engagement
under the auspices of 22 public-private-partnerships,
and will push forward on patient-focused drug
development, informed by public meetings with
advocacy groups and others.
THE JURY IS STILL OUT ON EFFORTS TO MEET RAPIDLY DEVELOPING
THREATS TO PUBLIC HEALTH
Ebola Products in Development to Enhance U.S. Public Health and Medical
Preparedness
Number of products
Number of sponsors
60
n Regulatory agencies will expand use of new
tools, standards, and approaches to evaluate new
­technologies and novel products. For example,
the FDA is focusing its efforts on nanotechnology
and nanomaterials; the EMA is relying on new
methods and tools to study the impact of juvenile
diabetes and age-related macular degeneration;
Japan’s Pharmaceutical and Medical Devices
Agency is looking to become the world leader for
conditional approval of, and accelerated reimbursement for, regenerative medicines.
50
40
30
20
10
0
n European and U.S. regulators will continue to
encourage use of expedited development programs
aimed at bringing new drugs to market more
quickly: the European Medicines Agency (EMA)
has launched an adaptive licensing pilot program,
while the FDA’s Breakthrough Therapy Designation
program is booming – with more than 200 requests.
2006
2010
2014
Source: Tufts Center for the Study of Drug Development
The Medical Countermeasures Initiative—launched in 2002 to coordinate development,
preparedness, and response against threats to U.S. and global public health, including
from emerging infectious diseases and pandemics—has spawned a growing number
of compounds now in development. The chart above demonstrates the increase in the
­pipeline over time for just one such threat – Ebola. In addition to biopharmaceutical
sponsors, a fledgling R&D sector comprised of small firms and public sector research
institutes is working to counter rapidly developing threats to public health, but there
remains an open question whether it can proceed fast enough.
5
B
iotechnology Sector Trends
The pace of biotech development and product
approvals will build on recent activity—25
biological approvals in the U.S. in the first
10 months of 2014—as the sector gains a
growing share of total pharmaceutical sales.
n A resurgence of genetic therapies, now underway
for near-term product opportunities, will continue,
evidenced by the number of biotech companies
focused on RNA inhibition products (20+) and
gene therapies (25+). Development agreements
between pharma companies and bio-genetic
­companies will increase.
n Cell therapies (CT) and stem cell therapies (SCT)
have become a significant focus of product
development, with 30+ CT companies and 20+
SCT companies engaged in all stages of clinical
research.
VARIETY AND NUMBER OF PRODUCTS IN DEVELOPMENT BODE WELL
FOR BIOTECH INDUSTRY GROWTH
Biotechnology Product Phase III Clinical Trials in 2014
Product Categories
Number of
Products*
Therapeutic Areas
Number of
Indications*
Monoclonal antibodies
74 (14)
Oncology
71 (23)
Recombinant proteins
46 (4)
Rheumatology
25 (6)
Biotech vaccines
23
Hematology
Cell therapy
14
Cardio-vascular
12 (3)
Genetic therapies
14
Neurology
11 (1)
Peptides
5
Diabetes mellitus
Other
7 (1)
TOTALS
183 (19)
14
11
Other areas (7 in total)
46 (14)
TOTALS
190 (47)
*N
umber of investigational biotech products in Phase III clinical trials; figure in parentheses is the number
of already marketed products undergoing Phase III trials for new indications (as of October 2014)
Source: Tufts Center for the Study of Drug Development
New biotech development—driven largely by monoclonal antibody products based on
novel platforms and recombinant protein compounds—will highlight biotech advances
in 2015 and beyond. Novel monoclonal antibodies include blockbuster potential treatments for hypercholesterolemia and further antibody drug conjugates in oncology.
Novel second-generation ­proteins will be a major development area, e.g., pegylation of
molecules may extend the duration of action, allowing for reduced dosing frequency.
6
n Immunotherapy is evolving rapidly, especially in
oncology, with a broader variety of novel molecules and mechanisms of action and higher
expected efficacy levels, e.g., chimeric antigen
receptor t-cells, newly targeted monoclonal
­antibodies, bispecific antibodies, and improved
vaccines.
n Alliances between pharma and biotech companies
will continue to be a mainstay of venture capital
and other investment, building on the recent past,
e.g., 392 antibody drug conjugate deals from 2009
through August 2014 (about 50 to 70 per year)
generated sales reported at more than $31 billion.
n Biosimilars are poised to have a significant impact
on the U.S. and EU markets, with monoclonal
antibodies constituting the biggest target for
developers. In the fourth quarter of 2014, 13 U.S.
and EU companies had 30 to 40 molecules in late
stage clinical trials, while an estimated 100 to 200
emerging market companies were engaged in trials
at different stages.
P
rescription Drug Policy
The continued rise in prices charged for
specialty pharmaceuticals will be tempered
by competition in several key therapeutic
classes, as well as the introduction of
biosimilars.
n Orphan drugs – Currently, more than one-third
of U.S. marketing approvals for new medicines are
for orphan drugs. This trend will likely continue,
with nearly 40% of new orphan approvals during
the next five years expected to be related to
­cancer treatment.
BIOSIMILARS ARE COMING IN THE UNITED STATES
Originator biologic
Selected indication(s)
Introduced in U.S.
Biosimilar
Genotropin (somatropin)
Growth failure
2006
Omnitrope
Xaparin (enoxaparin)
Blood thinner
2010
Lovenox
Originator biologic
Selected indication(s)
Expected U.S.
introduction
Biosimilar
Neupogen (filgrastim)
Bone marrow stimulant
2015
NA
Epogen (epoetinalfa)
Renal anemia
2015
NA
Humalog (insulin lispro)
Diabetes
2015
NA
Enbrel (etanercept)
Psoriasis, Rheumatoid arthritis
2016
NA
Humira (adalimumab)
Rheumatoid arthritis, Crohn’s
disease, Ulcerative colitis,
Psoriasis
2017
NA
Rituxan (rituximab)
Rheumatoid arthritis,
Non-Hodgkin’s lymphoma,
Chronic lymphocytic leukemia
2017
NA
Remicade (infliximab)
Rheumatoid arthritis, Ulcerative
colitis, Crohn’s disease
2018
NA
Herceptin (trastuzumab)
Breast cancer
2019
NA
Source: Tufts Center for the Study of Drug Development
Patent expirations on several high-profile biologics in 2013 and 2014 paved the way for
the introduction of biosimilars. With biosimilars expected to be priced 25% – 30% below
the price of originator biologics, payers in the U.S. are likely to save tens of millions of
dollars over the next five years.
7
n Neglected diseases – The Ebola outbreak will
renew focus on policies to stimulate R&D spending
for neglected disease drug development. Drug
companies will enhance their drug donation programs targeting neglected disease patients in the
developing world.
n Pricing – High-priced drugs to treat a number
of diseases for which inadequate or no therapies
currently exist—for example, a typical 12-week
course of treatment with Sovaldi for a patient
with Hepatitis C costs $84,000—will face growing
resistance from payers, who increasingly will seek
lower-priced alternatives.
n Biosimilars – U.S. approval of a relatively large
number of biosimilars is likely within one to three
years, now that a regulatory pathway is in place.
In Europe, where a pathway was enacted in 2006,
uptake has been slow due to safety concerns and
lack of familiarity among physicians. Similar
challenges are initially likely to occur in the U.S.,
but then biosimilar uptake will expand rapidly as
payers look to biosimilars to reduce costs.
R
&D
Management and Operations
Drug sponsors will implement new
strategies to improve clinical study design
feasibility, data transparency and disclosure, and collaborative effectiveness with
CROs and investigative sites to achieve
higher levels of study volunteer engagement and satisfaction.
NUMEROUS FACTORS ARE ESSENTIAL TO LEVERAGING THE VALUE OF
STRATEGIC RELATIONSHIPS
Change Orders by Outsourcing Relationship Model
Transactional relationships
Strategic relationships
Average Number per Study
6
5
4
3
2
1
0
Phase I
Phase II
Phase III
Phase IV
Source: Tufts Center for the Study of Drug Development
Although it is widely anticipated that strategic alliances will result in fewer change orders
(defined as formal, written changes to the original scope of work agreement), due to
greater shared upfront planning between sponsors and CROs and more operating
­autonomy transferred to contract service providers, a recent Tufts CSDD study found
no difference in the frequency of change orders between traditional transactional relationships and strategic alliances. This suggests that the latter have a limited impact on
development efficiency.
8
n Simultaneous and inconsistent use of contract
research organization (CRO) partners to support
project- and program-specific responsibilities is
causing operating friction and inefficiency, which
will lead some sponsors to rethink their outsourcing strategies.
n Private equity will consolidate the global investigative site landscape to drive up scale efficiencies
as sponsors and CROs demand higher levels of
performance in recruiting and retaining volunteers
at contained costs.
n Adoption of simple (e.g., early futility, sample size
re-estimation) and more sophisticated (e.g., dose
response, randomization ratios) adaptive clinical
trial designs will accelerate as functions within
sponsor companies vie to increase data quality
and program success rates.
n Sponsors and CROs will make greater use of large
structured and unstructured datasets to perform
predictive analytics, refine research agendas and
protocol designs, identify and engage study volunteers, gather real-time management metrics, and
improve regulatory submissions.
S
elected CSDD Publications
Listed below are selected articles published in 2014 by Tufts CSDD research staff.
R&D TRENDS
DiMasi JA. Pharmaceutical R&D performance by firm
size: Approval success rates and economic returns.
American Journal of Therapeutics 2014;21(1):26-34.
DiMasi JA, Kim J, Getz KA. The impact of collaborative and risk-sharing innovation approaches on
clinical regulatory cycle times. Therapeutic Innovation
and Regulatory Science 2014;48(4):482-487.
Getz KA, Lamberti MJ, Kaitin KI. Taking the pulse
of strategic outsourcing relationships. Clinical
Therapeutics 2014;36(10):1349-1355.
Evens RP, Kaitin KI. The biotechnology innovation
machine: A source of intelligent biopharmaceuticals
for the pharma industry – mapping biotechnology’s
success. Clinical Pharmacology and Therapeutics
2014;95(5):528-532.
Kaitin KI. Editorial. Integrated partnerships and transformation of pharmaceutical research and development. Clinical Therapeutics 2014;36(10):1346-1347.
Milne C-P, Garafalo S, Bryan C, McKiernan M.
Trial watch: Personalized medicines in late-stage
development. Nature Reviews Drug Discovery
2014;13(5):324-325.
Smed M, Getz KA. Site characteristics influencing
the translation of clinical research into clinical practice. Therapeutic Innovation & Regulatory Science
2014;48(5):628-634.
Stergiopoulos S. Non-clinical drug development in
Asia. Pharma Focus Asia 2014;(20):5-6.
PRESCRIPTION DRUG REGULATION AND
POLICY
Cohen JP, Felix AF. Complying with state and federal
regulations on essential drug benefits: Implementing
the Affordable Care Act. American Journal of Managed
Care 2014;20(2):31-36.
Cohen JP, Felix AF. Are payers treating orphan drugs
differently? Journal of Market Access & Health Policy
2014;2:1-5.
9
Cohen JP, Felix AE, Riggs K, Gupta A. Barriers to
market uptake of biosimilars in the US. Generics and
Biosimilars Initiative 2014;3(3):107-114.
Cohen JP, Sturgeon G, Cohen A. Measuring progress
in neglected disease drug development. Clinical
Therapeutics 2014;36(7):1037-1042.
DiMasi JA, Milne C-P, Tabarrok A. An FDA report
card: Wide variance in performance found among
agency’s drug review divisions. Project FDA Report.
No. 7, April 2014; Manhattan Institute for Policy
Research.
Getz KA. The Gift of Participation: A Guide to Making
Informed Decisions About Volunteering for a Clinical
Trial. 2nd ed. Boston: CISCRP;2014.
Milne C-P, Davis J. The Pediatric Studies Initiative:
After 15 years have we reached the limits of the
law? Clinical Therapeutics 2014:36(2):156-162.
Von Eschenbach A, Sharp P, Kaitin KI. Op-Ed. An Rx
for making wonder drugs. Boston Herald. August 26,
2014:p16.
R&D MANAGEMENT AND OPERATIONS
Getz KA. Adoption of adaptive trial designs poised to
accelerate. Applied Clinical Trials 2013;22(11):16-18.
Getz KA. Improving protocol design feasibility to
drive drug development economics and performance.
International Journal of Environmental Research and
Public Health 2014;11(5):5069-5080.
Getz KA, Stergiopoulos S. Therapeutic area variability in the collection of data supporting protocol
end points and objectives. Clinical Investigation
2014;4(2):125-130.
Lamberti MJ, Getz KA, Naik P, Costello M. Clinical
supply capabilities, practices, and perceptions
among investigative sites. Applied Clinical Trials
2014;23(8/9):20-24.
A
genda2015
T U F TS C S D D RE S E A RC H PROJ EC TS D U E FO R CO M PLE T I O N
R&D TRENDS: STRATEGY, OPERATIONS, AND MANAGEMENT



n
n
n
n









n
n
n
n
n
n
n
n
n
C
ost of pharmaceutical R&D
Measuring
R&D costs by therapeutic class
P redictors of success rates for compounds entering late-stage clinical trials
C
urrent state of personalized medicine and companion diagnostic development: update of 2010 Tufts
CSDD assessment
D
rug-diagnostic co-development in late-stage personalized medicine pipeline
A
daptive clinical trial designs: adoption and impact
O
utsourcing strategies and operations
U
se and impact of new investigative site start-up practices and solutions
P rotocol amendments: direct and indirect costs [CSDD Multi-Company Project Series]
B
ig Data adoption and use in clinical research [CSDD Multi-Company Project Series]
B
enchmarking risk-based monitoring practices [CSDD Multi-Company Project Series]
N
ew investigative site management strategies [CSDD Multi-Company Project Series]
C
linical supply logistics strategies and their impact [CSDD Multi-Company Project Series]
REGULATORY TRENDS

n F DA’s Breakthrough Therapy Designation program: a progress report
n Medical countermeasures for bioterrorism: impact of new regulatory policies and procedures on product
landscape
n Cost of regulatory harmonization [CSDD Multi-Company Project Series]
BIOTECHNOLOGY SECTOR TRENDS



n R
ates of return for new biologics and biosimilars compared to new small molecules
n Landscape for biopharmaceutical products and sponsors
n Trends in vaccine development and regulation
PHARMACEUTICAL POLICY AND MARKET TRENDS






n R
elative contribution of the private and public sectors to the R&D of the most transformational drugs of
the last quarter century
n Market for prescription to over-the-counter switches in the U.S. and EU
n Drug and device reimbursement policies: impact on innovation
n Pharmaceutical industry donation programs targeting neglected diseases
n Drug shortages: causes and impact
n Assessing the personalized medicine landscape
10
A
genda2015
T U F TS C S D D E D U C AT I O N A L PROG R A M S
February 2-6, 2015
Postgraduate Course in Clinical Pharmacology, Drug Development, and Regulation
BostonNow in its 42nd year, the Tufts CSDD Postgraduate Course provides advanced instruction in clinical pharmacology, drug development, clinical trial strategies, biopharmaceutical development, drug safety, and the
­regulatory process. The 2015 course features lectures, breakout groups, and an interactive panel discussion.
Over five days, expert faculty will examine clinical trial ethics, outcomes research, epidemiology, and vaccine
development. The program includes an interactive, mock presentation to regulators, providing participants with
a unique opportunity to identify and analyze the impact of drug design protocols on the regulatory process.
February 26, 2015
Tufts CSDD Executive Forum Roundtable: FDA’s Breakthrough Therapy Designation –
Boston A Three-Year Assessment
The Tufts CSDD Executive Forum Roundtable Series brings together R&D leaders from industry, academia,
and contract services organizations to discuss strategic R&D issues and new approaches that will guide the
research-based industry to future success. More on Inside Back Cover.
May 14, 2015
Boston Tufts CSDD Executive Forum Roundtable: Diagnostic-Therapeutic Co-development
Strategies and Best Practices
See Inside Back Cover.
July 7-8, 2015
Leadership for Drug Development Teams: Improving Cross-Functional R&D Performance
BostonDesigned in collaboration with industry R&D leaders, the curriculum is based on challenges experienced by
hundreds of development teams, program managers, and functional directors. Two-thirds of the course is
devoted to hands-on casework, with the rest focused on interactive discussion with faculty. Attendance is
limited to 35.
September 17, 2015
Boston
Tufts CSDD Executive Forum Roundtable: Novel Approaches to Overhauling the Clinical
Development Process
See Inside Back Cover.
November 12, 2015
Boston
Tufts CSDD Executive Forum Roundtable: Patient Recruitment and Retention 2.0
See Inside Back Cover.
LOOKING AHEAD :
February 2016
Boston
Postgraduate Course in Clinical Pharmacology, Drug Development, and Regulation
See description above.
For more information about these programs, call the Tufts Center for the Study of Drug Development at
617-636-2170, email to [email protected], or visit http://csdd.tufts.edu and click on the “COURSES & FORUMS”
section.
11
T
Professionals worldwide who need to understand the current state of drug development
and regulation read the
ufts CSDD Impact Report
Shouldn’t you?
T ufts CSDD Impact Reports provide a bi-monthly, authoritative analysis of critical drug development issues,
highlighting current research from the Tufts Center for the Study of Drug Development – clearly, concisely.
Each issue, presented in an easily accessible four-page format, delivers original research, analysis, and insight
on mission-critical topics relating to the nature and pace of drug development and regulation, which can’t be
found anywhere else.
It’s why, year after year, readers describe Tufts CSDD Impact Reports as “thoughtful and timely” and
“a real asset.”
Available electronically or in hard copy.
2015 EDITORIAL CALENDAR:
n J
anuary/February — The Current Investigative Site Landscape
n March April — Personalized Medicines: Development and Market Trends
n M
ay/June — Trends in Vaccine Development
n July/August — The Biosimilars Market
n S
eptember/October — Clinical Success Rates in New Drug Development
n November/December — New Outsourcing Strategies and Operations
Volume 16, Number 1 • January/February 2014
Tufts Center for the Study of Drug Development
Impact
TUFTS UNIVERSITY
Substantial amount of data collected doesn’t support primary and key secondary endpoints
Distribution of Endpoint Type and Procedure Type per
Protocol
REPORT
Phase II
Protocols
Endpoints
ANALYSIS AND INSIGHT INTO CRITICAL DRUG DEVELOPMENT ISSUES
Impact
New Breakthrough Therapy Designation
program aims to cut clinical trial time
Impact
Only 30% of the first 113 BTD requests were approved
REPORT
CNS drugs take longer to develop, have
lower success rates, than other drugs
U.S. approval rate for CNS compounds less than half that of all other compounds
Mean clinical development time for CNS drugs approved for marketing in the United
States from 1999 through 2013 was 12.8 months, or 18%, longer than that for nonCNS compounds.
The overall clinical approval success rate for CNS compounds first tested in human
subjects from 1995 to 2007 was 6.2%, or less than half the 13.3% rate for non-CNS drugs.
The overall approval success rate for CNS compounds first tested in human subjects
during 1995-07 varied from a low of 3.7% for 1997-00, to a peak of 11.3% for 2001-04,
and then to 4.7% for 2004-07.
During 1999-13, mean approval phase time for CNS compounds approved for marketing
in the U.S. was 19.3 months, or 31% longer than the 14.7 months for non-CNS approvals.
From 1999 to 2013, about one in six CNS compounds received a priority review
rating from the U.S. Food and Drug Administration (FDA), compared to nearly half
of all non-CNS compounds.
Despite longer clinical and approval phase times, and lower clinical success rates,
CNS approvals have held steady, accounting for about one in 10 of all U.S. approvals
since the 1980s.
The BTD was designed to supplement and complement the FDA’s other expedited
development and review programs – priority review, fast track, and accelerated approval.
of the BTD program.
how to set up a page or site, and privacy issues
study volunteers
Nearly all sponsors have developed guidelines to
address employee use of social media.
7.1%
20.7%
30.6%
Objectives of Procedures Collecting Non-Core Data
6
7
8
15%
10%
0%
Safety
Efficacy
Outcomes
the CSR
The extent of risk-sharing and collaborative clinical development relationships
6
4
2
Mobile
Apps
Source: Tufts Center for the Study of Drug Development
Tufts CSDD Impact Report • page 2
Other
appeared in
the TLF
appeared in
the Appendix
among firms varied by therapeutic class; 25% of AIDS antiviral approvals involved
L
Other concerns include encouraging non-adherence
pharmaceutical and biotechnology companies in recent years increasingly have
and early drop-out, providing medical advice regarding engaged in innovative partnerships that include joint development, mergers and
safety and efficacy, violating privacy and confidential- acquisitions (M&A), and in-licensing of drug candidates developed by others.
Tufts CSDD Impact Report • page 2
ity, and influencing patient willingness to participate.
While such collaborations can yield important advances, they also can interrupt the
drug development process and affect program-level clinical and regulatory cycle times.
Tufts CSDD sought to identify and quantify the impact of such interruptions.
Highlights of that assessment are summarized in this report.
arrangement, or an M&A transaction—called interrupted development programs in this
Twitter
Tertiary/
Exploratory
Source: Tufts Center for the Study of Drug Development
Data from all
As a result of widespread concerns, nearly all comrisk-sharing, compared to 65% of central nervous system
drug approvals.
procedures
94.3%
panies report fragmented and uncoordinated use
(N=5,929)
of social media with little policy or guiding practice
Mean clinical phase time was 8.9 months longer for new drugs in multi-firm, riskin place.
Non-core
datawas 9.5 months
sharing clinical development relationships, and total phase
time
Blog
Sponsors place a premium on the ability to track the
impact of social media on recruitment and retention: 12 of 13 companies report tracking number of
leads generated; 10 of 13 report tracking number of
patients screened; 8 of 13 report tracking screen
failure rates and subject randomization rates.
On average, approximately one-quarter of a study
budget’s direct costs were dedicated to procedures
that collect non-core data.
Less than 20% of procedures that collected noncore data supported outcomes-related endpoints,
(e.g., quality of life assessments, reimbursement)
and approximately 3% gathered biomarker data.
5%
programs take 14.8 months longer
than uninterrupted
About half of all new therapeutic drugs approved in 2000-11 involved a risk-sharing
Patient recruitment for clinical trials through social
report—have longer clinical phase durations than uninterrupted development programs.
media is expected to grow, with 9 of 14 companies
This finding supports anecdotal reports from the front lines: adjusting to a new operating
planning to increase adoption of social media to environment and new partners and uncertainty concerning resources most likely conrecruit in the U.S. and 5 of 12 planning to do so in
tributes to diminished development speed.
Western Europe.
8
Wide variation in the proportion of procedures
collecting non-core data was observed across therapeutic areas.
A large proportion of non-core procedures—particularly in Phase III studies—was associated with safety
and efficacy endpoints.
20%
Based on company reports, social media is being
used for patient recruitment on an estimated 11%Most notably, the analysis showed that active drug development programs that experience
a change in management structure, including a licensing, joint venture, co-development
of all trials.
12
Patient
YouTube
Community
Phase III Protocols
25%
approach to clinical development.
21% of procedures in Phase II protocols and nearly
one-third of procedures in Phase III protocols
collected data that are non-core, i.e., the data do
not support primary or key secondary endpoints,
regulatory requirements, or standard baseline
assessments.
RTypically,
E Pone-quarter
O RofT
clinical study budgets is devoted to collecting non-core data
ooking to reduce the high risks, costs, and inefficiencies of drug development,
5
10
Facebook
3.7%
9.7%
Non-core
92.4%
Platforms Used for Patient Recruitment (n=14)
Number of Companies Using
58.6%
Standard
appeared in
is adverse event reporting
Patient recruitment through social media is popular and growing
0
64.9%
Required
TUFTS
U N I V E R S I T Y4.6%
Primary and key secondary endpoints represented
53% of Phase II protocols and 44% of Phase III
protocols.
Source: Tufts Center for the Study of Drug Development
Only one in five companies that use social media
directly interacts with patients; most contract out The share of new drugs developed clinically under the auspices of a single developer
Most non-core data are source data verified and
declined from 47% of 2000-03 approvals to 41% of 2008-11 approvals.
engagement to a third party or use more passive
Assessing Data Usage
approaches, including placing banner ads on social
The share of co-developed drugs rose from 12% in 2000-03 to 22% in
2008-11.
Proportion
that Proportion that Proportion that
media sites.
Source: Tufts Center for the Study of Drug Development
To better understand the unique development challenges of CNS drugs, Tufts CSDD
examined the development and approval histories of 274 CNS and 1,168 non-CNS
investigational compounds that were first tested in human subjects from 1995 to 2007.
Tufts CSDD also examined the development and approval phase times of 42 CNS and
345 non-CNS therapeutic compounds approved in the U.S. from 1999 to 2013.
26.1%
96.6%
95.3%
56.7%
47.6%
only relationships.
(N=1,267)
longer, compared to new drugs that did not involve these
Top concerns cited include introducing research
bias (e.g., falsifying eligibility; un-blinding treatment
CSR = Clinical Study Report; TLF = Tables, Listings, and Figures
assignment) and distorting adverse event experiences
Source: Tufts Center for the Study of Drug Development
associated with study drug.
Number of Companies Mentioning
C
29.7%
19.1%
30%
Most companies report that they began using social
media in clinical research in Interrupted
2010 or later.
development
• Guidelines concerning authorized personnel use of social media
• Social
Board-specified
practices
s part of its reauthorization of the Prescription
DrugMedia
UserAdvisory
Fee Act
(PDUFA) in
• Guidance
for posting video
online
2012, Congress created the Breakthrough Therapy
Designation
(BTD),
a process
that allows the U.S. Food and Drug Administration
(FDA)
to expedite
the
• Directives
that stipulate
one-way
communication between
personnel
and patients
involvedwhere
in clinical studies
development and review of drugs intended to treat
a serious
condition
over
therapy
preliminary clinical evidence suggests substantial improvement
• Restrictions, e.g.,
foravailable
company business
only
on a clinically significant endpoint or on symptoms that represent serious consequences
Tufts drug
Centerdevelopment—priority
for the Study of Drug Development
of the disease. Although the FDA already had toolsSource:
to speed
review, fast track, and accelerated approval—those programs are limited in their ability
to address scientific, regulatory, and economic factors that are dramatically shifting the
Social media use raises many concerns; topmost
R&D landscape. Wher eas the BTD program generally has a higher evidentiary threshold
Top Concerns About Social Media Use (n=13)
for approval (i.e., substantial improvement on clinically significant endpoints), it provides
Adverse guidance
event reportingand organizational
a greater degree of facilitation by FDA (i.e., early intensive
commitment involving senior managers).
Poor targeting of
entral nervous system, or CNS, drugs, which treat a wide array of psychiatric and
neurodegenerative disorders, including depression, psychosis, epilepsy, and
Alzheimer’s Disease, are more challenging to develop than other medicines, because
the conditions they aim to treat are typically chronic and complex, and the clinical
endpoints are often difficult to measure. That’s why CNS drug development takes longer
and has a lower likelihood of overall clinical success than non-CNS drug development. CNS
drugs also experience longer regulatory approval times compared to non-CNS compounds.
27.8%
Exploratory
35%
Drug sponsors are primarily using social media to
distribute information (e.g., about drugs, diseases, and
the company) and to listen to patient and professional
conversations.
Representative Social Media Policies
Orphan and oncology drugs dominated the first class
awarded
bybusiness
the FDA.
• RulesofforBTDs
discussing
company
on personal sites,
Compliance
withfactor for the
Launched in mid-2012, the BTD is still in its infancy. A key
success
country-specific regulations
drug sponsors and the FDA work
program will be whether it serves the goal of helping
Cross functional
together to cut development time, while encouraging
the utilization
of new developcoordination within company
ment tools and methodologies, such as targeted diagnostics
and
adaptive
clinical trial
Patient
privacy
and
designs. This report provides an early look at how the
BTDofprogram
protection
personal datadiffers from FDA’s
other expedited development and review programs, and
what the first graduating class of
Unblinding of clinical data
BTDs may contribute to addressing unmet medical needs in orphan diseases, oncology,
0
1
2
3
4
and other critical therapeutic areas.
Tertiary
Collaboration & risk-sharing programs
experience longer development times
Drug sponsors use social media primarily to support marketing, not clinical research
Nearly All Drug Sponsors Have Corporate Level Social
Central nervous systems drugs and diagnostics are
likely
to be significant beneficiaries
Media
Policies
A
34.8%
ANALYSIS AND INSIGHT INTO CRITICAL DRUG DEVELOPMENT
ISSUES
Phase II Protocols
BTD drugs can utilize biomarkers to measure impact on irreversible morbidity and
mortality (IMM).
9.4%
38.3%
Procedures
Core
Tufts Center for the Study of Drug Development
TUFTS UNIVERSITY
ANALYSIS AND INSIGHT INTO CRITICAL DRUG DEVELOPMENT ISSUES
14.8%
Key Secondary
Volume 16, Number 3 • May/June 2014
Volume 16, Number 6 • November/December 2014
Tufts Center for the Study of Drug Development
Phase III
Protocols
Primary
Volume 16, Number 4 • July/August 2014
Tufts Center for the Study of Drug Development
Impact
TUFTS UNIVERSITY
REPORT
ANALYSIS AND INSIGHT INTO CRITICAL DRUG DEVELOPMENT ISSUES
Patients face new challenges accessing
a growing number of orphan drugs
included in the CSR and submission docs
Procedures collecting non-core data were evenly
distributed across the entire schedule of assessments.
Orphan drug reimbursement varies widely across markets
80% of all Phase II non-core data and 87% of all
Phase III non-core data collected were source data
verified by study monitors.
Although non-core data do not support primary and
key secondary endpoints, sponsor companies
reported that nearly all of the non-core data
appeared in the clinical study report (92%) and the
tables, listings, and figures (95%) in the regulatory
submission.
Since 1983, 7% more orphan drugs have been approved in the United States than in
Europe, and 17% more were approved first in the U.S. than were approved first in Europe.
Several European countries formally evaluate up to 75% of new orphan drug
approvals. Cost-effectiveness evaluations of orphan drugs are expected to increase in
the near future.
There are fewer denials of orphan drug coverage in the U.S. than in Europe.
Patient cost-sharing is higher in the U.S. than in Europe.
While U.S. payers often require prior authorization as a condition of reimbursement,
Volume 16, Number 5 • September/October 2014
European health authorities employ more stringent conditions, such as on-label
indication restrictions, step edits, and coverage with evidence development.
I
n 1983, the U.S. enacted the Orphan Drug Act to encourage development and commercialization of drugs to treat rare diseases. Seventeen years later an analogous law
was passed in Europe. Both pieces of legislation are considered major successes in
terms of spurring development and launches of orphan drugs. In the past five years, 39
orphan drugs were launched in the U.S. across numerous therapeutic categories, including
multiple myeloma, chronic myelogenous leukemia, metastatic non-small cell lung cancer,
hemophilia, tuberculosis, homozygous familial hypercholesterolemia, and cystic fibrosis.
In 2013 alone, nine orphan drugs were approved, the most in a single year.
In the U.S., the growing number of commercially available orphan drugs and the high
cost of various orphan treatments have led to reconsideration of payer reimbursement
policies. Tufts CSDD examined patient access to orphan drugs to identify possible barriers to orphan drug treatments. Differences in U.S. and European orphan drug approvals,
as well as payer reimbursement policies for orphan drugs in the U.S., France, Germany,
Netherlands, and the United Kingdom, were analyzed, and are summarized in this report.
Volume 16, Number 2 • March/April 2014
To preview Tufts CSDD Impact Reports, visit http://csdd.tufts.edu/reports for a complimentary PDF
download. To subscribe, visit http://csdd.tufts.edu/reports to order online.
Tufts CSDD corporate subscriptions are available at volume discounts. Contact Jonathan Hsieh at
617-636-0840 or email [email protected] for details.
12
TUFTS CSDD EXECUTIVE FORUM ROUNDTABLE SERIES
n ongoing program of highly interactive, one-day roundtable discussions for R&D leaders, ­hosted by
A
the Tufts Center for the Study of Drug Development.
February 26, 2015
FDA’s Breakthrough Therapy Designation – A Three-Year Assessment
Breakthrough Therapy Designation (BTD), part of the reauthorization of the Prescription Drug User Fee Act in
2012, allows the FDA to expedite the development and review of drugs intended to treat a serious condition
where preliminary clinical evidence suggests substantial improvement over available therapy on a clinically
significant endpoint or on symptoms that represent serious consequences of the disease. The roundtable will
open with a review of recent CSDD data on the BTD program in its first three years. This will be followed by
individual company experiences and lessons learned.
May 14, 2015
Diagnostic-Therapeutic Co-development Strategies and Best Practices
The R&D portfolio of many pharmaceutical companies currently includes personalized and targeted medicines.
However, having an effective strategy for the co-development of a complementary or companion diagnostic
often represents a significant bottleneck in the R&D process. In this roundtable, we will explore different
diagnostic-therapeutic co-development strategies and discuss insights and best practices.
September 17, 2015 Novel Approaches to Overhauling the Clinical Development Process
The time, cost, and risk of drug development remain formidable obstacles for drug sponsors and CROs.
This roundtable will explore novel approaches that are being piloted and widely adopted by leading pharma
­companies to speed development time, lower cost, improve efficiency, and increase the probability of success
for clinical candidates. As we review these novel and innovative approaches, the goal will be to assess what
works and what doesn’t work.
November 12, 2015 Patient Recruitment and Retention 2.0
The convergence of clinical care data, clinical research data, and engaged patient communities has introduced
promising new approaches to identifying, attracting, and retaining study volunteers for pre- and post-approval
clinical trials. This roundtable will begin with a CSDD assessment of a variety of novel approaches and
their impact to date. We will then discuss specific case examples in detail to shed light on strategic insights
and opportunities.
Roundtables are held 10 a.m. – 4 p.m. at the Tufts Center for the Study of Drug Development in Boston.
For more information, call Robert Chung at 617-636-2187, or email [email protected].
Tufts Center for the Study of Drug Development
TUFTS UNIVERSITY
75 Kneeland St., Suite 1100
Boston, MA 02111 USA
TEL
617-636-2170
FAX
617-636-2425
EMAIL [email protected]
WEB http://csdd.tufts.edu