Download The New Drug Development Process

Overview of Drug Development Process
Gopala Kovvali M.Sc., M.Phil., Ph.D.
Editor-in-Chief, Journal of Carcinogenesis
Disclaimer:
The material presented in this lecture is intended
only for educational purpose and the presenter
does not intend to support or oppose any
particular compound.
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Drug Development Process at a Glance
Medicine
Clinical Trial
management, Finance
management, Data
management etc.
Science
Management
Globalization
Business
Costs, Profits, Growth
Regulatory apparatus
Patients
Psychology,
Philosophy
Personalities
Investigators
Drug Development is a SMART Process
Science
Management
Art
Research
Technology
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Gopala Kovvali Ph.D.
Duration and odds of making a drug
Adapted from Pharmaceutical Industry Profile 206, PhRMA, March 2006.
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Developing a Molecular Entity Into a Drug
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Pathway from Molecule to the Market
2, 71-74 (January 2003)
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The New Drug Development Process
(Steps from Test Tube to New Drug Application Review)
Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm053131.htm
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Growth in Global R&D Expenditure
Note: P - Projected figures have been calculated based on an average annual growth in R&D expenditure between 2000 and 2005.
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Cost of Developing a Drug
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The R&D Process
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What are Clinical Trials?
• A controlled and monitored study process
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with new drug treatments.
The purpose is to prevent, diagnose or treat a
disease
Designed to answer key scientific questions
Most clinical trials study new drugs
All patients who participate are volunteers.
Every clinical trial has a protocol
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The First Known Clinical Trial
• The first actual clinical trial was conducted in
1747 by James Lind on board the British ship
Salisbury.
• Lind took 12 patients, separated them into pairs
of two and tried different remedies on each pair
to try and find a remedy for scurvy.
• Outcome of the experiment:
Fresh oranges and lemons were the effective
treatment.
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Evolution of the Drug Development in US.
• From
• From
• From
• From
“silos” to multi-disciplinary teams.
local to global.
slow and unfocused to fast and efficient.
doing everything to outsourcing.
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Key Drug Development Decisions
• Which discovery leads will we develop?
• Decision to go to human trial.
• What is the “killer experiment.”
• Decision to go to phase III.
• Decision to file. Decision to launch
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“Killer Experiment”
• Understand almost all drug candidates fail.
• Design studies where you can fail early.
• Define and test key efficacy and safety
assumptions as quickly as possible.
• “Kill early and often.” - Good advice?
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Focus on the Indication
• Solid scientific data
• Substantial market - Always the case?-Orphan drugs
• Clear regulatory path
• Manageable clinical trial
• Timely completion
• Avoid multiple indications
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Oncology Drug development process
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Lifespan of Drug Development
• Mean length of phase III
1990 - 1997: 4.5 years vs 3.8 years more recently
• Time from submission to FDA approval:
 2 years in the 1960’s
 1.6 years in 1990-1996
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Duration of Development and Success
• Nearly three quarters of drugs fail to successfully
complete clinical trials
• The average drug has a 26.4% chance of successfully
reaching the market
• Average duration from the beginning of Phase I to
reaching the market is slightly over 8 years
• The chance of a drug successfully reaching the
marketplace decreases as the time to complete
clinical trials increases
• Drugs in development during 1995 to 2002 had
shorter trial durations than those in development
from 1989 to 1994
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Number of Anticancer Drugs in
Development During the last Decade
As of March 2002:
• 1345 drugs in development
• 801 in preclinical stage
• 205 Phase I
• 250 Phase II
• 76 phase III
J Clin Oncol, 21 (2003) 3685-3695
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New Types of Oncology Drugs
Cytotoxics:
• Broad activity
• No selectivity
• Recommended dose close to MTD
• Activity high
Molecular Targeted Therapies (MTT)
- Targeted activity
- Selective
- Optimal dose may be very different from MTD, if
MTD
- Moderate activity
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Oncology- Approvals in 2013
Gazyva (obinutuzumab); Genentech; Approved October of 2013
For the treatment of previously untreated chronic lymphocytic
leukemia,
Gilotrif (afatinib); Approved July 2013
Boehringer Ingelheim; For the treatment of metastatic non-small
cell lung cancer with EGFR mutations,
Kadcyla (ado-trastuzumab emtansine); Genentech; Approved
February 2013
For the treatment of HER2-positive metastatic breast cancer,
Mekinist (trametinib); Approved May of 2013
GlaxoSmithKline; For the treatment of unresectable or metastatic
melanoma with BRAF V600E or V600K mutations,
Pomalyst (pomalidomide); Celgene; Approved February 2013
For the treatment of relapsed and refractory multiple myeloma,
Revlimid (lenalidomide); Celgene; Approved June 2013
For the treatment of mantle cell lymphoma
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Oncology- Approvals in 2013
Contd.
Stivarga (regorafenib); Bayer; Approved February 2013
For the treatment of gastrointestinal stromal tumor,
Tafinlar (dabrafenib); GlaxoSmithKline; Approved May 2013
For the treatment of unresectable or metastatic melanoma with BRAF
V600E mutation,
Valchlor (mechlorethamine) gel; Ceptaris Therapeutics; Approved
August 2013
For the treatment of Stage IA/IB mycosisfungoides-type cutaneous Tcell lymphoma,
Xgeva (denosumab); Amgen; Approved June 2013
For the treatment of giant cell tumor of bone,
Xofigo (radium Ra 223 dichloride); Bayer Healthcare Pharmaceuticals;
Approved May 2013
For the treatment of prostate cancer with bone metastases
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Overview of Drug Developement
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Clinical Trials: Requirements
for Drug Approval
• Safety (FDAC, 1933)
• Efficacy demonstrated in adequate and well
controlled studies (1962)
• Basis for efficacy:
• Regular approval
• Clinical benefit, or
• Established surrogate for clinical benefit
• Accelerated approval
• Surrogate (reasonably likely to predict CB)
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Phase II Clinical Development
Key Protocol Design Elements (I)
• Background
– Relevance of target
– Preclinical efficacy and safety data
– Rationale for development of drug/study design
• Disease
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Definition of patient population
Disease - diagnosis, stage, line of therapy
Permissible prior therapy for disease
Permissible concomitant therapy
• Treatment
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Dose - preparation, route, frequency
Duration of treatment
Management of toxicity
Dose modification criteria
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Phase II Clinical Development
Key Protocol Design Elements (II)
• Endpoints
– Primary - Efficacy
• Method/frequency of measurement, quality control
– Secondary-Efficacy
– other organ system beneficial effects
– secondary benefits on primary disease
– PK/PD correlations
– Safety
• Methods (clinical/laboratory), frequency, special
safety issues
• Statistical design
– Sample size - justification, power
– Analytical plan
• Efficacy - primary endpoint
• Dose response relationship
• Safety
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End of Phase II- This is What We Know..
• Efficacy
– Dose - amount (preferably single dose level), frequency
– Degree of efficacy - to meet or exceed the TPP (target product
profile)
– Appropriateness of endpoint - method/timing of measurement
• Safety
– Frequency of AEs
– SAEs - Frequency, severity, reversibility; equal or better than TPP
• Pharmacology
– Pharmacology of the drug well understood
• Variability
– PK/PD relationships
– Final market formulation (preferable)
– No significant DDI
• Development issues
– Trial designs, endpoints, regulatory considerations
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Phase II Clinical Development
Prerequisites
• Formulation
– Preferably (near) final market formulation
• Toxicology - chronic, Up to 6 month toxicology data required
• Dosing Schema
– 3-5 dose levels
– Should include a sub-therapeutic dose level - no effect level
– May include a placebo
– Frequency of administration
• based on T1/2, AUC, need for sustained, threshold
exposure
– Duration of treatment
• Long enough to see therapeutic effect
• Must be justifiable by the available toxicology data
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Phase III Trials
• Earlier phases (multiple trials) have determined:
– Safety/tolerability
– Pharmacokinetics/ADME
– Proof of concept
– Surrogate endpoints/trends/biomarkers for efficacy
– Formulation/dose - MTD/method of administration
• Next phases address:
– True efficacy
– Long-term safety
– Impact of compliance on efficacy
– Cost/Benefit
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Globalization: Facts
Clinical Research is becoming more global:
• In 1990
only 271 foreign clinical investigators in FDA
database
• In 1999
4458 investigators in FDA database
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Globalization: Challenges
• Experience in conducting clinical trials varies widely
across the globe
• Level of human subject protection may vary
significantly
• Performance of foreign Institutional Review Boards
may vary significantly
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Example of a Success Story
• The exciting story of HER pathway leading to
Herceptin.
• Herceptin is the first targeted monoclonal
antibody approved.
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Timeline for Development of Herceptin
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Examples of Pathway Targets
Involved in Cancer
types
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HER
VEGFR
c-KIT
Bcr-Abl
Breast, lung and other cancers
Colon, lung and other cancers
Gastrointestinal stromal tumors
Chronic myelogenous leukemia
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Drug Development Process-Schematic
Medicine
Clinical Trial
management, Finance
management, Data
management etc.
Science
Management
Globalization
Business
Costs, Profits, Growth
Regulatory apparatus
Patients
Psychology,
Philosophy
Personalities
Investigators
CLINICAL TRIALS AND ETHICAL ISSUES
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Laws and Regulations
• Federal Food, Drug, and Cosmetic Act of 1938
required drugs be shown to be safe prior to
marketing
• Public Health Service Act of 1944 provided for the
regulation of biological products
• Kefauver-Harris Drug Amendments of 1962 required
proof of efficacy prior to marketing
• Code of Federal Regulations, Title 21
• IND regulations: Part 312
• NDA regulations: Part 314
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History of Ethical Codes and
Regulations
Nuremberg Code – 1947
Council for International Organizations of Medical
Sciences (CIOMS): Established by WHO and UNESCO in
1949 Proposed the International Ethical Guidelines for
Biomedical Research Involving Human Subjects in 1993
Belmont Report – 1979
Declaration of Helsinki – initiated in 1964, fifth revision
in 2000
- established by the World Medical Association
- considered to be the most comprehensive document
for
ethical research and experiments with human subjects
U.S. Common Rule - 1991
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Declaration of Helsinki
Fundamental Ethical Principles in Human
Trials:
• Respect for all human beings – protection of human
health and rights
• Beneficence: trials designed to maximize benefits and
minimize risks
• Justice:
- Non-exploitative and careful protocol design and
execution
- Non-exploitative, non-biased and fair selection of
subjects (Belmont Report)
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Institutional Review Board (IRB)
• Formally empowered by FDA in the U.S.
• Conducts advance and periodic review of research
protocols
• Gives official approval to trials
• Monitors the ongoing procedures, commands clinical
trial design modifications as needed
• Reviews Informed Consent documents for human
rights protection and subject confidentiality
• All clinical trials require IRB approval before human
subject enrollment
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Public Trust in Clinical Research
Report and Recommendations NIH Director’s
Council of Public Representatives (COPR)
October 26, 2004
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The recommendations fall into the following areas
Building trust through community partnerships
Building relationships with patients
Building partnerships with community providers
Building trust in scientists
Building trust in the NIH and scientific research
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Recommendation
Focus on educational strategies to help patients and
communities better understand clinical research. This
will help scientists because educating the public will
empower and prepare individuals to be informed
partners in the clinical research process. An informed
and trusting public will enhance research participation.
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Building Trust in Scientists
Concept:
An increasing portion of the public perceives scientists as not
having the training and perspective that they need to build public
trust in clinical research. Current training for scientists doesn’t
seem to address issues related to considering community
participants as partners in the research process. This makes it
difficult to expect scientists to view community health in the same
way as the community itself views local health issues. Also,
scientists are trained to act as authority figures at the same time
that they encounter patients who do not understand clinical
research and who are expecting the “authority figure” to protect
them, tell them what to do, and cure them. Improvements in the
status quo and/or in these perceptions are needed if clinical
research is to be enhanced at the community level.
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Building Relationships with Patients
Concept: Besides a cure, what do patients want?
• Honesty about the study (true benefits/risks).
• To know the relevance of the study to themselves and/or their
community.
• To know that their own health is important and will be considered.
• To be treated with empathy (as a person, not a case number).
• To be invited, not coerced.
• To know they are protected (DSMB or other monitoring boards).
• To know that the researcher has fully disclosed any inherent
conflicts of interest related to the study and to know that these
conflicts of interest have been managed in an open and appropriate
way.
• To have their privacy/confidentiality protected.
• To have their participation facilitated where possible, i.e., remove
roadblocks such as inconvenience, long waits, no parking.
• To receive interim information about the study progress.
• Advice about patients’ post-study options for medical care.
• To hear about the study results.
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Recommendation
Incorporate into the NIH mission and philosophy that
it values the involvement of the community in
research and create language that expresses this
value.
Recommendation: Encourage change in the culture of
the scientific community to ensure that medical
research is viewed in the context of a long-term
commitment to the community, not a one-time
research study.
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Barbara Alving, MD, NIH
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Thank You!
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