Drug Development

Some Key Aspects

Estella Tembe-Fokunang, PhD
Summary of the drug
development process
Norvatis Perspective
GENERALITIES
 An Overview:
Drug Discover Research & Development
Timeline
Early Full Life Cycle
Research
Development Development Management
Clinical Trials
Pre-
Candidate
Discovery
Profiling clinical Phase 1 Phase IIa Phase IIb Phase III Phase IV
Phase
Phase
Phase

CSP sPoC DDP FDP 3CP SDP

Development Point
Proof of Concept

Decision Point

Decision Point
Selection Point

Development

Checkpoint
Selected for

Submission
Candidate

Full

Phase III
Overview of Development

• Early Development
• Full Development
 Preclinical - Early Development

DRUG SAFETY EVALUATION (DSE)

– Evaluate the safety profile including general
toxicology,
– safety pharmacology and
– genotoxicity to support immediate clinical
plan

• Other IND related activities include;

– synthesis of bulk drug for long-term
toxicology and clinical supplies,
– formulation work (if necessary), and
– preparation of IND submission
 Preclinical - Early Development
Investigative New Drug (IND)
PHARMACOLOGY:
1. Efficacy in animal model(s) and
2.Mechanism of action usually
defined.
Preclinical - Early Development
PHARMACOKINETICS AND DRUG
METABOLISM
– ADME properties characterized in the rat
and non-rodent toxicology species,
– Toxicokinetics/toxicodynamics
(TK/TD) support,
– Pharmacokinetics/pharmacodynamics (PK/PD)
in the pharmacology species,
– evaluate formulations,
– protein binding/RBC partition,
– in vitro human drug:drug interaction
potential, and
– project Phase 1 starting dose (and regimen)
 Disciplines of Clinical Research

Clinical Cardiovascular
Clinician
Trialist
Tissue Repair

Sexual Health
Common Core
Clinical Knowledge
Statistician Urology
Pharm
A&R

Regulatory Infectious
Diseases
Affairs
Pain
CLINICAL TRIALS
 Definition of a Clinical Trial
• A prospective study comparing the effect and value of
intervention(s) against a control in human subjects
NOTE:
• Prospective not retrospective
• Intervention/Equipment
– preventive -drug
– therapeutic -device
– diagnostic -procedure
– biologic
• Control Group
– no intervention -current standard therapy
– placebo (Diehl, 1938) -previous standard
• Humans not animals
– Ethics -informed consent
 Alternatives to Evidence based
Medicine
– Eminence-based medicine • Last-patient-
– Confidence-based medicine experience based med
– Eloquence-based medicine • Hot-tip-based med
– Vehemence-based medicine
• My-resident-told-me
– Providence-based medicine based med
– Diffidence-based medicine
• Chat-room based-med
– Nervousness-based medicine
• Direct-to-consumer
• Isaacs D, Fitzgerald D. Br advertising based med
Med J 1999;319:1618.
 Who Sponsors Clinical Trials?

• Physicians
• Medical Institutions
• Foundations
• Voluntary Groups
• Pharmaceutical Companies
• Federal Agencies (cooperative group research)
– NIH
– NCI (ACRIN is funded through the NCI as a cooperative group)
– DOD
– VA
 Types of Trials

The most commonly performed clinical trials evaluate

• new drugs,
• medical devices,
• biologics,
• or other interventions on patients in strictly
scientifically controlled settings, and are required for
regulatory authority approval of new therapies.
NIH organizes trials into 5 different categories.
 Types of Trials
1. Treatment Trials- test experimental treatments,
new combinations of drugs, or new approaches
to surgery or radiology/radiation therapy.
2. Prevention Trials- look for better ways to prevent
disease in people who have never had them or
prevent them from returning.
3. Diagnostic Trials- conducted to find better tests
or procedures for diagnosing a particular disease
or condition.
4. Screening Trials- test the best way to detect
certain diseases or health conditions.
5. Quality of Life- explore ways to improve comfort
and the quality of life for individuals with chronic
illness
 Treatment Trials

• Test safety and effectiveness

of new agents or
interventions
in people with cancer
• Possible benefit:
– Early access to new treatments
• Possible risk:
– Occurrence of unknown side 18
 Prevention Trials
• For people at risk of
developing cancer
• Action studies vs. agent
studies
• Possible benefit:
– Early access to new
interventions
• Possible risk:
– Unknown side effects and
effectiveness 19
Screening and Early-Detection Trials
• Assess new means of detecting cancer
earlier in healthy people
• Possible benefit:
– Detecting disease at an earlier stage, resulting
in improved outcomes
• Possible risks:
– Discomfort and inconvenience
– If imaging technique is studied, exposure to x-
rays or radioactive substances 20
 Diagnostic Trials

• Develop better tools for classifying types

and phases of cancer and managing patient
care
• Possible benefits:
– New technology may be better and less invasive
– Earlier detection of recurrences
• Possible risk:
– May require people to take multiple tests
21
 Genetics Trials

• These trials seek to:

– Determine how one’s genetic makeup can
influence detection, diagnosis, prognosis, and
treatment
– Broaden understanding of causes of cancer
– Develop targeted treatments based on the
genetics of a tumor

22
Quality-of-Life / Supportive Care
Trials
• Aim to improve quality of life for patients
and their families
• Possible benefit:
– Early access to new treatment
• Possible risk:
– May not benefit from participation

23
 Why Clinical Trials?
• Improve patient outcomes
• Improve quality of care
• Enhance systems efficiency
• Inform health policy
 Single & Double Blind
Clinical Trial

Single Blind: A clinical trial where the

participant/patient does not know the identity
of the treatment received

Double Blind: A clinical trial in which neither

the patient nor the treating physician knows
the identity of the treatment being
administered.
 Placebo Control Clinical Trial
Placebo: An inert substance made up to
physically resemble a treatment being
investigated for therapeutic benefit.
Used as a control treatment.
Design may be
1) treatment vs placebo or
2) Best standard of care plus either experimental
treatment or a matching placebo
ETHICS
 Informed Consent Process

• Consent must be obtained from subject or

their legally authorized representative
• Investigator may exert no coercion
• Information must be understandable
• Consent must be written.
 Informing the Patients
• Should newly diagnosed patients be entered in Phase
II Trials if therapies are available with proven
beneficial effects?
• If a physician is receiving funds on a per patient
basis, should the patient be informed?
• If a patient is participating in a clinical trial and a
treatment is found to be superior, should the patient
be informed prior to publication or presentation of
the results?
• If a patient is participating in a double blind trial and
wishes to know the identity of the treatment, should
the patient be informed?
 Ethical Issues

The informed consent process.

• Imagine that you are responsible for
conducting a clinical trial and would like to
inform subjects about it before they sign up.
• What are the things you would tell them?
Basic Contents/Informed Consent (1)

• Explanation of research study

– Purpose
– Duration
– Procedures
• Possible risks
• Possible benefits
– Patient
– Other individuals
• Disclosure of alternative treatment
Basic Contents/Informed Consent (2)

• Describe confidentiality of data

• Compensation in case of injury
• Patient contacts for questions or injury
• Participation is voluntary
 Additional Possible
Elements/Informed Consent
• Risks to fetus
• Investigator may terminate patient
participation
• Costs of additional tests
• Consequences of patient withdrawal
• Sharing of new findings during course
of trial
• Total number of subjects
 Developments
World Medical Association
• Revision of 1964 Declaration of Helsinki (Oct, 00)
• Placebos may be used in a clinical trial when no other
therapies are available for comparison with
experimental treatment.
• New therapies should be tested against best current
treatment.
• Suggests investigators divulge to patient how trial is
funded and possible conflicts of interest.
• All study results whether positive or negative should
be published.
CLINICAL TRIAL PROTOCOL
 DEFINITION
• The protocol is a document that describes
how a clinical trial will be conducted (the
objective(s), design, methodology,
statistical considerations and organization
of a clinical trial,) and ensures the safety of
the trial subjects and integrity of the data
collected.
 A Trial Protocol

• Required for all trials

• Basis of Review
– IRB/Ethics
– Funding
Review of protocols
Local/Regional/Country Ethics committee Review

IRB –Institutional Review Board

IEC (Independent Ethics Committee)

Team Review

Individual Review
 Purposes of a Protocol
• To assist the investigator in thinking through the
research.
• To insure that both patient and study management
are considered at the planning stage.
• To provide a “sounding board” for external
comments.
• To orient the staff for the preparation of forms
and data processing procedures.
• To guide the treatment of the patient on the
study.
• To provide a document which can be used by other
investigators who wish to “confirm” the results or
use the treatment in practice.
• Reference: Dana-Farber Cancer Institute: Outline
to Writing a Protocol
Protocol Outline: “A Blueprint” (1)

A.Background & Rationale

B.Objectives
1. Primary Question
2. Secondary Question
3. Subgroup Questions
4. Toxicities
Protocol Outline: “A Blueprint” (2)
C. Design
1. Population
-Inclusion criteria
-Exclusion criteria
2.Sample Size Rationale
3.Enrollment
-Recruitment strategy,-Informed consent
-Eligibility assessment,-Baseline exam
4.Randomization
5.Intervention
6.Follow-up Schedule
7.Outcome Ascertainment
-Data collection
Protocol Outline: “A Blueprint” (3)
D. Data Monitoring
1. Quality Control
2. Recruitment
3. Benefit/Risk
4. Early Termination
E. Data Analysis/ Reporting
F. Organization
1. Investigators
2. Committees
Protocol Outline: “A Blueprint” (4)
• Appendix
• Definitions
• Combined Outcomes
Sample protocol – lectures only
UK-453,061
A5271014
Final Protocol, 12 December 2006

CLINICAL PHARMACOLOGY PROTOCOL

AN OPEN, RANDOMIZED, TWO PERIOD, PLACEBO CONTROLLED,

CROSSOVER STUDY TO INVESTIGATE THE EFFECT OF MULTIPLE ORAL
DOSES OF UK-453,061 ON THE STEADY STATE PHARMACOKINETICS OF
ORAL ZIDOVUDINE IN HEALTHY MALE SUBJECTS

Compound: UK-453,061

Compound Name: N/A

US IND Number: N/A

Protocol Number: A5271014

Phase: 1

Version and Date: Final Protocol

12 December 2006

This document contains confidential information belonging to Pfizer. Except as otherwise agreed
to in writing, by accepting or reviewing this document, you agree to hold this information in
confidence and not copy or disclose it to others (except where required by applicable law) or use it
for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.
 Manual of Operations
Describes in detail how to implement the protocol at
the clinic, laboratories, and Coordinating Center
Generally includes:
1. Design portion of protocol,
possibly in more detail
2. Definitions of criteria
3. Standardization of procedures
• Laboratory (chemical or mechanical)
• Equipment
• Clinical
4. Forms and instructions for completion
 SUBMISSION TO
REGULATORY AUTHORITIES
 Submission
• Includes all aspects of the discovery
and development program.
• Sponsor to compile the data and
submit to relevant regulatory
authority.
 NDA - New Drug Application
MAA- Marketing Authorization Application
• The average NDA is 100,000 pages or longer
• Must provide all relevant data collected during R&D
• Consists of:
– Index - clinical pharm - clinical data
– Safety pharm - human toxicity - CRF’s
– safety update - case report tabulations
– pediatric data - statistics
– PK / Bioavailability - patent information / certification
– ISES (Integrated Summary of Efficacy and Safety)
– CER (Clinical Expert Report – summary of drug impact, how data supports)
– CSR (Clinical Study Reports)

• Can now be filed electronically

(a CTD = Commercial Technical Document)
• Review process: Target 10 months (but often longer)
48
 NDA Review Process
▪ Review Process
▪ standard
▪ expedited (in the case of life threatening diseases for
which the only medications available are of little or
limited effectiveness).
▪ Results of Review
▪ Approvable
▪ Approved
▪ Denied
▪ Negotiation of the labeling process
www.fda.gov
49
Drug Regulatory Agencies

EMEA
FDA Japan

World Health Organization WHO?

 Regulatory Agencies and
Regulations/Guidelines
• US Food and Drug Administration (FDA)
– Code of Federal Regulations
• European Medicine Agency (EMEA/EMA)
– International Conference on Harmonization (ICH)
Guidelines
• Japan Ministry of Health, Labor, and Welfare
– Policy, guidelines (including ICH), and final approval of
JNDA
– Pharmaceutical and Medical Devices Evaluation Center
(PMDEC) performs JNDA review, GCP inspections
(outside Japan)
– Organization for Pharmaceutical Safety and Research
(KIKO) reviews/approves clinical trials
 Regulatory Agencies and
Regulations/Guidelines (Cont.)
• Good Laboratory Practice Regulations
• Good Clinical Practice Regulations
• Good Manufacturing Practice Regulations
• Declaration of Helsinki
 The Clinical Development Plan
• A document including a projection of activities
to facilitate the clinical development of the
NCE (New Chemical Entity).
• Contains rational for various studies and the
timelines associated with each step.
• Major milestones identified.
• Potential risks.
• Defined timelines
• Clinical team to present to R&D management
 Clinical Development Plan
Illustration Sample Gantt charts
 Clinical Development

• Filing of an IND
• If the FDA has no concerns with the IND, testing in
humans can commence 30 days post filing.
– Phase I: evaluation in healthy volunteers, DDI, and
special populations (Clinical Sciences)
– Phase II: test for efficacy in patients
– Phase III: pivotal efficacy trials conducted
– Phase IV: post-marketing support (Pfizer
Pharmaceutical Group)
• N.B. - Chronic toxicology studies, reproductive
toxicology studies, and the bioassays are run in parallel
with the clinical program
Sample Plan for Illustration
 Drug development process-1
The Exploratory Development has four stages
Preclinical:
• preliminary toxicology, pharmaceutical sciences,
pharmacokinetics and drug metabolism and
pharmacology
Phase I:
• pharmacokinetic, pharmacodynamic, safety, and
toleration trials usually in healthy volunteers, as
well as a variety of other studies (biomarkers, key
drug interactions, etc)
Phase II:
• Phase IIa: demonstrating Proof of Concept (POC)
and further evaluating safety in patients
• Phase IIb: refinement of dose-response and
safety profiles to support Phase III studies
 Meeting with Regulators
• End-of Phase II Meeting with FDA
• Requested by sponsor to seek;
– Agreement that the data support initiation of
the Phase III program
– Agreement that planned studies could produce
a “file-able” NDA
– Treated as a formal commitment by FDA
• Sponsor;
– Full development plan unveiled
– Submission of proposed phase III protocols
– Discussion and agreement between regulators
and sponsors.
 An Overview:
Check the Milestones

Early Full Life Cycle

Research
Development Development Management
Clinical Trials
Pre-
Candidate
Discovery
Profiling clinical Phase 1 Phase IIa Phase IIb Phase III Phase IV
Phase
Phase
Phase

CSP sPoC DDP FDP 3CP SDP

Development Point
Proof of Concept

Decision Point

Decision Point
Selection Point

Development

Checkpoint
Selected for

Submission
Candidate

Full

Phase III
 Drug development process-2
Full Development (Phase III)
Target Patient population
• Registration and Approval
– US-FDA
– EMA
– Japan
 Drug development process-2
Post Marketing (Phase IV)
– New indications
– New dosage forms
– New populations
– Increase focus on outcomes
– Annual reports
– DSS (Drug, safety and surveillance)
FOCUS ON PHASE I
 Activities at Each Clinical
Development Stage
Phase I –
• Objective: evaluate pharmacokinetics, safety and
tolerance in healthy volunteers,
– establish the maximum tolerated dose range,
– PK/PD characterized,
– Genotype studies (investigate polymorphisms)
– Drug-drug interactions
– Food-drug interaction
– Bioavailability studies
Other
– mass balance and metabolite profiling/ID performed,
– Bioequivalence,
– In-vitro in-vivo correlation
 Clinical Trials – Summary of Phases

Length
Phase Purpose Subjects Scope
(per phase)

Safety, ADME, Healthy

bioactivity, volunteers or
I subj. w/
20-80 6-12 mos
drug-drug interaction indications

Short-term side Subjects with Several 1-2 yrs

II effects & efficacy indications hundred

Safety & efficacy

Subjects with Hundreds-
III Basis for labeling,
indications thousands
2-3 yrs
new formulations

New indications, Subjects with Hundreds-

IV QoL, surveillance indications thousands
1-5 yrs
64
 Typical Phase I Studies
• First in human
Objectives:
1. Evaluate safety and tolerability
2. Determine maximum dose associated with acceptable
safety profile
3. Characterise dose-limiting adverse effects
4. Characterise pharmacokinetics (including dose-
exposure relationships)
5. Pharmacodynamics if possible PK/PD relationships
 Typical Phase I Studies
• First in human
Study population:
1. Healthy volunteers unless safety concerns preclude
use of such (agents of low therapeutic index intended
for life threatening conditions)
2. Expectation of special population showing different
tolerability e.g. Children
Outcome: Data will be used along with pharmacology and
toxicology information to build information around
likely toxic and efficacious concentrations.
Design of multiple dose study depends on the results of
the FIH study.
 Typical Phase I Studies
• First in human
Study design:
1. Number of subjects is based on confidence in safety,
nature of expected adverse events and expected PK
variability.
2. Minimum 6 subjects on NCE and 2 on placebo at each
dose level
3. Cross over /sequential cohorts.
 3-period crossover, sequential
cohorts, placebo substitution.
Number of Period and Treatment
subjects
Cohort I II III

A 3 P 2 3
3 1 P 3
3 1 2 P

B 3 P 5 6
3 4 P 6
3 4 5 P

P = placebo, 1- 6 active doses from lowest to highest

Compare with interleaving and sequential designs
 Parallel group design
Cohort Subjects Treatments
I II III IV V VI
A 6 1
2 P
B 6 2
2 P
C 6 3
2 P
D 6 4
2 P
E 6 5
2 P
F 6 6
2 P

Requires more subjects 3x

More cautious design
Takes longer
London Drug Trial Catastrophe –
Collapse of Science and Ethics
• Drug trial that went horribly wrong On 13
March 2006, six healthy young volunteers took part in a clinical trial and became violently ill
minutes after having been injected with a drug developed to fight autoimmune disease and
leukaemia [1-5]. One of the two additional volunteers injected with a placebo who showed no
ill effects recalled to newspaper reporters [2]: “The men went down like dominoes. They
began tearing their shirts off complaining of fever, then some screamed that their heads were
going to explode. After that they started fainting, vomiting and writhing around in their
beds.”

• The drug tested, TGN1412, was developed by

the company TeGenero based in Würzburg,
Germany, and manufactured by Boehringer
Ingelheim.
 TeGenero
• It claimed that the safety of TGN1412 was
extensively tested on “rabbits and monkeys”, that
“there were no drug related deaths despite
administering doses up to five hundred times the
dose to be used in the phase 1 clinical trial”.
Nevertheless, in pre-clinical tests, 2 monkeys
experienced a transient increase in the size of
lymph nodes, but TeGenero considers that not a
drug related side effect.
 Indirect Risk
• The London drug trial episode came in the
wake of 11 otherwise healthy people who
tested positive for tuberculosis in Montreal,
Canada, after they were paid to volunteer
for research conducted by a private
company.
• The volunteers apparently caught TB from
an infected subject they’d been housed with
as part of the study paid for by a Canadian
company, but conducted by the CRO SFBC
International.
INTRODUCE PHASE 0
 Phase 0?

• Recent designation for exploratory, first-in-human trials conducted in

accordance with the FDA’s 2006 Guidance on Exploratory
Investigational New Drug (IND) Studies.

• Designed to expedite the development of promising therapeutic or

imaging agents

• Involve the administration of single sub therapeutic doses to a small

number of subjects (10-15).

• Gather preliminary data on the pharmacokinetic and

pharmacodynamic properties and mechanism of action.
 Phase 0 Study/ Microdosing
• Study of new drug in microdoses to derive the
PK information before undertaking phase I
studies is called PHASE 0.
• Microdose: More than 1/100 of the dose of a
test substance calculated to produce
pharmacological effect with a max dose <
100micrograms.
• Objective: to obtain preliminary PK data
• Preclinical data: sub-acute toxicity data in one
species by two routes of administration.
 Microdosing/Phase 0 Study
• Early studies to determine the PK and PD
properties of a potential drug in humans.
• Microdosing could accelerate drug
development without compromising clinical
safety.
• Helps researchers select better drug
candidates for clinical trials by providing
early human PK and bioavailability data.
 Microdosing/Phase 0 Study
Advantages
• Less chances of adverse effects
• Short duration
• Less number of volunteers
• Reduced cost of development
• Reduced drug development timeline
Disadvantages
• Study mainly based on PK parameters not efficacy and
safety based.
• Agents which differ in PK between microdose and full
dose are not usually evaluated by Phase 0
• Limited use with non-linear PK
Phase II Clinical rials
Concept of Clinical Trials
 Phase II
• First in patient [ different from healthy volunteer]
• IIa Early phase [20 – 200 patients with relevant
disease, sometimes healthy volunteers] Pilot
– Therapeutic benefits & ADRs evaluated
– Establish a dose range to be used in late phase
– Single blind [Only patient knows] comparison with standard
drug
• IIb Late phase [ 50 – 500 patients] Pivotal
– Double blind
– Compared with a placebo or standard drug
• Outcomes
– Assesses efficacy against a defined therapeutic endpoint
– Detailed P.kinetic & P.dynamic data
– Establishes a dose & a dosage form for future trials
• Takes 6 months to 2 years [ 35% success rate]
Phase II Risk is caused by:
 Phase II trials
Phase IIa
• clinical pharmacology in patients with the
target disease (tens – 100/200)
• Assess pharmacodynamics,
pharmacokinetics, and dose ( or
concentration) effect responses for
preliminary safety and efficacy and to
validate surrogate endpoints.
Phase IIb
• Larger scale (several hundreds) in patients
to formally assess the dose response
relationship and continue to expand the
efficacy and safety databases.
PHASE III
 Phase III
• Multi centre
• Multi national
• Diverse populations
• Males/females
• Hundreds/Thousands of patients
• Determines efficacy and safety on a
substantial scale; comparison with
existing drugs; usually includes three
or more doses of test drugs
 Phase IIIa
• Phase IIIa:Trials conducted after efficacy of the medicine
is demonstrated, but prior to regulatory submission of a
New Drug Application (NDA) or other dossier. These
clinical trials are conducted in patient populations for
which the medicine is eventually intended.
• They generate additional data on both safety and efficacy
in relatively large numbers of patients in both controlled
and uncontrolled trials.
• Also conducted in special groups of patients (e.g., renal
failure patients) , or under special conditions dictated by
the nature of the medicine and disease. These trials often
provide much of the information needed for the package
insert and labeling of the medicine.
 Phase IIIb
• Phase IIIb: Clinical trials conducted after
regulatory submission of an NDA or other
dossier, but prior to the medicine's approval
and launch. These trials may supplement
earlier trials, complete earlier trials, or may
be directed toward new types of trials (e.g.,
quality of life, marketing) or Phase IV
evaluations. This is the period between
submission and approval of a regulatory
dossier for marketing authorization.
PHASE IV
 Phase IV
• Post licensing studies in the target
population
• Widening of entry criteria to broaden
experience in clinical practice.
• Study objectives may be marketing,
further formal therapeutic and
comparator trials and surveillance for
safety.
• Post marketing surveillance.