APGO Interaction with Industry:
A Medical Student Guide
Pharmaceutical
Development and
Review Process
Rev. 10/21/2014
Objectives
 Learn the processes involved in drug discovery and
development in the United States
 Understand the role of the Food and Drug
Administration (FDA) in the drug development and
review process in the US
 Define the phases involved in FDA drug approval
Overview-Research and
Development Process (R&D)
 Development of new drugs is a complex and costly
process
 It takes an average of 9 years and $850 million to
take a “chemical entity” from the lab to the
pharmacy shelf
 R&D involves discovery, preclinical studies and
development
 One out of every 1,000 compounds that begin
preclinical studies will ultimately be marketed
Brief Flow Diagram of the Drug
Approval Process
Preclinical/animal studies
Investigational new drug (IND) application
Clinical studies (Phases 1-3)
New drug application
FDA/CDER review
Approval
Post approval evaluation/Phase 4
A History of Federal Oversight of the
Drug Development Process
 The Food and Drug Administration (FDA) is the
Federal agency that is required by law to review and
approve all new drugs in the US.
 The 1906 Food and Drugs Act prohibited
mislabeling but did not require pre-market approval
of drugs.
 The 1938 Food, Drugs and Cosmetics Act required
submission of evidence of a drug’s safety before it
could be marketed.
The Role of the FDA
 The FDA reviews and evaluates new drugs based on
evidence presented from the clinical research
studies performed by the drug sponsor-typically a
pharmaceutical company
 The Center for Drug Evaluation and Research
(CDER) is the largest of the FDA’s five centers and is
responsible for prescription and over-the-counter
(OTC) drug safety and efficacy
Preclinical Studies
 Synthesis and purification of the new drug
 Pharmacology of the new drug:
 Pharmacokinetics: absorption, distribution,
metabolism, excretion, half-life
 Pharmacodynamics: mechanism of action and
estimates of therapeutic effects
 Toxicology including carcinogenicity, mutagenicity
and teratogenicity
 Safety studies on animals
Definitions-Investigational New
Drug (IND)
 New drug applications (NDAs) require clinical trials using the
candidate chemical compound for safety and efficacy,
usually in centers in multiple states
 Federal law requires that a drug be the subject of a
marketing application before transporting across state lines
 The IND is the process by which an exemption to the law is
obtained
 Studies in humans can only begin after IND is reviewed and
approved by the FDA and an institutional review board (IRB)
Overview of Clinical Study Phases
 Phase 1: Safety and tolerability studies on healthy
volunteers
 Phase 2: Clinical studies to demonstrate proof of
concept and dose findings
 Phase 3: Efficacy and safety studies on large
number of subjects
 NDA regulatory review
 Phase 4: Post-marketing safety studies
Phase 1 Clinical Studies
 Typically 20-80 healthy volunteers
 Emphasis on drug safety
 Identify major side-effects, metabolism, routes of excretion
 Duration: about 1 year
 Sufficient information about pharmacokinetics and effects to
permit design of well-controlled Phase 2 studies
 About 70% that make it to this phase will pass
Phase 2 Clinical Studies
 Typically involves 100-300 individuals who have the target
disease
 Emphasis on effectiveness
 Closely monitored, can evaluate short-term side-effects and
risks
 Patients receiving the drug are compared to similar patients
receiving a placebo or another drug
 Duration: about 2 years
 About 33% of drugs will pass this phase
Phase 3 Clinical Studies
 Typically involves 1,000-3,000 patients
 Emphasis on safety and effectiveness
 Investigates different populations and dosages as well as
combination with other drugs
 Extrapolation to a general population
 Acquire data used for physician labeling
 Duration: about 3 years
 25-30% pass this phase
The Role of the Institutional Review
Board (IRB)
 IRBs ensure the rights and welfare of people
participating in clinical trials, both before and
during trial participation
 IRBs make sure that participants are fully informed
and have given written consent before participating
in studies
 IRBs are located in hospitals and research centers
Definition-New Drug Application
(NDA)
 Starting with the 1938 and subsequent (increasingly
demanding) amendments, all the data gathered
during the animal studies and human clinical trials
of an Investigational New Drug (IND) are required to
become part of the NDA
 While varying by type of compound, an NDA can
consist of as many as 15 different sections
NDA (cont’d)
 Pre-NDA period: FDA and drug sponsors meet
 Submission of NDA: Formal step asking FDA to
consider approving a drug for marketing
 FDA has 1 year to decide whether it will file the
NDA for approval consideration
 If filed, a review team is assigned to evaluation the
new drug
FDA Approval
 FDA review team evaluates the research on safety
and effectiveness
 Labeling information reviewed
 Inspection of production facilities
 Decision and justification letter:
 Not approvable
 Approvable
 Approval
FDA Approval (cont’d)
 Not approvable: Lists deficiencies in application and
why it cannot be approved
 Approvable: Ultimately can be approved and lists
deficiencies that can be corrected, including
labeling changes and requests for post-approval
studies
 Approval: Drug is approved
Phase 4 Clinical Studies
 Post-market surveillance of the drug to continually
assess safety of the drug
 May include incidence and severity of rare adverse
reactions, cost-effectiveness analyses, comparative
trials, and quality of life studies
http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm Accessed 7/9/2014
http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm Accessed 7/9/2014
Resources
 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/d
efault.htm
 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/H
owDrugsareDevelopedandApproved/ApprovalApplications/I
nvestigationalNewDrugINDApplication/ucm176522.htm