pharmaceutical development and review process rev. 10/21/2014 apgo interaction with industry: a...
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Pharmaceutical Development and
Review Process
Rev. 10/21/2014
APGO Interaction with Industry: A Medical Student Guide
ObjectivesLearn 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 FDAThe 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 StudiesSynthesis and purification of the new drug
Pharmacology of the new drug:Pharmacokinetics: absorption, distribution,
metabolism, excretion, half-lifePharmacodynamics: mechanism of action and
estimates of therapeutic effectsToxicology 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 PhasesPhase 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 subjectsNDA regulatory review
Phase 4: Post-marketing safety studies
Phase 1 Clinical StudiesTypically 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 StudiesTypically 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 StudiesTypically 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 ApprovalFDA review team evaluates the research on safety
and effectiveness
Labeling information reviewed
Inspection of production facilities
Decision and justification letter:Not approvableApprovableApproval
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 StudiesPost-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