1. Pharmaceutical Development and Review Process Rev. 10/21/2014 APGO Interaction with Industry: A Medical Student Guide

2. 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

3. 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

4. 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

5. 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.

6. 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

7. 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

8. 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)

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htmhttp://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm Accessed 7/9/2014

20. http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htmhttp://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm Accessed 7/9/2014

21. Resources http://www.fda.gov/Drugs/DevelopmentApprovalProcess/d efault.htm http://www.fda.gov/Drugs/DevelopmentApprovalProcess/d efault.htm http://www.fda.gov/Drugs/DevelopmentApprovalProcess/H owDrugsareDevelopedandApproved/ApprovalApplications/I nvestigationalNewDrugINDApplication/ucm176522.htm http://www.fda.gov/Drugs/DevelopmentApprovalProcess/H owDrugsareDevelopedandApproved/ApprovalApplications/I nvestigationalNewDrugINDApplication/ucm176522.htm