1) The drug development process involves multiple phases of clinical trials to evaluate safety and efficacy, taking on average 10-15 years from discovery to approval. 2) Key players in clinical research include the FDA, study sponsors, principal investigators, institutional review boards, study coordinators, and study monitors. 3) Each player has distinct roles and responsibilities to ensure research is conducted properly and that human subjects are protected.

1. History & Overview of the Drug Development Process & Timeline Brown Bag lunch series (1/6) JoAnn Pfeiffer November 17, 2010

2. Goal Through training on the conduct of human subject research the Velos staff will acquire a better understanding and knowledge of the steps and requirements in the day-to-day operations of a clinical trial. Through a better understanding of clinical trial operations the Velos staff will be able to respond more effectively to client requests and requirements.

3. Session One Agenda History Drug Development Process Key players- roles and responsibilities

4. Session One Objectives At the end of session the participant will be able to : Describe the drug development process & timeline Identify the key players involved in research Describe the roles & responsibilities of the key players

5. Historical Events Pre 1906: all drugs could be bought or sold like any other consumer good Pure Food & Drugs Act (1906) Upton Sinclair: “The Jungle” Prohibits interstate commerce of misbranded or adulterated foods, drinks, and drugs Regulated product labeling Did not address drug safety or efficacy

6. Historical Events The Federal Food, Drug and Cosmetics Act—1938 Sulfanilamide: treat streptococcal infections Massengill Co: introduced a liquid form (1937) 107 people died that year Contained diethylene glycol First time FDA required that drugs must be safe before being introduced to the market.

7. Tuskegee Syphilis trial (1932 - 1972) Sponsored by PHS Study the effects of untreated syphilis in black men Exposed by media in 1972 Ramifications into late 1990’s $9M, free medical treatment to survivors & descendants Presidential apology in 1997 History Drug Development Process Study Design Roles/ responsibilities Tuskegee

8. U.S. Code of Federal Regulations (CFR) Nuremburg Code (1947-1948) Nuremburg war crimes trials: Nazi experimentation Ten points for legitimate medical research Voluntary consent; fruitful results; based on animal experimentation; free of unnecessary physical or mental suffering; end result cannot be death or disability; risk/benefit; conducted by scientifically qualified persons; subject at liberty to withdraw; terminate if cause to believe harm; adequate facilities Declaration of Helsinki (1964) World Medical Association Set of ethical principles for the medical community regarding human experimentation History Drug Development Process Study Design Roles/ responsibilities

9. Thalidomide Thalidomide (1950’s & 60’s) Approved as sedative in Europe and Japan Mfg. sent “samples” to US physicians Patients not informed that the drug was investigational in US Used for morning sickness > 10,000 children in 46 countries were born with deformities in late 1950’s and early 1960’s History Drug Development Process Study Design Roles/ responsibilities

10. Milgram Study The Milgram Study (1961 – 1962) 67.5% administered the max shock (450 V) Teacher – Learner Teacher ask multiple choice questions Administer a shock if answer incorrect Start at 45 volt, could go up to 450 volt shock All paused to question experiment None refused prior to 300 volt shock Female subjects –same results, higher stress

11. Kefauver-Harris Amendment Kefauver-Harris Amendment – 1962 Subjects informed of experimental nature Informed consent must be obtained Safety and efficacy must be proven prior to approval to market Belmont Report – 1978 Respect Beneficence Justice

12. History Drug Development Process Study Design Roles/ responsibilities

13. Phase I Primary Objective: First in human Safety and tolerability 20 – 80 healthy volunteers Single dose or repeated doses Low dosage, escalate to higher doses Determine maximum tolerated dose History Drug Development Process Study Design Roles/ responsibilities

14. Phase II Primary Objectives Determine optimal dose and regimen Safety & efficacy Patients with disease Up to 200 subjects Multi-center Adverse events History Drug Development Process Study Design Roles/ responsibilities

15. Phase III Primary Objectives Gather additional information to evaluate the overall benefit-risk relationship Large: up to thousands Multi-center : representative of patient pop Most expensive, time consuming History Drug Development Process Study Design Roles/ responsibilities

16. Key Players FDA Sponsor Principle Investigator (PI) Institutional Review Board (IRB) Study Coordinator Data Manager Study Monitor History Drug Development Process Study Design Roles/ responsibilities

17. FDA Protect safety of the consumer Code of Federal Regulations IND and NDA (drugs) IDE and PMA or 510k (device) Post-approval Inspections Recalls Fines History Drug Development Process Study Design Roles/ responsibilities

18. Study Sponsor Academic institution Pharmaceutical company Device/ biologic/ drug Investigator initiated Government NCI/ NIH/ CDC/ NSF, etc History Drug Development Process Study Design Roles/ responsibilities

19. Sponsor roles Develop Investigator Brochure (IB), protocol, informed consent IND submission to FDA (30 days) IRB approval Site evaluations/ selection Monitor the study sites (compliance) NDA submission Post-market evaluation History Drug Development Process Study Design Roles/ responsibilities

20. IRB roles Institutional or central IRB Ensure safety of the study subjects Review/ approve protocols Review/ approve consents Review/ approve any marketing materials Review/ approve any amendments Review AE & SAE reports Review periodic reports from each sites History Drug Development Process Study Design Roles/ responsibilities

21. IRB Operation Procedure A Proposed Research Protocol IRB receives a proposed research protocol with informed consent Requires modification General board reviews, discusses and votes IRB disapprove the protocol IRB notifies investigator of protocol approval IRB conducts ongoing review Research Yes Change protocol? History Drug Development Process Study Design Roles/ responsibilities

22. Investigator role Understand the IB and protocol Conduct study in compliance with protocol Responsible for the safety of study subjects Delegate work to qualified staff Informed consent process Report any SAE/ AE Maintain accurate records for inspection Ensure protocols, consents, amendments have been approved by IRB History Drug Development Process Study Design Roles/ responsibilities

23. Study Coordinator Role Conduct study from screening to close-out Informed consent process Screening process to determine eligibility Schedule/ conduct patient visits Responsible Study documents (drug logs, AE logs, conmeds, medical history, patient procedures/visits, etc) CRF or eCRF Report AE/ SAE History Drug Development Process Study Design Roles/ responsibilities

24. Data Manager role Oversight data collection Review accuracy and completeness Create queries Oversight for biostatisticians: analyze & report on data Data lock History Drug Development Process Study Design Roles/ responsibilities

25. Data Flow Data Management Paper CRF or Electronic data PI Approves Data query Automatic or manually CRC Clinical Database Database revised Database lock Resolve all the queries Data Analysis (Statistical analysis)

26. Study Monitor role Study Monitor represents the sponsor All study documents complete & submitted Review all study related documents for accuracy and completeness Generate queries based on review Drug Accountability logs Conduct trainings Ensure site compliance Study site close-out History Drug Development Process Study Design Roles/ responsibilities

27. Participant Knowledge Assessment List 2 – 3 roles/responsibilities of each of the following: FDA Sponsor IRB Investigator Coordinator Monitor