Clinical trial brownbag session 1 nov 17 2010


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  • The motivating factors for legislative changes regarding food, drugs and cosmetics can be traced to significant societal problems, human tragedy, and governmental inefficiencyJungle: revealed the unsanitary practice in meat packing
  • First miracle drug
  • 399 black men in late stages of syphilisMost were illiterate share croppers from the poorest county in AlabamaMost had never been to a doctor before.Received a free hot meal and medical treatment Subjects were never told that they had syphilis or the seriousness of the disease (tumors, heart disease, paralysis, blinding, insanity, & death)They were told they were being treated for “bad blood”Data for the experiment was to be collected from autopsies.
  • Became the cornerstone of the CFR
  • Teacher and learner separated during the test.Learner sits in chair with electrodes attached to his body.Teacher at control panel, asks multiple choice question.Learner gave wrong answer, administered a 45 volt electric shock, goes higher as continue.If do not respond, treated as wrong answerExperiment continues till: teacher requests to stop or a maximum 450 volt shock given 3 times in succession67.5% administered maximum shock
  • Preclinical: 1- 4 yrs.INDPhase 1: 1 – 2 yrs. Phase 2: 1 – 2 yrs. Phase 3: 2 – 4 yrs.NDAUser Fee = $1,542,000Priority Review (6 mos) = $4,582,000Supplements/Non-clinical = $771,000 For every 100 drugs developed, one makes it to market8 – 10 years for one drug to get to market. Manufacturer has 7 -8 years of exclusivity before patent expires. Patent for 20 years.Cost produce one drug = $800,000,000
  • Evaluate Safety (tolerated dose range for single and multiple doses)Pharmacokinetics (ADME: Adsorption, Distribution, Metabolism, Elimination)Possible drug-drug interaction
  • Ensure sites have the resources (staff, space, equipment, abilities for recruitment), no bad records on FDA,
  • Voluntary (can drop-off any time), risk, study Study staffs: study nurse, pharmacist, coordinator assistants, recruiters, lab ppl
  • Clinical trial brownbag session 1 nov 17 2010

    1. 1. History & Overview of the Drug Development Process & Timeline<br />Brown Bag lunch series (1/6)<br />JoAnn Pfeiffer<br />November 17, 2010<br />
    2. 2. Goal<br />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.<br />
    3. 3. Session One<br />Agenda<br />History<br />Drug Development Process<br />Key players- roles and responsibilities<br />
    4. 4. Session One<br />Objectives<br />At the end of session the participant will be able to :<br />Describe the drug development process & timeline<br />Identify the key players involved in research<br />Describe the roles & responsibilities of the key players<br />
    5. 5. Historical Events<br />Pre 1906: all drugs could be bought or sold like any other consumer good<br />Pure Food & Drugs Act (1906) <br />Upton Sinclair: “The Jungle”<br />Prohibits interstate commerce of misbranded or adulterated foods, drinks, and drugs<br />Regulated product labeling<br />Did not address drug safety or efficacy<br />
    6. 6. Historical Events<br />The Federal Food, Drug and Cosmetics Act—1938<br />Sulfanilamide: treat streptococcal infections<br />Massengill Co: introduced a liquid form (1937)<br />107 people died that year<br />Contained diethylene glycol<br />First time FDA required that drugs must be safe before being introduced to the market.<br />
    7. 7. Tuskegee Syphilis trial (1932 - 1972)<br />Sponsored by PHS<br />Study the effects of untreated syphilis in black men<br />Exposed by media in 1972<br />Ramifications into late 1990’s<br />$9M, free medical treatment to survivors & descendants<br />Presidential apology in 1997<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />Tuskegee <br />
    8. 8. U.S. Code of Federal Regulations (CFR) <br />Nuremburg Code (1947-1948)<br />Nuremburg war crimes trials: Nazi experimentation<br />Ten points for legitimate medical research<br />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<br />Declaration of Helsinki (1964)<br />World Medical Association<br />Set of ethical principles for the medical community regarding human experimentation<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    9. 9. Thalidomide<br />Thalidomide (1950’s & 60’s)<br />Approved as sedative in Europe and Japan<br />Mfg. sent “samples” to US physicians<br />Patients not informed that the drug was investigational in US<br />Used for morning sickness<br />> 10,000 children in 46 countries were born with deformities in late 1950’s and early 1960’s<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    10. 10. Milgram Study<br />The Milgram Study (1961 – 1962)<br />67.5% administered the max shock (450 V)<br />Teacher – Learner<br />Teacher ask multiple choice questions<br />Administer a shock if answer incorrect<br />Start at 45 volt, could go up to 450 volt shock<br />All paused to question experiment<br />None refused prior to 300 volt shock<br />Female subjects –same results, higher stress<br />
    11. 11. Kefauver-Harris Amendment<br />Kefauver-Harris Amendment – 1962<br />Subjects informed of experimental nature<br />Informed consent must be obtained<br />Safety and efficacy must be proven prior to approval to market<br />Belmont Report – 1978<br />Respect<br />Beneficence<br />Justice<br />
    12. 12. History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    13. 13. Phase I<br />Primary Objective: <br />First in human<br />Safety and tolerability<br />20 – 80 healthy volunteers<br />Single dose or repeated doses <br />Low dosage, escalate to higher doses<br />Determine maximum tolerated dose <br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    14. 14. Phase II<br />Primary Objectives<br />Determine optimal dose and regimen<br />Safety & efficacy<br />Patients with disease<br />Up to 200 subjects<br />Multi-center<br />Adverse events<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    15. 15. Phase III<br />Primary Objectives<br />Gather additional information to evaluate the overall benefit-risk relationship<br />Large: up to thousands<br />Multi-center : representative of patient pop<br />Most expensive, time consuming<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    16. 16. Key Players<br />FDA<br />Sponsor<br />Principle Investigator (PI)<br />Institutional Review Board (IRB)<br />Study Coordinator <br />Data Manager<br />Study Monitor<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    17. 17. FDA<br />Protect safety of the consumer<br />Code of Federal Regulations <br />IND and NDA (drugs)<br />IDE and PMA or 510k (device)<br />Post-approval <br />Inspections<br />Recalls<br />Fines<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    18. 18. Study Sponsor<br />Academic institution<br />Pharmaceutical company<br />Device/ biologic/ drug<br />Investigator initiated<br />Government<br />NCI/ NIH/ CDC/ NSF, etc<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    19. 19. Sponsor roles<br />Develop Investigator Brochure (IB), protocol, informed consent<br />IND submission to FDA (30 days)<br />IRB approval<br />Site evaluations/ selection<br />Monitor the study sites (compliance)<br />NDA submission<br />Post-market evaluation<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    20. 20. IRB roles<br />Institutional or central IRB<br />Ensure safety of the study subjects<br />Review/ approve protocols<br />Review/ approve consents<br />Review/ approve any marketing materials<br />Review/ approve any amendments<br />Review AE & SAE reports<br />Review periodic reports from each sites<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    21. 21. IRB Operation Procedure<br />A Proposed Research Protocol<br />IRB receives a proposed research protocol with informed consent<br />Requires modification<br />General board reviews, discusses and votes<br />IRB disapprove the protocol<br />IRB notifies investigator of protocol approval<br />IRB conducts ongoing review<br />Research<br />Yes<br />Change protocol?<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    22. 22. Investigator role<br />Understand the IB and protocol<br />Conduct study in compliance with protocol<br />Responsible for the safety of study subjects<br />Delegate work to qualified staff<br />Informed consent process<br />Report any SAE/ AE<br />Maintain accurate records for inspection<br />Ensure protocols, consents, amendments have been approved by IRB <br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    23. 23. Study Coordinator Role<br />Conduct study from screening to close-out<br />Informed consent process<br />Screening process to determine eligibility<br />Schedule/ conduct patient visits<br />Responsible<br />Study documents (drug logs, AE logs, conmeds, medical history, patient procedures/visits, etc)<br />CRF or eCRF<br />Report AE/ SAE<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    24. 24. Data Manager role<br />Oversight data collection<br />Review accuracy and completeness<br />Create queries <br />Oversight for biostatisticians: analyze & report on data<br />Data lock<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    25. 25. Data Flow<br />Data Management<br />Paper CRF or Electronic data<br />PI Approves<br />Data query<br />Automatic or manually<br />CRC<br />Clinical Database<br />Database revised<br />Database lock<br />Resolve all the queries<br />Data Analysis <br />(Statistical analysis)<br />
    26. 26. Study Monitor role<br />Study Monitor represents the sponsor<br />All study documents complete & submitted<br />Review all study related documents for accuracy and completeness<br />Generate queries based on review<br />Drug Accountability logs<br />Conduct trainings<br />Ensure site compliance<br />Study site close-out<br />History<br />Drug Development Process<br />Study Design<br />Roles/ responsibilities<br />
    27. 27. Participant Knowledge Assessment<br />List 2 – 3 roles/responsibilities of each of the following:<br />FDA<br />Sponsor<br />IRB<br />Investigator<br />Coordinator<br />Monitor<br />