The Pursuit of Excellence in Today’s Challenging Clinical Trials Environment

1. Bruce C. Ross, PA-C Wednesday, March 26th 2008 presented at The Methodist Hospital Houston, Texas The Pursuit of Excellence in Today’s Challenging Clinical Trials Environment

2. Regulatory History and Current Trends The origins of the FDA was a one-man operation just prior to passage of the 1906 Pure Food and Drug Act Lyman Frederic Kebler (Chief Chemist at Smith Kline and French) Became the Director of the Drug Laboratory in March 1903

3. 1906 Pure Food and Drug Act • Signed into law June 30th, 1906 by President Theodore Roosevelt • Prohibited interstate commerce in misbranded and/or adulterated food and drugs • 1914 – Harrison Narcotic Act • Limited the amount of narcotics and/or cocaine in medicines sold to the general public

4. 1937 – the Sulfanilamide Incident • Sulfanilamide was a miracle drug used to treat streptococcal infections in tablet form • A liquid formulation was created by the S.E. Massengill Co. (Bristol, TN) by dissolving sulfanilamide in diethylene glycol • The company’s lab tested it for flavor, appearance, and fragrance… but not for toxicity • The food and drugs law of the time did not require safety studies on new drugs. • Selling toxic drugs was not illegal! • More than 100 people died as a result

5. The Federal Food, Drug, and Cosmetic Act of 1938 • Required new drugs to be shown safe before marketing • Extended FDA’s control to cosmetics and therapeutic devices • Provided that safe tolerances be set for unavoidable poisonous substances • Authorized standards of identity, quality, and fill-of-container for foods • Authorized factory inspections • Added the remedy of court injunctions to the previous penalties of seizures and prosecutions

6. 1962 – Kefauver-Harris Drug Amendments (after the thalidomide tragedy) • To ensure drug efficacy and greater drug safety • Drug manufacturers required to prove to FDA the effectiveness of their products before marketing • FDA was given more control over investigational drug studies • FDA inspectors granted access to additional company records • Manufacturers had to demonstrate the efficacy of products approved prior to 1962

7. Recent Changes and Trends 1991 – FDA publishes regulations to accelerate reviews of drugs for life-threatening diseases 1996 • International Conference on Harmonisation - Good Clinical Practice regulation was implemented (ICH-GCP or E6) • HIPAA – Health Insurance Portability and Accountability Act (HIPAA) 21st Century • Increasing globalization of clinical trials • International regulation of clinical trials

8. Crystal Ball… Regulation of the clinical trials industry will continue to increase in response to the public’s perceived needs

9. First, let’s define a few terms! Study Coordinating “Study Coordinating” is inclusiveof: • All tasks performed by the co-/sub-investigators, research nurses, medical assistants, & study coordinators who participate in the conduct of a clinical trial,and • Who perform those tasks under the supervision of a Principal Investigator

10. Study Coordinator • Any person, other than the Principal Investigator (PI), who performs study specific tasks on behalf of the PI • In the United States, the majority of clinical trial activities are performed by study coordinators • Thus, the scope and nature of study coordinating is often of far greater importance to the success of a clinical trial than a PI may realize!

11. It’s not just transcription of CRFs and keeping the monitors happy… Study coordinating is the ∑ (sum) of all clinical trial management activities performed by individuals other than the Principal Investigator

12. Investigator • “A person responsible for the conduct of the clinical trial at a trial site.” Principal Investigator • “If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.” ICH GCP (E6)

13. Sub-Investigator A sub-investigator (co-investigator) is any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). ICH GCP (E6)

14. Understand the PI’s role The PI signs and dates a legally binding contract with the Food and Drug Administration at the start of every clinical trial they conduct! Form FDA-1572

15. Form FDA-1572Section 9 9. COMMITMENTS: • I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects. • I agree to personally conduct or supervise the described investigation(s). • I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met. • I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64. • I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug. • I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments. • I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68. • I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects. • I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312. Yadayadayada… sign here, please!

16. It’s a lot of responsibility for one person!

17. Question: How does a PI ensure that the clinical trial is properly conducted? • Judicious delegation of authority to individuals who possess the appropriate education, training & experience to perform the assigned tasks • Effective and timely supervision

18. Delegation of Authority The delegation of authority helps the PI comply with two of the most critical responsibilities: “I agree to personally conduct or supervise the described investigation(s).” “I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.” It’s much more than just a staff signature page!

19. Pearls to Take Home: • Know your role in the study • Know your limits • Know the GCPs • Understand the regulatory process • Understand the disease being studied • Learn the protocol • Know how to handle the IP • Know the AE assessment criteria

20. Pearls to Take Home: • Understand the Data Management process • Use a systematic approach to your job • “ALCOA” all source documentation • Identify, report, correct, and prevent Protocol Deviations/Protocol Violations • Be prepared for visits by monitors, QA audits, and the FDA

21. Know your role in the study

22. Know your role in the study

23. Know your limits Regardless of your individual background – including education, expertise, training, and previous clinical trial experience: • You may perform only those specific tasks delegated to you by the PI • Each task must be performed in compliance with the protocol • The principles of Good Clinical Practice (GCP) must be adhered to at all times • You must keep the PI informed of what you are doing and report any adverse events that occurred

24. Know the GCPs The 15 second GCP review • A qualified investigator • Upon the approval of a properly constituted IRB • Enrolls only eligible subjects • Who have given their informed consent • With all study procedures/labs performed per protocol • And all study drug is administered and accounted for • With all on-study experiences assessed & documented • And AEs assessed, graded, and reported • Maintaining accurate and complete case histories, and • All trial data are accurately reported

25. If it’s so easy, then why are… The Most Common Deficiencies Found During QA Audits / FDA Inspections: • Inadequate drug accountability (12%) • IRB not informed of changes (6%) • Unapproved concomitant therapies (3%) • Unavailable patient records (2%) • IRB approval not obtained (2%) • Sub-investigators not on FDA-1572 (2%) • Failure to obtain informed consent (1%)

26. Understand the regulatory process • Sponsor submits protocol, investigator’s brochure, & informed consent template to the FDA for review If no FDA response in 30 days (for 1st trial of the product in this disease indication) the trial may begin • Sponsor selects & qualifies potential investigators; FDA-1572 & Financial Disclosure • Investigators submit protocol, IB, and informed consent form to IRB for review • Investigator is responsible for ensuring the IRB is properly constituted and operating IAW the regulations

27. Regulatory Process – cont’d. • IRB reviews and either approves or does not approve the investigator, site, protocol, and informed consent form • IRB approvals must be documented in writing • If investigator is a member of the IRB, he/she must abstain from discussions and voting on the study; this abstention must be documented, too! • IRB approvals may be valid for up to one year, shorter review cycles are required for trials which pose particular risks

28. Regulatory Process – cont’d. Investigator provides periodic reports to the IRB regarding status Enrollment: If enrollments reach the upper limit stated in the original submission, the investigator should notify the IRB and request approval to exceed the original enrollment goal Safety: When new safety information becomes known the investigator must notify the IRB Closure: When the study is closed, the investigator must notify the IRB

29. Regulatory Process – cont’d. • The sponsor locks and analyzes the trial database, and a clinical study report (CSR) written • The CSR is submitted to the FDA May be submitted later on, or as the keystone of a New Drug Approval submissions • If the trial data are being submitted as part of a New Drug Approval (NDA), the sponsor must submit their investigators’ financial disclosure data at the same time

30. Understand the disease being studied i.e.:Non-Insulin Dependent Diabetes • Etiology & Pathogenesis • Patient Population • Symptoms • Treatments • Laboratory Abnormalities and their significance • Which aspect or symptom of the disease does the study address? • i.e.: improved control of hemoglobin A1C levels

31. Learn the protocol • The disease being studied by the protocol • Investigational Product (IP) and reason why is it being studied in this disease • Patient population being studied • Inclusion/exclusion criteria • Study procedures & their timing • Visits and visit windows • Administration of IP (when & how) • Stopping rules • Anticipated benefits/risks and adverse events for the enrolled subjects

33. Know how to handle the IP • The right drug(e.g.: lot number, randomization number, product, strength, formulation, expiry date) • Received/stored in the right way(e.g.: shipped appropriately as to method, time/temperature, and recipient; product storage correct as to security, limited access; and temperature correct [ambient, refrigerated, frozen, ultra-cold]) • Prepared in the right manner(including correct diluent, temperature, syringes/needles, mixing technique)

34. Investigational Product (IP) – cont’d. • Dispensed to the right patientat the right date/timeand in the right way • Subjects must be provided with necessaryinstructions on properly using, handling, storing, and returning the investigational product(s).

35. Know how to handle the IP – cont’d. • Residuals (e.g.: used vials, returned unused product) were stored or disposed of in accordance with the protocol and institutional guidelines • And documented in the right way • Shipping invoices complete/correct • Receipt inventory performed with condition/quantity verified • Recorded on approved product accountability logs • Destruction/returns recorded on approved forms • Destroyed or return shipped using approved methods

37. Know how to assess abnormal laboratory and diagnostic results • All out-of-range laboratory results need to be assessed for clinical significanceby an investigator Not Clinically Significant (NCS) – is out of range but not clinically significant Clinically Significant – is out of range and is clinically significant • Requires an intervention (treatment, new or changed conmeds, or IP hold, dose-reduction, or cessation) • Re-testing performed to confirm results

39. Know the AE assessment criteria Many trials use specific AE assessment criteria! • Severity • CTCAE3 (Common Toxicity Criteria for Adverse Events, Version 3)? • Study-specific? • Clinical impact? • Causality • Seriousness

40. Know the AE assessment criteria • Severity • CTCAE3 (Common Toxicity Criteria for Adverse Events, Version 3)? • Study-specific? • Clinical impact?

41. Know the AE assessment criteria Many trials use specific AE assessment criteria! Causality

42. Know the AE assessment criteria Seriousness • Is fatal or life-threatening • Requires or prolongs hospitalization • Is significantly or permanently disabling or incapacitating • Constitutes a congenital anomaly or a birth defect • Is medically significant, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above

43. Know the AE assessment criteria Events generally not considered to be serious adverse events are hospitalizations for the: • Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition. • Treatment, which was elective or pre-planned, for a pre-existing condition that did not worsen • Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of serious given above and not resulting in hospital admission. Pregnancy, although not itself a serious adverse event, should also be reported on a serious adverse event form or pregnancy form and be followed up to determine outcome, including spontaneous or voluntary termination, details of birth, and the presence or absence of any birth defects or congenital abnormalities.

44. Remember - only an investigator may grade the severity of an Adverse Event! • The PI is responsible for ensuring that all AE are accurately and thoroughly reported • Delegated authority may be granted by the PI for assessing AE but only to an appropriated qualified individual • Per industry standards this is a physician, perhaps even a nurse practitioner or physician assistant, but not a nurse or study coordinator!

45. Understand Data Management • Proper use of the CRFs • Process for submission and revision of trial data • How the query process works • When being queried: • Answer the question being asked • Supply context as appropriate

47. Use a systematic approach to your job: • Validate all data and procedures at the site • Ask yourself “how many ways are there for the critical elements to fail?” and then search for any evidence of failure • If failures are found, ask yourself “are the failures an isolated event or evidence of a more systematic problem?” • Document/report your findings as appropriate, then fix them so they stay fixed!

48. Source Documentation • Source data (unique data points) are found in source documents, and source documents must be: • Original documents, duplicate copies (e.g.: NCR) of original documents, or copies certified as being true and accurate copies of original documents, or original printouts from secure, validated systems (e.g.: printouts from a central laboratory computer); • Unaltered in content, date, or time; • Created by an authorized person; and • Are accessible for inspection by monitors, auditors, and other authorities

49. ALCOA The FDA has provided similar guidelines1: “ALCOA” • Attributable • Legible • Contemporaneous • Original • Accurate Stan Woolen, Deputy Director, Division of Scientific Investigations, presentation at DIA Annual Meeting, June 29, 1999.

50. Informed Consent Informed consent is a process, not just a patient’s signature on a form! A valid informed consent must fulfill the 6 rights: • The right form • Given to the right patient • Presented in the right way • Administered by the right person • Obtained at the right time • Signed/dated by the right people