Protection of Human Research Subjects: A Key Investigator Responsibility

1. Protection of Human Research Subjects:A Key Investigator Responsibility Charles H. Pierce, MD, PhD, CPI

2. What you can expect: • Drug Development overview • Protecting Human Subjects is the key • Why human Study Participants need protecting • FDA form 1572 • Protected Health Information • International Conference on Harmonization • Investigator Responsibilities: everything including • Adverse Events • Informed Consent Form and process • Source documents, • Safety reporting

4. Physician Investigators Have a dual responsibility and a potential conflict of commitment, if not interest • Goal of clinical care is to diagnose, treat, and cure disease or to reduce pain and suffering in individual patients - Patient care oriented. • The goal of clinical research is to systematically collect information from groups of persons to produce generalizable findings to ….. . . . in a whole population - Drug effect oriented

5. Achieving Ethical Clarity To view clinical trials as therapeutic and as falling under the physician-patient relationship because some aspects of research are associated with care constitutes an ethical distortion that ought to be scrupulously resisted Miller & Rosenstein, NEJM 2003; 348(14):1383-1386

6. Patient Perceptions WhitesBlacks Believe they could be usedas 52 80 “guinea pigs” for medical research Do NOT trust doctor to fully 23 42 explain their participation on a study Docs would enroll patients on a 20 37 research study that was harmful Do not feel they can freely ask or 8 15 question their doctors G. Corbie-Smith et al, Arch Int Med;162:2458,2002

7. Guarantees to Protection • Physicians and Nurses are an integral part of the process of clinical research – built in privacy + HIPAA • Independent oversight committee (the IRB / IEC) • Informed Consent is a process not just a signature • Principles of GCP in research with human subjects • Conflict of Interest (CoI) guidelines • Data & Safety Monitoring Plans (DSMP) / Boards (DSMB) • Research Subject Advocacy (RSA) program • Physician Investigator certification (CPI, CI) is available

8. The power of Law: the 1572 Signing a 1572 is the PI’s commitment in writing that she/he will be responsible for the study in question;totally responsibleand for everything This means she/he agrees to follow: • 21 CFR 50 - Informed Consent process • 21 CFR 56 - IRB does what it should • 21 CFR 312 • 21 CFR 312.64 - AE reporting • 21 CFR 312.62 - Record keeping • 21 CFR 312.68 - Being audit ready

9. The commitments of the 1572 • Personally conduct or supervise the investigation • Ensure that all associates, colleagues, and employees assisting in the study conduct are informed of obligations • Conduct the study in accordance with the protocol • Comply with all requirements / obligations of the PI including preparation and maintenance of study records • Inform the SP of the investigational nature of the study • Ensure that the IC process is clear / valid and all IRB requirements are met • Accurately report all AE’s to the sponsor • Read and understand the Investigators Brochure (IB)

10. PHI Protection • Health Insurance Portability and Accountability Act (Aug 96 - 14 Apr 2003) • Effects the collection, recording, transmission, and storage of patient health information • The effect is your ability to access and use this information for research • Protected Health Information (PHI) • Individual identifiable health information past, present, or future physical or mental health condition in any medium (oral, paper, or e)

11. HIPAA means • One obtains “permission” to use PHI • Authorization to use PHI for research • Waiver to use the information for …. • De-Identified data: the list is not short • Prior agreement to use the data or limited use • OK to use for SOC including payments • Subject has access to the records • The right to inspect and copy • Access may be suspended during trail conduct

12. International Conference on Harmonization - ICH The Efficacy topics concern the Clinical Investigator. They are: ICH - E1 - Exposure of the agent to populations E2 - Clinical Safety E3 - Study Reports - structure and content E4 - Dose Response Studies E5 - Ethnic Factors in acceptance of data

13. ICH E6 Topics E6 - Good Clinical Practice 1. Glossary 2. Principles of ICH GCP 3. The IRB / IEC 4. The Investigator 5. The Sponsor 6. The Trial Protocol and Amendments 7. The Investigators Brochure 8. Essential Documents

14. ICH E6 Topics E7 - Special Populations e.g. Geriatrics E8 - Clinical Trial Design general considerations E9- Statistical Principles of Clinical Trials E10 - Choice of Control group in clinical trials E11 - Pediatrics E12 - Therapeutic categories • E12A is Clinical trials on antihypertensives

15. GCP and the Investigator E6 - Good Clinical Practice 1. Glossary 2. Principles of ICH GCP 3. The IRB / IEC 4. The Investigator 5. The Sponsor 6. The Trial Protocol and Amendments 7. The Investigators Brochure 8. Essential Documents

16. Investigator Responsibilities ICH - E6 4.1 - Investigators Qualifications 4.2 - Adequacy of Resources 4.3 - Medical Care of Study Participants 4.4 - Communication with the IRB / IEC 4.5 - Compliance with the Protocol 4.6 - Investigational Product care

17. Investigator Responsibilities ICH - E6 4.7 - Randomization & unblinding proced. 4.8 - The Informed Consent 4.9 - Records and Reports 4.10 - Progress Reports 4.11 - Safety Reporting 4.12 - Stopping or suspending a study

18. Investigator Responsibilities ICH - E6 4.1 - Investigators Qualifications • Properly qualified to assume the responsibilities for conduct of the study. • Very familiar with the drug under investigation • Will comply with Regulations and be prepared for audits and monitoring • Has available detailed list of all to whom responsibility is delegated

19. Investigator Responsibilities - E6 4.2 - Adequacy of Resources • Can recruit SP in sufficient numbers & on time • There is enough time to complete the study • There are enough qualified staff and adequate facilities to complete the study • The staff are well informed about the Test Agent and the Protocol

20. Investigator Responsibilities - E6 4.3 - Medical Care of Study Participants • All medical decisions are made by qualified physicians • All medical acts are performed by qualified physicians • The Investigator is responsible for care of SP when there are “Adverse Events”* • The primary physician of the SP is notified regarding the participation of their patient on the (or a) study • The Study Physician knows when and why a Study Participant leaves a study - accounting for all SP

21. Adverse Eventsare: • Signswhich are asymptomatic findings as: changes in BP, temperature, rashes, etc. • Symptomsrepresent a change in function such as unsteady gait, lightheadedness, nausea, HA • Lab resultof concern i.e. well beyond the reference range for the protocol or judgment • Inter- current Illnessoccurring while on study even if (the usual case) unrelated to the test medication • Study conditionscausing or contributing to an abnormality i.e. shivering, hematoma, fainting...

22. Investigator Responsibilities - E6 4.4 - Communication with the IRB / IEC • Written approval is obtained before the Study begins • Informed Consent is in the language of the SP • The IRB has a current Investigators Brochure • The IRB has all documents when needed • The IRB is immediately informed of SAE (deaths etc) • Protocol amendments are submitted on time • The IRB / IEC gets an annual report of each study

23. Investigator Responsibilities - E6 4.5 - Compliance with the Protocol • Has signed Protocol confirming agreement to comply with it to the letter • Has not deviated from the Protocol without written agreement from the sponsor and the IRB / IEC • Has documented each and every deviation (for subject safety reasons) from the protocol when it occurs • Implements deviations to avoid risk but immediately submits amendments to IRB, Sponsor and the FDA

24. Investigator Responsibilities - E6 4.6 - Investigational Product care • Accepts responsibility for the product, its usage, and its storage according to the Protocol • Only a Pharmacist involved under PI’s supervision • Explains to SP, and uses test agent, properly only • Detailed records of test agents use kept throughout the study • Retained unused test agent and destroy only under the written instruction from the sponsor

25. Investigator Responsibilities - E6 4.7 - Randomization and unblinding procedure • The study randomization procedures (documented in the protocol) are followed exactly • The randomization code is only broken in accordance with the protocol • If the study was blinded, any unblinding was documented and sponsor notified in writing

26. Investigator Responsibilities - E6 4.8 - The Informed Consent • Insure that the declaration of Helsinki and the principles of GCP are adhered to • Insure that there is no coercion, of subjects to be on, or stay on, a study at any time • Insure SP understanding* of the information they are presented by you or your designees • Insure that the Informed Consent is signed and dated by the SP or SP’s legal representative

27. Informed Consent “Process” • Assure the sponsor that the IRB is functioning in compliance with 21 CFR 56 • Seek consent only under circumstances that provide sufficient opportunity to consider whether or not to participate - 21 CFR 50.20 • The process must minimize the possibility of coercion or undue influence • Provide the ICF in a language understandable to the subject – 6th grade reading level recommended • Insure that the ICF contains no exculpatory language • Confirm that the ICF contains all of the required elements – 21 CFR 50.25

28. Essential Elements of an ICF CFR 50.25 - Essential elements of an “informed consent” That the study is research The risks and discomforts are described The benefits for subject and others Disclosure of alternative therapies or procedures Statement regarding confidentiality of the records Explanation of what will happen on the study Who to contact for questions and their rights That participation is completely voluntary

29. Essential Elements of an ICF CFR 50.25 - Additional (read: also essential) elements of an “informed consent” are statements which state: Statement regarding risks to the SP, an embryo, or fetus; The circumstances regarding termination of the subjects participation without their consent; Any additional costs to the subject resulting from participation in the research study; The consequences of withdrawal and tests that would need to be completed; Statement regarding disclosure of new information as it becomes available; The approximate number of subjects involved in the study

30. Investigator Responsibilities - E6 4.9 - Records and Reports • Data is ALCOA (accurate, legible, contemporaneous, original and attributable) and complete • Data on the CRF’s is consistent with (exactly the same as) that of the source documents (raw data) • All changes to a CRF are dated and signed such that the original data is not obscured • Essential documents are retained at least 2 years after the last approval of the test agent for market

31. It’s the Data, s….. • How and where the data is recorded is the Key • Good, auditable data is “ALCOA” • Accurate • Legible • Contemporaneous • Original • Attributable • If it is not documented, it does not exist

32. Source Documents Source documents are original documents and records for each study subject. Be clear - this is any and all original documents Their purpose is to verify the existence of the subject and verify the integrity of collected data.

33. Source Documents Examples: • All Study related Medical Hx and Px forms • Demography sheets • Dosing documentation sheets • Blood draw recording sheets • Vital sign recording sheets • Subject diaries • Notes to file • Laboratory records • Phone records (even yellow sticky’s) • Study related data even on scrap paper

34. Source Documents Other Administrative points: • Never erase or overwrite – use single horizontal line to strike through unwanted words etc. • No blank spaces on any page • All loose pages are identified clearly • All entries are legible and self explanatory • Corrections are clearly and consistently made • Subject / patient identifiers are consistent • All loose pages are identified clearly • All entries are initialed and dated when done

35. The Handling of data is Important Corrections: documentation CPierce25 Jun04 Clear documantation is … Date Format goal is to be unambiguous: Day = 2 digits Month = 3 letters Year = 2 digits i.e. 25/Jun/04 or 25-Jun-04 08/Sep/03 or 08-Sep-03

36. Investigator Responsibilities - E6 4.10 - Progress Reports • A written report is submitted to the IRB /IEC at least annually is required but…. • Low Risk – yearly is OK • Moderate Risk – twice a year • High Risk – monthly to quarterly as needed • A written report is submitted to the IRB / IEC if the PI notes any change that might significantly change the conduct of the trial

37. Investigator Responsibilities - E6 4.11 - Safety Reporting • All SAE’s are immediately reported to the sponsor and followed up by a written report forthwith • Study Participants are not to be identified to anyone • All AE’s critical to the safety evaluation are reported to the sponsor per protocol • The sponsor and the IRB are given all details in the event of a death of a SP while on study

38. Monitoring Data Safety • Subject Safety under the microscope • Data & Safety Monitoring Plans (DMP, DSMP) • Data & Safety Monitoring Committee (DMC, DSMB) - Separate and independent - No conflict of interest (scientific, financial, etc) • When to discontinue a study – one of the main functions of a DSMB is to establish “stopping rules”: • Clear evidence of harm or harmful AE’s • No likelihood of demonstrating benefit • Overwhelming evidence of benefit

39. Aims of a DSMP • To ensure the safety of all participating subjects to the greatest extent possible • On-going oversight and monitoring of the conduct of a study • To ensure the validity and integrity of the data • To periodically decide whether of not the study should continue or be stopped • To specify the responsibilities and charter of the DSMB if one is required

40. Adverse Events (AE’s) AE’s are one of the key ways the Clinical Investigator has of monitoring the safety of subjects or patients in her/his charge. Determining the relationship between the study drug and an AE requires not only the physicians power of observation but great care. The algorithm: 1 - Likely / almost certainly 2 - Probably 3 - Possibly 4 - Unlikely / remotely possible 5 - Unrelated

41. Investigator Responsibilities - E6 4.12 - Premature stopping or suspending a study • All SP are informed if a study is terminated or even suspended • The institution, the sponsor, and the IRB are informed in writing if the PI terminates the study • The institution and the IRB are informed in writing if the sponsor terminates the study • The institution and the sponsor are informed in writing if the IRB terminates the study

42. Investigator Responsibilities - E6 4.13 - Final Report(s) by Investigator • The Principal Investigator is expected to file a written report at the conclusion of a study

43. Final Report Upon completion of the study, the investigator must notify the IRB and the sponsor. The final report should contain the introduction, description of the methods, results, and discussion of the findings. Of greatest importance to the Investigator is the section dealing with the effect of the test article on the Study Participants as reflected in the AE / test article relationship

44. What the FDA is Finding • Protocol is not followed - I/E criteria, tests & timing, route of admin., timing of events • Informed Consent inadequacies - Timing, elements missing, risks listed, copies • Test article accountability problems - Dispensing, inventory & receipt records • Reporting deficiencies - AE’s, final reports, Yearly IRB reporting • IRB approvals missing - Timing, amendments, ICFs, Advertising • Records in disarray - Corrections, storage requirements, equipment maintenance

45. An Answer • Investigator Certification • AAPP - Certified Physician Investigator (CPI) • ACRP - Certified Clin. Res. Investigator (CCRI) • SoCRA - Certified Clin. Res. Professional (CCRP) • DIA - Certified Clinical Investigator (CCI) • Study Personnel Certification • ACRP - CCRA (’95), CCRC (’92) • SoCRA - CCRP (’91) • IRB Certification

46. Summary The overall role of the clinical investigation team is to protect the rights and safety of volunteers and patients enrolled in studies. Moreover, the clinical investigation team is charged with ensuring that the data obtained from trial subjects is accurate and valid.

47. Clinical InvestigatorResponsibilities In the end… …a physician doing clinical research is still a physician with all that that entails. She/he takes great care in all aspects of the care of those with whom she/he is responsible. This care includes accurate record keeping, patient safety and clear documentation of ones thought process

48. Addendum The Drug / Adverse Event relationship algorithm

49. AE / Study Drug Relationship Algorithm 1 - Likely / almost certainly 2 - Probably 3 - Possibly 4 - Unlikely / remotely possible 5 - Unrelated

50. 1 - Likely / almost certainly a causal relationship exists when the event: - is a well known effect of the drug (PDR, IB) - follows a clear temporal sequence from the drugs administration - ceases with discontinuation of the test agent (and reoccurs on restarting) - is not related to study / environment