Protocol Mechanics

1. Protocol Mechanics • Why do we write one? • How to begin • Requirements for submitting a research protocol and types - Nuts and Bolts • Basic elements of informed consent • COI • IRB protocol review standards • ProtoType

2. Protocols: Why do we write them? • CFR Title 21 Food and Drugs • Several other Manuals, Reports • European Directive on GCP 2001/20/EC • ICH guidelines • Guidance developed the Expert Working Group of theInternational Conference on Harmonizationof Technical Requirements for Registration of Pharmaceuticals for Human Use(ICH) • Recommended by EU, Japan, and the US. • Published in the Federal Register May 9, 1997 (62 FR 25692 • Represents the Agency’s current thinking on good clinical practices • Alternative approaches can be used if they meet the requirements outlined

3. Title 45 – Code of Federal Regulations – Part 46 (45CFR46) • Subpart A: Federal Policy for the Protection of Human Subjects: IRB membership, functions, and records. • Subpart B: Additional DHHS Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization. • Subpart C: Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects. • Subject D: Additional DHHS Protections for Children Involved as Subjects in Research.

4. Code of Federal Regulations (21 CFR) • Part 50: Protection of human subjects including informed consent • Part 56: Regulates the conduct of the IRB • Part 312: Investigational New Drug (IND) application to the FDA • Part 11: Regulates management of electronic records

5. International GuidelinesThe rules for Clinical Research International Conference on Harmonization(ICH) Unified International standard to facilitate the mutual acceptance of clinical data by regulatory authorities E6- Guidelines for Clinical Practice E2A- Clinical Safety Data Management Definitions and Standards for Expedited Reporting E8- General Considerations for Clinical Trials

6. If you plan to do clinical research you need a copy of the regulations www.clinicalresearchresources.com

7. Thinking about writing a Protocol? • Protocol- “ …a complete written description of, and scientific rationale for, a research activity involving human subjects.” (Protomechanics NIH) • 3 general types of protocols: • 1. Retrospective review- usually with data • 2. Natural History study- may get tissue samples, DNA • 3. Interventional – Phase I/II most common, Phase III, Phase IV

8. Writing a Protocol – First steps • As PI, you usually are the one who has an idea • Is it reasonable? Do we have the resources? • Significant risks? • Do you have the patient population? • Include those important to the conduct of the protocol as an Associate Investigator • IND request, outside investigators, COI • Initially most ICs will ask you to write an abbreviated conceptual sheet outlining what you wish to do- to the Pre-IRB committee

9. What happens to your protocol when submitted? FDA DSMC OBA New Protocol Pre-IRB committee Dr Gallin Continuing Review or Amendment IRB Office of Protocol Services FDA DSMC OBA

10. Writing a Protocol • Nuts and Bolts

11. http://www.cc.nih.gov/ccc/protomechanics/foreword.html

12. An 1195 that begins every Protocol at the NIH

13. A continuing Review 1195 Filled in for every Protocol

14. Face Sheet Glossary Précis-Abstract Objectives, study population, design and outcome parameters Introduction & Background Background, references Hypothesis & Objectives What you are testing Study Design and Methods Benefits and risks/discomforts: Importance of study Subject Enrollment Inclusion and exclusion criteria Study Analysis Adverse Event Reporting Data and Safety Monitoring Plan Human Subject Protection Monitoring subjects, criteria for withdrawal from study Pharmaceutical, Biologic & Device Info References & Appendices Consent/Assent Forms The major topics to be covered in a Protocol

15. Protocols for INDs(312.23 CFR) • Statement of objectives • Name/address/qualifications of investigators • Criteria for patient selection • Description of the design of the study • Method for determining doses • Description of observations and measurements to be made • Description of the clinical procedures and lab tests

16. Protocols for INDs(312.23 CFR)Required by FDA but need not be in the protocol but usually is • Chemistry, manufacturing, and control information • Pharmacology and toxicology information • Previous human experience with the investigational drug • Additional information such as radioactive drugs, pediatric studies,

17. Consent Forms Why all the fuss?

18. The Doctors Trial at Nuremburg KARL BRANDT KARL GENZKEN OSKAR SCHROEDER PAUL ROSTOCK SIEGFRIED HANDLOSER WOLFRAM SIEVERS HELMUT POPPENDICK JOACHIM MRUGOWSKY KARL GEBHARDT • The EXPERIMENTS • High Altitude Exps • Freezing Exps • Malaria Exps • Lost (Mustard) Gas Exps • Sulfanilimide Exps • Bone, Muscle, and Nerve Regeneration and Bone Transplantation Exps • Sea Water Experiments • Epidemic Jaundice Exps • Sterilization Exps • Spotted Fever Exps • Experiments with Poison • Incendiary Bomb Experiments • Crimes against Humanity SIEGFRIED RUFF HANS WOLFGANG ROMBERG GEORG AUGUST WELTZ KURT BLOME RUDOLF BRANDT GERHARD ROSE VIKTOR BRACK HERMANN BECKER- FREYSENG WILHELM BEIGLBOECK HERTA OBERHEUSER FRITZ FISCHER KONRAD SCHAEFER WALDEMAR HOVEN ADOLF POKORNY USHMM

19. Voluntary consent is essential The experiment should yield fruitful results for the good of society, unprocurable by other methods or means of study Design of study based on animal work and natural hx of disease and the results justify the experiment Avoid all undue physical and mental pain No exp to be done with death as endpoint (except if MD) Degree of risk never outweighs the results of the experiment Proper care to prevent adverse events Experiment should be conducted only by scientifically qualified persons Subject has the right to stop at any time The PI should be prepared to stop exp if patient is at risk of harm. The Nuremburg Code

20. Not only in Germany-The Tuskegee Exps • From 1932-1972, the Tuskegee Public Health Study was conducted by the U.S. Public Health Service to observe 400 sharecroppers with untreated syphilis to document the course of the disease in African-Americans and the racial differences in the clinical manifestation of the disease. • These men were not informed of their disease status nor given counseling to avoid the spread of the disease • In 1972, the study was disclosed to the public

21. Trial involves research Purpose of trial Treatments and Randomization Trial procedures Subject’s responsibilities Experimental aspects Risks or inconveniences to subject or fetus Expected benefits if any Alternative therapies Compensation or rx for trial related injury Prorated payment if any Expenses to the subject if any Participation is voluntary; subject may refuse or withdraw at any time Who will granted access to the subject’s original files; subject’s legal representative has access also Records kept confidential; if published identity is confidential Subject will be informed in a timely fashion of information important to the conduct of the trial Contact information re rights, complaints, injuries Reasons why subject could be terminated from the study Duration of participation in study Approximate number of subjects in the trial Consent form and discussion requirements:ICH 4.8.10

22. NIH Informed Consent • Compensation • Costs to participants • Procedures for withdrawal • Confidentiality concerns • Introduction • Purpose of the study • Duration of study • Research tests or procedures • Research drugs or treatments • Risks and discomforts • Benefits • Alternatives to participation • Uses of samples or information • Genetics research: risks to family members • Financial or other conflict of interest • Assent procedures

23. Part of the Protocol submission Conflict of Interest of the Clinical Researchers

24. A Guide to Preventing Financial and Non-financial Conflicts of Interest In Human Subjects Research at NIHJanuary 4, 2005 ( Revised, December 2005) • Avoiding financial and other conflicts of interests is important for NIH, where the trust and protection of research subjects is vital to our mission to improve the public health. • This specific guide applies to all investigators who substantively participate in the development, conduct, or analysis of clinical research protocols, both diagnostic and therapeutic, and are listed as investigators on the front sheet of protocols • The Principal Investigator is responsible for assuring that each investigator listed on the protocol front sheet receives a copy of the Guide. In addition, the PI is responsible for providing his or her IC Deputy Ethics Counselor (DEC) with a list of all investigators on the protocol before beginning the scientific review.

25. Examples of Investigator COI • Serving as a director, officer or other decision-maker for a commercial sponsor of the human subjects research; • Holding any stock or stock options in a commercial sponsor of the human subjects research(unless held in a diversified, independently managed mutual fund); • Receiving compensation for service as consultant or advisor to a commercial sponsor of the human subjects research(excluding expenses); • Receiving honoraria from a commercial sponsor of the human subjects research; • Personally accepting payment from the human subjects research sponsor for non-research travel or gifts(government receipt of in-kind, research-related travel is not included); • Obtaining royalties or being personally named as an inventor on patents (or invention reports) for the product(s) being evaluated in the human subjects research or products that could benefit from the human subjects research(special rules apply in this case when NIH holds the patent); • Receiving payments based on the research outcomes; • Having other personal or outside relationships with commercial sponsors of the human subjects research • Having financial interest in companies with similar products known to the investigator to be competing with the product under study.

26. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) CFR 56.102 and ICH 3.1 This is set in law in the US • An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects • IRB functions in accord with the NIH (Institution’s) Multiple Project Assurance. • CFR 56.107. IRB should have at least 5 Members of varying background. The choices should promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. At NIH need to include a biostatician, bioethicist,and nonscientist. • PIs are expected to present new protocols and to respond directly to questions. • CFR 56.109: An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by these regulations

27. Some Protocol Elements the IRB looks for • The proposed research design is scientifically sound and will not expose subjects to risk unnecessarily. • Risks are reasonable relative to anticipated benefits: minimize risks to subjects? • Subject safety is maintained • Subject selection is equitable: rationale for inclusion and exclusion criteria • Safeguards to protect vulnerable subjects are in place. • Informed consent is obtained from research subjects or their legally authorized representatives • Will the research contribution to generalizable knowledge be worth exposing subjects to risk? • Equipoise (Benjamin Friedman): A trial can be ethical if there is equal uncertainty among groups

28. Some Protocol Elements the IRB looks for • Subject privacy and confidentiality are maximized. • Will personally-identifiable research data be protected to the extent possible from unauthorized access or applications? • Are special privacy and confidentiality issues properly addressed, e.g., use of genetic information?

29. Regulatory Elements for IRB Review:Additional Considerations • Ionizing radiation: Is the use of ionizing radiation medically indicated or for research purposes only? • Collaborative research: Is this an international or domestic collaborative project? Are SPAs or other assurances in place? • FDA-regulated research: Is an IND or IDE involved in this protocol?

30. IRB Minutes • Attendance • Actions • Votes • Discussion • Stipulations

33. 2003 Protocol Review Process

35. ProtoType The Automated Protocol Writing System An Overview Warren Grant Magnuson Clinical Center National Institutes of Health Bethesda, MD February, 2006

36. Tools to Facilitate Clinical Research ProtoType Assisted protocol writing system Scientific and Regulatory Document Basic Clinical Care Plan Conflict-of-Interest Report of Investigators (to ICD) NLM ClinicalTrials.gov Adverse Events Reporting System CRIS-AE CC Depts & ICD Protocol Mapping System CD & SD IRB Cost Projections CRIS Protocol Monitoring Regulatory Agencies (FDA, OBA,etc) Results / data tagged Data Mining Data Warehouse Institute Research Data Collection Systems DSMB Management Advanced Rules Engine CRIS AE Reporting Template 2 Hospital Epidemiology

37. NIH/Clinical Center ProtoType encompasses 4 areas: • Protocol Writing • Adverse-Event Reporting • Protocol Tracking • (Limited mapping capabilities) ProtoType (the Protocol Typewriter) A web-based clinical protocol-writing application

38. NIH/Clinical Center Value Added: • Maximizes use of IT . . . employs a paperless system • Standardizes the process – while offering flexibility • Provides a standardized template for investigators and reviewers • Improves resource allocation • Enhances patient care and safety • Facilitates the process for all • Increases speed of protocol writing and review • Consolidates other protocol-management programs ProtoType (the Protocol Typewriter) A web-based clinical protocol-writing application

39. NIH/Clinical Center Elements of a Protocol • Face Sheet • Glossary • Précis-Abstract • Introduction & Background • Hypothesis & Objectives • Study Design • Subject Enrollment • Study Analysis • Adverse Event Reporting • Data and Safety Monitoring Plan • Human Subject Protection • Pharmaceutical, Biologic & Device Info • References & Appendices • Consent/Assent Forms ProtoType (the Protocol Typewriter) A web-based clinical protocol-writing application

40. NIH/Clinical Center Elements of a Protocol • Face Sheet • Glossary • Précis-Abstract • Introduction & Background • Hypothesis & Objectives • Study Design • Subject Enrollment • Study Analysis • Adverse Event Reporting • Data and Safety Monitoring Plan • Human Subject Protection • Pharmaceutical, Biologic & Device Info • References & Appendices • Consent/Assent Forms ProtoType (the Protocol Typewriter) A web-based clinical protocol-writing application

41. NIH/Clinical Center Customization and Flexibility • Format is NIH Institute-specific • Only relevant fields appear • e.g., Natural history study vs. Clinical Trial study • Recommended language is available, but can be modified as the Investigator sees fit. ProtoType (the Protocol Typewriter) A web-based clinical protocol-writing application

42. . . . Welcome to ProtoType, and Your Protocols:

43. Create a protocol:

44. Select Interventions: NIH Pharmacy Formulary pre-loaded to choose from

45. (Presentation of interventions in the protocol)

46. Reflecting interventions in the Study Timeline:

47. Using standard-language cassettes (Consent Form) Edit capabilities can be held on special components Language pre-loaded when consent created.

48. An electronic Comments feature:

49. Compare protocol versions, with markup: New Text Bracketed Old Text Crossed Out

50. Electronic approval signaturing: