1. Clinical Research Overview Kathryn Candler M.A. VCU Massey Cancer Center Bone Marrow Transplant Program November 13, 2008

2. 2 Why is research important?

3. 3 Just about every drug, test and intervention done in BMT is the direct result of clinical research

4. 4 What are the goals of this presentation? What is research? Why is research important? What research is being done here? How does a research idea get implemented? How do clinical trials lead to drug development? Why and how is research regulated?

5. 5 What is the definition of research? According to the code of federal regulations it is “a systematic investigation…designed to contribute to generalizable knowledge” So, innovative therapy, off-label use of medications, and any other practice changes designed to treat a specific patient are not defined as research if the intent is not to contribute to generalized knowledge

6. 6 What research is done in the BMT program? Industry sponsored trials in phases I, II, III, and IV Chemotherapy agents – Vidaza Antifungals – Voriconazole and combination therapies Antivirals – Maribavir Drugs to control side effects of treatment – KGF, Osiris Mobilization regimens – AMD 3100 Investigator initiated studies Vidaza to transplant – McCarty Non-myeloablative transplantation – Toor Cooperative group studies CALGB, SWOG, BMT CTN,

7. 7 Why is research regulated? Remember - According to the code of federal regulations research is “a systematic investigation…designed to contribute to generalizable knowledge” Therefore, the subject in a study is the means to achieving the goals of the research (this means that the study subject is exposed to risk for the benefit of others) and is thus vulnerable to exploitation

8. 8 Where did current regulations come from? 1947 Nuremburg Code – written in response to nazi experiments on prisoners; required the voluntary consent of human subjects, absence of coersion, reasonable scientific goals and concern for the wellbeing of study subjects 1964 Declaration of Helsinki – written by the World Medical Association to further clarify acceptable practices; defines the ability of children and the mentally disabled to participate as research subjects with extra safeguards on their treatment 1979 Belmont Report - rather than produce another list of rules about what was acceptable and what was not this report defines the basic ethical principles that should underlie the conduct of human subjects research 2001 Common Rule – code of federal regulations dealing with research

9. 9 How is research regulated? The federal government has passed a number of laws that lay out very specific rules for the process of drug development, the purpose and function of Institutional Review Boards (IRB), the process for obtaining informed consent, and the overall protection of subjects in research These began with guidelines designed to address inappropriate behavior and have progressed to include very detailed federal regulations and guidance meant to ensure that the rights of subjects are protected They assign the FDA to enforce these laws and to perform audits of clinical sites to ensure that the regulations are followed and that subjects are protected

10. 10 Pre Clinical Studies What are the phases of drug development? Synthesis and development of promising compounds, testing in lab and possibly animal models to obtain information about efficacy, toxicity, pharmacokinetics Normally a small group of healthy volunteers, in cancer treatment trials often a small group with the disease under study, used to determine appropriate dosing and not designed to look at efficacy, may include pharmacokinetic studies to assess how the drug is metabolized and excreted Phase I Phase II Phase III Phase IV Assess how well the new drug works and continue safety assessments – usually done with larger groups Usually very large randomized multi-center trials aimed as definitive assessment of how effective the new drug is compared with standard of care Post marketing surveillance – may be required by the FDA to evaluate drug interactions, combination therapies or prompted by the pharmaceutical company to assess new populations such as children

11. 11 Drugs are expensive, this is why…

12. 12 How does a research idea get implemented? Ask a question in a systematic way Have an idea Decide on who will be included, what and how to measure Write a protocol Include required elements of consent Write a consent form

13. 13 How does a research idea get implemented? Review for scientific validity and feasibility Submit to Massey P.R.M.S. Review for appropriate treatment of subjects Submit to IRB Celebrate Get regulatory approval

14. 14 How does a research idea get implemented? Train staff to carry out study Train staff Informed consent process Enter subjects in study Enroll subjects Ensure required information is collected Collect data

15. 15 How does a research idea get implemented? Analyze for investigator initiated study Analyze and/or submit data What do results mean, were assumptions correct? Interpret data Communicate methods, subject details, results, analysis Write results

16. 16 How does a research idea get implemented? Need to repeat for each phase of development Repeat as necessary Send data for review Submit data to FDA Marketing begins Have pens printed Drug is approved

17. 17 What is the Institutional Review Board (IRB)? An IRB is a group of people designated to review research, the board must have at least five members with varying backgrounds, some in science others non scientists At VCU there are multiple IRB boards who meet regularly to review new and ongoing research The IRB must review the study protocol and the informed consent process to ensure that adequate safeguards are in place to protect human subjects, that any risks of the research are balanced by the potential benefits and that any potential conflicts of interest are disclosed to the subjects

18. 18 What is Informed Consent? Subjects must be given the opportunity to determine what happens to them (to the degree they are able), this is insured by obtaining informed consent. To have all the necessary elements of consent the subject must: Be provided all necessary information Comprehend the information Agree to participate voluntarily

19. 19 What is the informed consent form? Federal regulations require 8 elements in consent form What is the purpose and duration of participation? What are the risks? What are alternatives to participating in the research? What are the potential benefits of the research? How will confidentiality of records be assured? What is the plan for compensation if there are injuries? Who is the person to contact with questions? Participation is voluntary and they have the right to withdraw The consent is documented on an IRB approved informed consent form (ICF) but the overall process is much more involved than just signing the form.

20. 20 What makes clinical research ethical? EJ Emanuel, Chairman of the Department of Clinical Ethics at NIH has proposed a series of 7 ethical principles that, if followed minimize the potential for exploitation Ethical requirementExplanation Social or scientific valueEvaluation that will improve health or increase knowledge Scientific validityUse of science in a way that will produce reliable and valid data Fair subject selectionSelected so that vulnerable subjects are not selected for risky research and that powerful subjects are not favored for potentially beneficial research Favorable risk / benefit ratioMinimize risk, enhance possible benefits, risks to the subject are proportionate to benefit to society Independent reviewReview of study design, subject population and risk / benefit ratio by individuals unaffiliated with the study Informed consentProvide information about study to subjects about purpose of the research, risks, potential benefits, alternatives so that subject understands the information and can make a voluntary decision Respect for subjectsPermit withdrawal, protect privacy, inform subjects of new information about risks / benefits, inform subjects of results of research, maintain overall welfare of subjects JAMA May 24/31 2000- Vol. 283, No 20

21. 21 The Clinical Trial Volunteer’s Bill of Rights To be told the purpose of the clinical trial To be told all the risks, side effects or discomforts that might be reasonably expected To be told of any benefits that can be reasonably expected To be told what will happen in the study and whether any procedures, drugs or devices are different than those that are used as standard medical treatment To be told about options available and how they may be better or worse than being in a clinical trial

22. 22 The Clinical Trial Volunteer’s Bill of Rights 2 To be allowed to ask any questions about the trial before giving consent and at any time during the course of the study To be allowed ample time, without pressure, to decide whether to consent or not to consent to participate To refuse to participate, for any reason, before and after the trial has started To receive a signed and dated copy of the informed consent form To be told of any medical treatments available if complications occur during the trial Getz, K., & Borfitz, D. (2002). Informed Consent. Boston, MA: Thomson CenterWatch

23. 23 How do we enroll a BMT patient to a study? At weekly meetings we discuss whether a patient might be eligible for a specific study BMT physicians meet with the potential subject to discuss the study The potential subject asks questions and discusses the consent form and the study procedures with the physician If the subject agrees to participate they are asked to sign the informed consent form The research staff begins testing for eligibility and if appropriate enrolls the subject in the study If new information about risks, benefits or procedures develops the subject is informed and if required another consent form is signed

24. 24 What have we covered? Informed consent form Placebo controlled Double blind FDA Randomized IRB Subject / Patient Phases of drug development Cooperative group Historical factors in the practice of clinical research Ethical principles used to make determinations about research Regulatory agencies involved in research Definition of consent process Limitations of consent

25. 25 What is the bottom line? Our purpose is to carry out clinical research to enhance patient care while insuring the protection of human subjects