Clinical Trial Overview

1. Clinical Trial Overview

2. The Role of Statistics in Clinical Trials? (1) • Clinical research involves investigating proposed medical treatments, assessing benefits of competing therapies, and establishing optimal treatment combinations. • Before widespread use of experimental trials, clinicians used experiences of individual patients to generalize to the population at large. • The concepts of variability among patients and its sources were noted but not formally addressed.

3. The Role of Statistics in Clinical Trials? (2) • In the 20th Century, the field of statistics developed and was applied to clinical research. • Statistics is the “theoretical science or formal study of the inferential process especially the planning and analysis of experiments, surveys, and observational studies.” (Piantadosi 2005). • The use of statistics allows the clinical researcher to form reasonable and accurate inferences from collected information and to make sound decisions in the presence of uncertainty.

4. The Role of Statistics in Clinical Trials? (3) • Statistical reasoning is characterized by the following: (Piantadosi 2005) • Establishing an objective framework for conducting an investigation. • Placing data and theory on an equal scientific footing. • Designing data production through experimentation. • Quantifying the influence of chance. • Estimating systematic and random effects. • Combining theory and data using formal methods.

5. The Role of Statistics in Clinical Trials? (4) • Clinical and statistical reasoning are both crucial to progress in medicine. • In both sciences, empirical knowledge is generated from observations and data. • Medical theory is based upon established biology and hypotheses. • Statistical theory is derived from mathematical and probabilistic models.

6. What is a clinical trial?Definitions of a Clinical Trial A clinical trial is a controlled experiment in human subjects which involves an intervention and observation of the subsequent effect of that intervention. Disease … • Desire to impact on patient condition (i.e., improve outcome) CT tests whether new treatment is effective or better than another treatment

7. FFD: "… a prospective study that compares the effect and value of an intervention against a control in human beings." Pocock: "… a planned experiment involving patients, designed to identify a more appropriate treatment for future patients." Meinert: "… a planned experiment designed to assess the efficacy of a treatment in man by comparing the outcomes in a group of patients treated with the test treatment with those observed in a comparable group of patients receiving a control treatment, where patients in both groups are enrolled, treated, and followed over the same time period."

8. The term “clinical trial” is preferred over “clinical experiment” since the latter may connote disrespect for the value of human life.

9. Essential elements • Human subjects • Intervention • Prospective in nature with follow-up observations • Inclusion and exclusion criteria • Risks and benefits for patients • Informed consent required • High cost • Limited number of subjects • Cannot completely control a subject’s environment

10. Starts from a defined point in time unique for each individual subject • Sequential enrollment of subjects • Observation begins upon enrollment on the study Trial intiation Trial closure

11. Generally, a comparison between two treatment approaches, one of which is a control treatment • Control subjects, as a group, should be reasonably the same as treated subjects to ensure comparability • Control subjects often receive “standard of care” treatment, other times they receive a placebo.

12. An intervention is meant to be active in that it will affect some aspect of the subject. Types of interventions: • Therapeutic 80% • Prophylactic 15% • Diagnostic 5% Interventions may be: • Agents • Regimens • Procedures • Devices

13. Did investigator assign exposures? Yes No Experimental study Observational study Random allocation Comparison group? Yes No Yes No Randomized Controlled trial Non- Randomized Controlled trial Analytical study Descriptive study Direction? Exposure and outcome at the same time Outcome Exposure Exposure Outcome Cohort study Case-control study Cross-sectional study Source: Grimes and Schulz, The Lancet 359:57-61 (2002)

14. Types of Clinical Trials PHASE I TRIAL Assess how well a drug or procedure can be tolerated in humans Determine a reasonable dose or technique Phase II TRIAL Estimate biologic activity or effect (Efficacy) Assess rate of adverse events (Toxicity) Phase III TRIAL Assess effectiveness in comparison to standard treatment or placebo Phase IV TRIAL Long-term surveillance (monitoring) Assess long-term morbidity and mortality

15. What is NOT a clinical trial? Observational or retrospective studies: • Case-control studies • Cohort studies • Chart reviews • Case studies

16. Case-control study (retrospective study) – comparisons are made between individuals who have a particular disease or condition (the cases) and individuals who do not have the disease (the controls). Cohort study – investigation in which a group of individuals (the cohort) is identified and followed prospectively, perhaps for many years, and their subsequent medical history recorded. Case studies - are used to collect descriptive data through the intensive examination of a phenomenon in a particular individual, group, or situation. Case studies are particularly useful for studying rare or complex phenomena.

17. What is the origin of clinical trials?History of Clinical Trials Sequential patient entry Randomization in agriculture Placebo Scurvy trial 1750 1799 1898 1926 First randomized trial Placebo control Blinding Multi-center trial Random numbers used to assign treatments 1931 1938 1940 1948

18. Formation of public agencies and co-op groups IRB guidelines Medical devices trials First randomized therapeutic trial 1948 1950 1966 1976 Multi-disciplinary approach to clinical trials (SCT) Group-sequential methodology 1979 2002 Recognition of randomized controlled trials as the preferred and accepted approach- - - Phase I - II - III - IV

19. Why should clinical trials be done?Justification of Clinical Trials Clinical trials provide a systematic framework within which scientific research in human subjects can be carried out efficiently and ethically. Experimental conclusions are reached in a manner that is statistically defensible.

20. How are patients benefited and protected? Rationale of Clinical Trials • Classic experimental design techniques cannot be freely practiced with humans due to ethical issues and practical constraints. • Clinical trials are the method for determining whether an intervention has a postulated effect. • Clinical trials develop scientific evidence with acceptable levels of risk and sufficient scientific defensibility. • Variability in measurement and subjects is inherent but accounted for in such studies. • Bias, which may exist in observational studies, is avoided through randomization and other techniques.

21. Why are clinical trials an acceptable form of research?Ethics of Clinical Trials • Obligation to patient • Benefit of future patients • Validity of statistical inference • Informed consent required • Placebo used if no known best therapy Failures --> Loss of convincing nature of the trial • Enrollment based on financial inducements • Study conduct "compliance" by investigator • Falsification of data (scientific misconduct)

22. Ethics of Clinical Trials

23. Physician/Patient Relationship • Dilemmas of physicians and health care providers with conflicting roles of helping the patient and gaining scientific knowledge. • A properly designed and conducted clinical trial is an ethically appropriate way to acquire new knowledge. • Clinical decisions for patient treatment without strong evidence of rigorous scientific support has ethical questions.

24. Clinical Research or Clinical Practice??? • How often is a physician certain of the outcome from a specific therapy for a particular patient? • If patient’s reaction is predictable, applying treatment is practice. • Physician is unsure of the outcome, applying the treatment could be considered research. • Actions by the physician for the benefit of individual patients have the potential of increasing scientific knowledge. • Scientific knowledge gained from research can be of benefit to individual patients.

25. When do ethical questions arise? • Unproven therapies are proposed to replace proven ones and are particularly acute for chronic or fatal illness. • Clinical trials are one of several settings in which the physician’s duty extends beyond his/her responsibility to the individual patient. • Example: vaccinations against communicable disease are promoted by physicians, yet the individual vaccinated incurs a small risk to benefit the population as whole.

26. Randomization (1) • Physicians and patients may feel it is inappropriate to base a patient’s treatment on chance. • Physicians may feel an obligation to have a preference even when the evidence does not favor any particular treatment. • Randomization is justified when there is relative ignorance about the best treatment.

27. Randomization (2) • Physicians and patients with firm preferences for treating a particular indication should not participate in a clinical trial. • Patients with strong preference about a treatment are likely to become easily dissatisfied with randomization to a treatment in the clinical trial. • Physicians with strong convictions could bias the clinical trial in a different direction.

28. Informed Consent • Patients (or parents/guardians/family members) must sign an informed consent prior to participation in a research study. • Sick and dying patients and their families maybe vulnerable and technical information may be presented in complicated ways!!! • Informed consent procedures were developed to protect patients from exploitation. • Currently informed consent is viewed as protection from litigation. • IRB must evaluate the informed consent form prior to the start of the study.

29. Confidentiality • The U.S. Department of Health and Human Service (HHS) sets the Standards for Privacy of Individually Identifiable Health Information under the Health Insurance Portability and Accountability Act of 1996 (HIPAA). • This provided the first comprehensive Federal protection for the privacy of personal health information. • Took effect April 14, 2003. • The DHHS (web site http://privacyruleandresearch.nih.gov) for further information about HIPAA.

30. Oversight Groups • Institutional Review Boards Checklist for informed consent Informed consent sample information • Scientific Review Committees • Data and Safety Monitoring Boards NCI policy on DSMBs • Office for Protection from Research Risks (OPRR)

31. Other Committees Steering committee Executive committee Treatment effects monitoring committee (DSMB) Advisory review committee (Conduct) . . .

32. Active-control Trials • Placebo trials are not always ethical. • Placebo control is untenable when the disease is life-threatening and an effective therapy is available. • Comparison is made between active control and the experimental treatment or therapy.

33. Historical Perspective • Nuremberg trials (1946-47): atrocities in WWII concentration camps committed by Nazi physicians. • 20 of the 23 tried for the crimes were physicians. • No international standards for ethical conduct in human experimentation during this time. • Results: Nuremberg Code adopted in 1947.

34. Nuremberg Code • Voluntary consent is essential • Must be no reasonable alternative to conducting the experiment • Anticipated results must have a basis in biological knowledge and animal experimentation must have potential for meaningful results for the good of society. • Avoid unnecessary physical and mental suffering and injury. • No expectation of death or disability. • Risk should not exceed humanitarian importance. • Protection against even a remote possibility of death or injury. • Qualified scientists. • Subject can stop at will. • Investigator has an obligation to terminate the experiment if injury or death seems likely.

35. Helsinki Declaration • The World Medical Association (WMA) adopted a formal code of ethics for physicians engaged in clinical research in 1964 in Helsinki, Finland. • Latest complete revision in 2000 (Helsinki Declaration). • It reiterates the principles of Nuremberg Code with particular attention to the duty of physician to protect the life and health of human subjects. • Written protocol must be reviewed by an ethical review committee independent from the investigator.

36. Other International Guidelines • 1. International Covenant of Civil and Political Rights (1976) adopted by • the United Nations General Assembly. • 2. The World Health Organization (WHO) • 3. The Council for International Organizations of Medical Sciences (CIOMS) • issued the International Ethical Guidelines for Biomedical Research • Involving Human Subjects.

37. Tuskegee Syphilis Experiment • The U.S. government's 40-year experiment on black men with syphilis in Tuskegee, Alabama (1936). • Long after the availability of penicillin, a proven cure in the 50’s, the US Public Health Service studied untreated black men. • The study was stopped in the early 1970’s after it was publicized. • President Clinton's apology for the Tuskegee Syphilis Experiment to the eight remaining survivors, May 16, 1997.

38. Modern Perspective • Congress established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research through the 1974 National Research Act. • The Commission produced the Belmont Report in 1974 which distilled basic ethical guidelines in research with human subjects. • Three principles: respect of persons or individual autonomy, beneficence and justice.

39. Individual Autonomy – patients have the right to decide what should be done for them with respect to their illness unless the result would be clearly detrimental to others. Beneficence – patient’s right to receive advantageous or favorable treatment. Justice – fairly distributing the benefits and burdens of research.

40. IRB • The U.S. National Institute of Health Policies for the Protection of Human Subjects (1966) established the IRB to protect human participants in research. • In 1981, U.S. regulations required IRB approval for all drugs or products regulated by the FDA. • Prerequisites set forth by the FDA: • Risks to participants are minimized • Risks are reasonable in relation to the anticipated benefits • Selection of study participants is equitable • Informed consent obtained appropriately • Adequate provisions for monitoring data collection • Privacy of the participants and the confidentiality of the data protected

41. Components of Informed Consent • Research nature of the study • Reasonable foreseeable risks and discomfort • Potential benefits and alternatives • Procedures for maintaining privacy • Treatment for injuries incurred • Individuals to contact for questions • Voluntary nature of the study and the possibility of withdrawal at any time • Not entering the study does not lead to loss of benefits

42. Statistical Ethics • Guidelines by ASA and Royal Statistical Society • Maintain professional competence and keep abreast of developments • Have constant regard for human rights • Present findings and interpretations honestly and objectively • Avoid untrue, deceptive, or undocumented statements • Disclose financial or other interest that may affect or appear to affect professional statements • Seek to advance public knowledge and understanding • Encourage and support fellow members in their professional development

43. Data Collection • Collect only the data needed for the purpose of the inquiry • Inform each participant about the nature and sponsorship of the project and intended uses of the data • Establish the intentions and ability of the sponsor to protect confidentiality • Inform participants of the strengths and limitation of confidentiality protections • Process the data collected according to the intentions and remove participant-identifying information • Ensure that confidentiality is maintained when data are transferred to other persons or organizations

44. Biostatistics Unit Functional Model Grant Development and Research Collaboration Research Data Systems Statistical Consulting Biostatistics Unit Collaboration with Research Groups Protocol Review Teaching Clinical Research Protocol Development Methodological Research

45. Literature of Clinical Trials • Books • Journals (Bibliography) • Government publications

46. Useful Books • Fundamentals of Clinical Trials (3rd). Lawrence Friedman, Curt Furberg, David DeMets. Mosby-Year Book, Inc. 1996. • Clinical Trials: Design, Conduct, and Analysis. Curtis L. Meinert. Oxford. 1986 • Clinical Trials: A Practical Approach. Stuart J. Pocock. Wiley. 1996. • Statistical Methods in Medical Research. Armitage and Berry. 1987 • Statistical Methods for Medical Investigators. Everitt. 1986 • Biostatistics in Clinical Trials, Carol Redmond and Theodore Colton • Good Clinical Practice, J Kolman, P Meng, and G Scott. Wiley. 1998 • The Little SAS Book, LD Delwiche and SJ Slaughter. SAS Institute Inc. 1998. • Dictionary for Clinical Trials, Simon Day, Wiley, 1999.

47. Journals Statistical methodology • Controlled Clinical Trials • Statistics in Medicine • Biometrics Applications • Various journals …

48. Government Publications • NIH (National Institutes of Health) • NCI (National Cancer Institute) • ICH (International Conference on Harmonisation )