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  1. STATISTICS 542Introduction to Clinical Trials David L. DeMets, Ph.D. Dept. of Biostatistics & Medical Informatics 600 Highland Avenue Room K6/446 Phone: 263-1706 E-Mail: demets@biostat.wisc.edu

  2. STATISTICS 542 - REFERENCES 1. Friedman, Furberg & DeMets (3rd edition, 1998) Fundamentals of Clinical Trials. Springer-Verlag, NY, NY. 2. Pocock (1986) Clinical Trials - A Practical Approach. Wiley and Sons, New York, NY. 3. Meinert (1986) Clinical Trials - Design, Conduct & Analysis. Oxford University Press, New York, NY. 4. Hill (1962) Statistical Methods of Clinical and Preventive Medicine. Oxford University Press, New York, NY. 5. Tygstrup, Lachin & Juhl (1982) The Randomized Clinical Trial and Therapeutics Decisions. Marcell Dekker, New York, NY. 6. Shapiro & Louis (1983) Clinical Trials - Issues and Approaches. Marcell Dekker, New York, NY. 7. Mike & Stanley (1982) Statistics in Medicine Research. Wiley and Sons, New York. 8. Bulpitt (1983) Randomized Controlled Clinical Trials. Martinus Nijhoff, Boston, MA. 9. Peto, Pike, Armitage, et al. (1976) Design and Analysis of Randomized Clinical Trials Requiring Prolonged Observation of Each Patient. British Journal of Cancer.

  3. Research Cycle Clinical Trials Research (human, comparative) Translational Research Basic Research (bench, animal) Observational Research (human, epidemiological)

  4. Evidence-Based Medicine • Ideally based on data from clinical trials • Need to understand fundamentals of good design and analysis • Not all published data of same quality

  5. TYPES OF EVIDENCE (1) • Randomized Clinical Trial (RCT) is gold standard • RCT minimizes bias • Can’t do RCTs for all important questions (time, funding, ethics) • Must make choices on what evidence to use for clinical guidelines

  6. TYPES OF EVIDENCE (2) • Need to remember limitations of evidence clinical guidelines based on • Continue to strive to improve evidence • Need to read the literature critically

  7. TYPES OF EVIDENCE (3) • Recent history teaches us to be cautious • Not seeking most rigorous evidence has proven to be problematic • Theory and observational studies based evidence have not always led to correct conclusion for important questions

  8. Types of Clinical Research 1. Case Report Anecdotal  Problem 2. Observational a. Case-Control/Retrospective (lung cancer) b. Cross Sectional (WESDR) Beaver Dam c. Prospective (Framington) WESDR-II  Associations 3. Drug Development Phase 0, Phase I, and Phase II 4. Experimental a. Historical Controls b. Concurrent (Non-randomized) c. Randomized  “Effect”

  9. Definition of a Clinical Trial A prospective study comparing the effect and value of intervention(s) against a control in human subjects NOTE: • Prospective not retrospective • Intervention/Equipment • preventive -drug • therapeutic -device • diagnostic -procedure • -biologic • Control Group • no intervention -current standard therapy • placebo (Diehl, 1938) -previous standard • Humans not animals • ethics • informed consent

  10. Clinical TrialsNatural Experiment • General Lancaster (1600) • East Indian Shipping Co. • 4 ships - Lancaster’s ship fortuitously had lemon juice on board • Lancaster’s ship remained free of scurvy • Natural Experiment, not planned

  11. Clinical TrialsPlanned Experiment • Smallpox Experiment (1721) • Perhaps first planned experiment • Lady Mary Wortley Montaque • Six inmates of Newgate Prison • Sentence commuted if they volunteered for inoculation • All remained free  Inoculation effective • No concurrent control group

  12. Clinical TrialsConcurrent Control • Scurvy Experiment - Lind (1747) • Used control group (concurrent) • On board Salisbury • 12 patients with scurvy • Evaluated 6 treatments (2 subjects/treatment) • One treatment (oranges and lemons) had two men recover

  13. Clinical Trials The Numerical Method Louis (1834): Essays on Clinical Instruction Introduced numerical methods or “Counting” Circumstances of age, sex, temperament and physical condition Real Difficulties in its Execution “Requires more labor and time than the most distinguished members of our profession can dedicate to it.”

  14. Clinical Trials • Concept of Randomization in designed experiments, introduced by Fisher into agriculture in 1926 • First randomized clinical trial 1931 by Amberson in tuberculosis patients randomized 12 12 blinded Control saline injection Sano crysin (gold compound)

  15. Clinical TrialsUse of Randomization • Multicenter Trials (1944) - Common Cold • Medical Research Council • Treatment of common cold • Different sites all using common protocol • Patulin vs. Placebo • MRC Tuberculosis Trial (1948) - Grandfather Trial (Ref: British Medical Journal, 1948) • Randomized (by random numbers) • Streptomycin vs. Placebo • Based on work of Bradford Hill, founder of modern day clinical trial • Supported Concept of Randomization

  16. The General Flow of Statistical Inference Sample* Protocol Patients On Study Patient Population Observed Results Inference about Population *Sample of Opportunity: random or non-random?

  17. Ethics and Clinical Trials • Background • History • Code of federal regulations • Ethical issues informing the patient • Recent developments • Ethical omniscience

  18. Ethics • Moral quality of a course of action • Rules or standards governing the conduct of a profession • Society’s view of ethical behavior in the context of a course of action changes over time. • Ethical behavior may vary with individuals, ethnic groups and countries.

  19. Some History • Nuremberg Code (1947): Set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners. • Helsinki Declaration (1964, 1975 rev). • Various Guidelines issued by HHS (latest revision 1991). • FDA Guidelines (similar to HHS, revised 2000). • Uniform Federal Policy for protection of human subjects was adopted by 16 Federal departments and agencies. • Guidelines for human investigations have been issued by many medical societies and hospitals.

  20. Nuremberg Code Formulated in 1947 in Nuremberg, Germany by American judges sitting in judgment of Nazi doctors accused of conducting murderous and torturous human experiments in the concentration camps. Examples: Approximately 200 internees placed in vacuum chamber 40% died-anoxia, ruptured lungs. Approximately 300 internees immersed for hours in tubs of ice water, others fed nothing but salt water for days; others outside, in sub-freezing weather – 30% died. Experiments involving battlefield medicine-deliberate gunshot wounds, amputations, chemical and biological exposures, etc.

  21. The Nuremberg Code (1)Some Principles • Voluntary consent • Experiments yield results for good of society • Experiments based on animal experiments and knowledge of natural history of disease • Avoid all unnecessary physical, mental suffering and injury • No experiment if a prior reason to believe that death or disabling injury will occur

  22. The Nuremberg Code (2) Some Principles • Degree of risk should never exceed humanitarian importance of problem to be solved. • Protect subject against remote possibility of injury. • Experiments conducted only by scientifically-qualified persons • Human subject should be at liberty to bring experiment to an end. • Scientist in charge must be prepared to terminate experiment if probable cause that continuation of experiment is likely to cause injury, disability or death.

  23. The Declaration of Helsinki(1964,2000) • Many of the Nurenberg Principles became formalized in the Helsinki Declaration in 1964 • Declaration has been modified or updated • Most recent modification addresses use of placebo controls when a proven therapy exists

  24. Belmont Report (1979)Ethical Principles & GuidelinesSponsored by NIH • Respect for Persons • Persons with diminished autonomy are entitled to protection (e.g. children, prisoners) • Beneficence • Maximize possible benefits and minimize possible harm. • Justice • Fairness in distribution & access to experimental treatment

  25. Code of Federal Regulations (HHS)Design Issues “Risks to subject are minimized by using procedures which are consistent with sound research design and which do not necessarily expose subjects to risk.” “Research plan makes adequate provision for monitoring data collected to insure safety of subject” “Adequate provisions to protect the privacy of subjects and to maintain confidentiality of data,” new HIPAA rules Ref. 45CFR46 par. 111

  26. Food and Drug Administration (FDA) • Responsible for approval of new drugs, biologics and devices • The FDA has different regulations which apply to products regulated by FDA. In spirit they are the same as the HHS regulations with regard to scientific issues

  27. Federal RegulationsProtection of Human Subjects • The Office for Protection of Research Risks (OPRR), now Office of Human Research Protection (OHRP) in HHS – ultimate authority • Issues, requirements and policies • Reviews, IRBs for compliance • May shut down research at an institution for non-compliance

  28. Institutional Review Boards (IRB) • Required for each research institution by Federal regulations • Must review each new protocol for • Merit and ethics • Consent process/document • Must conduct annual review • Responsible for patient safety

  29. Ethical IssuesInforming the Patients (1) • One principle is that patients must be properly informed and consent to trial • Must be written as well as oral (if possible) • Consent document should be clear and straightforward

  30. Ethical IssuesInforming the Patients (2) • Should newly diagnosed patients be entered in Phase II Trials if therapies are available with proven beneficial effects? • If a physician is receiving funds on a per patient basis, should the patient be informed? • If a patient is participating in a clinical trial and a treatment is found to be superior, should the patient be informed prior to publication or presentation of the results? • If a patient is participating in a double blind trial and wishes to know the identity of the treatment, should the patient be informed?

  31. Recent Developments (1) Shelby Amendment (1998): Requires federally funded researchers to make available raw data that support results used “by the federal government in developing policy or rules”. - May require full document of data. - Possibility of researchers being “scooped”. - May generate many secondary analyses. - Privacy of medical records cannot be guaranteed. - Consent forms may warn that privacy cannot be guaranteed.

  32. Recent Developments (2) U.S. National Bioethics Advisory Commission • Recent recommendations for research abroad should provide “established, effective treatment” to all study participants whether or not it would usually be available. Exception is made if providing treatment would render study irrelevant in host country • Pre-study requirement --- How will treatments that prove successful be made available to research participants and to the country as a whole?

  33. Recent Developments (3) World Medical Association Revision of 1964 Declaration of Helsinki (Oct, 00) • Placebos may be used in a clinical trial when no other therapies are available for comparison with experimental treatment. • New therapies should be tested against best current treatment. • Suggests investigators divulge to patient how trial is funded and possible conflicts of interest. • All study results whether positive or negative should be published.

  34. Monitoring of Clinical Trials • Shalala • NEJM (2000) • Press Release (2000) • IRBs often not provided sufficient information to evaluate clinical trials fully • NIH will require monitoring plans for Phase I, II and III trials • FDA will issue guidelines for Data & Safety Monitoring Boards and IRBs

  35. Ethical Omniscience Sero-Positive Pregnant Women And Infant R A N D AZT Placebo EXAMPLE: The AIDS Clinical Trials Group study on sero-positive pregnant women and their infants. (15-30% of infants become sero-positive) Parents may consent on behalf of their children • Requires consent from both mother and father (if available)

  36. Ethical Imperialism “Imposition on one society of solutions culturally appropriate to another society on the pretext that they represent cultural absolutes”. - Gilks and Ware - NEJM (1990) Discussion motivated by Western countries carrying out studies in developing countries. Tacit agreement is that sponsor of research has the authority to demand that their ethics be imposed.

  37. Ethical OmniscienceMedical Journal Policies “Journal will not publish reports of unethical research regardless of scientific merit…the approval of the IRB (when there is one) and the informed consent of the research subjects are necessary but not sufficient conditions.” - New England Journal of Medicine “An editor who vetoes decisions reached by local review boards is in the precarious position of claiming to have insight into ethical matters that is superior to that of all others and so to be justified is unilaterally rejecting decisions made by duly constituted review boards.” - Greene (NEJM)

  38. Institutional Review Boards ( IRBs) • Review all protocols for ethical aspects and informal consent • May provide limited scientific review • Design • Population studied • Adequacy of sample size • Must review each protocol progress annually • Responsible for monitoring patient safety

  39. Informed Consent Process • Effective informal consent must be obtained from subject or their legally authorized representative • Investigator may exert no coercion • Information must be understandable

  40. Basic Contents/Informal Consent (1) • Explanation of research study • Purpose • Duration • Procedures • Possible risks • Possible benefits • Patient • Other individuals • Disclosure of alternative treatment

  41. Basic Contents/Informal Consent (2) • Describe confidentiality of data • Compensation in case of injury • Patient contacts for questions or injury • Participation is voluntary

  42. Additional Possible Elements/Informal Consent • Risks to fetus • Investigator may terminate patient participation • Costs of additional tests • Consequences of patient withdrawal • Sharing of new findings during course of trial • Total number of subjects

  43. Consent Waiver • Approval by local government • No other way to carry out research • Research involves no more than minimal risk • Waiver does not adversely affect subject rights/welfare

  44. New Federal Regulations • Health Information Portability and Accountability Act (HIPAA)

  45. I’m from the Federal Government And I am here to help you In your clinical research activities

  46. National Health Information Infrastructure (NHII) Task Force Issues • Lack of Standards • prevents interoperability and sharing of data • Lack of Incentives • value of collecting data electronically not appreciated at the point of care • Insufficient Funding • of projects that lead to improved health care delivery using measures of better quality, improved patient safety and reduced costs based on evidence. • Privacy concerns • security and confidentiality • SO NEED FOR STANDARDS IMPLIES A NEED FOR PRIVACY AND SECURITY • BUT CONGRESS DID NOT ACT SOON ENOUGH

  47. HIPAA Motivation • Increased risk to patient privacy • A University has 4000 patient records hacked • 400 organ donors have identity released to recipients • Health care across state lines – need for standardization • Avoid employer & insurance discrimination

  48. HIPAA • Privacy Final Form August 2002 • Notice of Privacy Practices by April 15, 2003 • Security Final Form February 2003 • In effect by April of 2004 • DEVIL IS IN THE DETAILS • It may be years before we really understand what this means

  49. HIPAA Requires • Work force training • Patient Notification • Access to data on a “need to know” or a “need to use” basis • Limit research data to what is needed (NOT A BAD IDEA) • Upgrade data security (A GROWING ISSUE)

  50. Federal Involvement • Federal Government now involved in Health Information Standards • Simultaneously • National Health Information Infrastructure (NHII) Sponsoring thoughtful deliberation • Consolidated Health Informatics (CHI) Moving in like a bull and just “doing it” WITH NO PUBLIC PARTICIPATION