pharmacology

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. 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."
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."

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

9. • 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
Essential elements

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

13. Did investigator assign exposures?
Yes
Experimental study
No
Observational study
Random allocation Comparison group?
Yes No Yes No
Randomized
Controlled
trial
Non-
Randomized
Controlled
trial
Analytical
study
Descriptive
study
Direction?
Exposure
Outcome
Exposure and
outcome at the
same time
Cohort study Case-control study Cross-sectional study
Outcome
Exposure
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
1750 1799 1898 1926
1931 1938 1940 1948
Scurvy trial Placebo
Sequential
patient entry
Randomization
in agriculture
First randomized
trial
Placebo control
Blinding
Multi-center
trial
Random numbers
used to assign treatments

18. 1948 1950 1966 1976
First randomized
therapeutic trial
Formation of
public agencies
and co-op groups
IRB
guidelines
Medical devices
trials
1979 2002
Multi-disciplinary approach
to clinical trials (SCT)
Group-sequential
methodology
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?
•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.
Rationale of Clinical Trials

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

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 )