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STATISTICS 542 Introduction to Clinical Trials. David L. DeMets, Ph.D. Dept. of Biostatistics & Medical Informatics 600 Highland Avenue Room K6/446 Phone: 263-1706 E-Mail: [email protected] STATISTICS 542 - REFERENCES.

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Statistics 542 introduction to clinical trials l.jpg

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: [email protected]

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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.

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Rationale for Biostat 542

  • Common goal; critical review of the literature throughout our careers

    • Clinical practice

    • Clinical research

  • Special goal: to conduct clinical research, some understanding of study design & analysis is necessary

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Clinical Practice & the Literature

  • Not all published articles of the same quality, regardless of journal

  • Not all evidence of the same level

    • Anecdotal

    • Observational

    • Experimental

  • Practicioner needs to sort out the evidence

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Clinical Research

  • Many challenges

    • Clinical research workforce

    • Adequate training programs

    • Funding

    • Political & financial pressures

    • Practice vs research time conflicts

  • NIH initiatives

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NIH Road MapZerhouni (2003) Science

  • New Pathways to Discovery

  • Research Teams of the Future

  • Re-engineering the Clinical Research Enterprise

    • Translational Research

    • Clinical Research Networks

    • Clinical Research Workforce Training

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Discipline of Clinical Research




Common Core







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Clinical Research Training: a multidisciplinary workforce

  • Previous training “on the job”, sort of “trial and error”

  • Rigorous training programs are just starting

  • Many disciplines now involved in clinical research without formal training in this science

  • Threat of the “silver tsunami”

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Composition of the Physician Workforce in the U.S. - 1980-2003

Ref: JAMA 2005; 294(11):1343-51

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Aging of Funded NIH Investigators 1985-2004

Ref: JAMA 2005; 294(11):1343-51

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Multidisciplinary Clinical Research Career Development (K12)

NIH Clinical Research Career Development Programs

College Professional Post-Doc Prof. Advancement

Grad School

Pre-doctoral Clinical Research Training Program (T32)

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Training Pyramid in Patient-Oriented Research


MS Degree

Capstone Degree


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NIH RPG Funding Success Rates: 1985-2000“Similar Success”

Ref: JAMA 2005; 294(11):1343-51

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Application Trends for NIH Grants

Ref: JAMA 2005; 294(11):1343-51

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Physician Researchers

  • Have similar success rates in obtaining funding as PhD’s

  • Do not submit as many applications

  • Have not taken advantage of recent NIH budget increase

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Clinical Research

  • Clinic is a perfectly good laboratory

  • Clinicians busy in their practice can also participate / lead research efforts

  • Difficult to be in the clinic mostly & run a competitive wet lab

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NIH Initiative Clinical Translational Science Award (CTSA)

  • NIH grant investment in 60 research institutions

  • Focus on three areas

    • Training

    • Clinical research infrastructure

    • Community outreach

  • UW has submitted its application

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Wisconsin Network for Health Research (WiNHR) Howard Bailey MD, Dave DeMets Phd, on behalf ofWiNHR InvestigatorsSept, 2005

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WiNHR - Basic Idea

  • Create an efficient organizational network of selected clinical sites statewide who would agree to participate in clinical trials or other human subjects based research

  • Provide research staff support (infrastructure) at each site to provide quality control

  • Centralize some aspects of the research, e.g. create a data center at the UW-Madison or central IRB

  • Trial protocols could be generated by any participating site, with review for scientific merit

  • Individual protocols funded separately, taking advantage of existing infrastructure

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  • National recognition (e.g. NIH, FDA) of need for more and better evidence based medicine

  • Each sites local population isn’t large enough or diverse enough to perform efficient/representative research

  • Public forums expressed the following –

    • Promote expanded community-based clinical research trials

    • Build collaborations between community- and UW-based researchers

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Benefits of WiNHR

  • Provides population statewide access to clinical trials studying new diagnostic, preventative and therapeutic interventions

  • Provides statewide practitioners, especially those not involved with larger clinic or med school-based research groups, an opportunity to participate and have more rapid access to advancements in health care

  • Expands capabilities of Wisconsin researchers focused on human subjects research

    • More studies and done faster

    • Possible statewide clinical database of > 3 million lives which would provide a powerful research tool

  • Improve funding opportunities

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WiNHR Nodal Sites

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Green Bay




Freeport, IL


Potential WiNHRCollaborators

Wisconsin Oncology Network (WON) Sites

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WiNHR Long Range Benefits

  • Efficiency

  • A true statewide collaborative health care effort

  • Well-positioned to compete for health care research

    • Currently not feasible in single sites, e.g. 100-1,000 subjects per study

    • In the new post-genomics/informatics era.

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Wisconsin Oncology Network (WON)

  • Proof of Concept / UWCCC

  • 7 sites with collaborating oncologists

  • 15-20 protocols completed or underway

  • Patients being accrued, interventions being given

  • Dr Ann Traynor, WON Director

  • Largely volunteer basis – can’t expand

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Green Bay




Freeport, IL


Wisconsin Oncology Network

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Research Cycle

Clinical Trials Research

(human, comparative)

Translational Research

Basic Research

(bench, animal)

Observational Research

(human, epidemiological)

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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

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  • 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

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  • Need to remember limitations of evidence clinical guidelines based on

  • Continue to strive to improve evidence

  • Need to read the literature critically

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  • 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

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Types of Clinical Research

1.Case Report

Anecdotal  Problem


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


a.Historical Controls

b.Concurrent (Non-randomized)


 “Effect”

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The Cycle of Clinical Therapeutics










Califf R et al JACC 2002

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Comparison of ESC, ACC/AHA, CCS and HFSA

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Guidelines:Classes of Recommendation

Intervention is useful and effective

Evidence conflicts/opinions differ but lean towards efficacy

Evidence conflicts/opinions differ but lean against efficacy

Intervention is not useful/effective and may be harmful

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Comparison of pharmacology therapyESC, ACC/AHA, CCS and HFSA



  • ACE inhibitorAI AIAIA I

  • Beta-blockerAIAIAIA IAngiotensin receptor blocker

  • a) ACE inhibitor intolerantBIAIAIAIb) ACE inhibitor treated--BIIbAIAIIa

  • to reduce mortalityBIIa------

  • to reduce hospitalisationAI------

McMurray JV, Swedberg K. Eur Heart J Aug 2006

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Alternatives to Evidence Based Medicine

  • Eminence-based medicine

  • Confidence-based medicine

  • Eloquence-based medicine

  • Vehemence-based medicine

  • Providence-based medicine

  • Diffidence-based medicine

  • Nervousness-based medicine

    Isaacs D, Fitzgerald D. Br Med J 1999;319:1618.

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Alternatives to Evidence Based Medicine(Ref:Marc Pfeffer)

  • Last-patient-experience based med

  • Hot-tip-based med

  • My-resident-told-me based med

  • Chat-room based-med

  • Direct-to-consumer advertising based med

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Challenge: Attack on Clinical Trials

  • Pending Congressional Legislation

  • NIH/FDA leadership

  • Wall Street & WSJ

  • Patient Advocacy Groups

  • References

    • SCT (JCT, 2006)

    • Jacobsen & Parmet (JAMA, Jan 10, 2006)

    • Cancer Letter (Aug, 2005)

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Senate Bill 1956

  • An amendment to Federal Food, Drug & Cosmetic Act (Senator Brownback-K)

  • Known as the ACCESS Act

  • A three tiered approval system

  • More responsive to “the needs of seriously ill patients”

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Proposed Three Tier Approval

  • Tier I

    • Based on Phase I information

    • Based on clinical, not statistical analysis

    • May require post approval studies

  • Tier II

    • Based on biomarkers & surrogates

  • Tier III

    • Standard requirements

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Some Issues in Proposed Legislation

  • Challenge of placebo controlled studies

  • De-emphasize statistical analysis-no disapprovals solely on the basis of statistical analysis or 95% CIs

  • Evidence may be based on uncontrolled studies such as case histories, observational studies, mechanism of actions, computer models…

  • Outcome data may be a surrogate or biological marker

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Washington Leadership

  • Use modern mathematical tools…efficacy derived from large cohort of patients given same treatment

  • Use Bayesian statistics to glean strong conclusions from large cohort data, just like economists

  • Develop chemoprevention based on surrogates and biomarkers

  • RCTs not the best future approach

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WSJ Editorials

  • WSJ against 1962 Food, Drug & Cosmetic Act amendment

  • Places an unnecessary burden by demanding proof of efficacy

  • Terminally ill patients should be free to take Phase I tested interventions

  • An old argument getting renewed attention

  • Current target is FDA oncology

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Some Advocacy Groups

  • Abigail Alliance for Better Access

  • Oncologists have allowed statisticians to take over

  • A cult-like belief….that you can’t learn anything…unless you do a clinical trial

  • In environmental toxicology, when a statistician walks in, scientists cringe …you are doing battle with a functional idiot

  • Ref: Cancer Letter August 5, 2005

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Court Action

  • In 2003, Alliance sued for expanded access

  • August 2004, District Court dismissed case-no fundamental right to INDs

  • May, 2006 District Court ruling overturned, “access is a constitutional right”

  • Case probably headed to Supreme Court

  • Major implications for

    • Drug safety

    • Regulatory Authority

    • Clinical research & practice

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Definition of a Clinical Trial

A prospective study comparing the effect and value of intervention(s) against a control in human subjects


  • 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

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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

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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

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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

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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.”

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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





Control saline


Sano crysin

(gold compound)

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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

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The General Flow of Statistical Inference




Sample Patients On Study

Patient Population

Observed Results




Inference about Population

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Ethics and Clinical Trials

  • Background

  • History

  • Code of federal regulations

  • Ethical issues informing the patient

  • Recent developments

  • Ethical omniscience

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  • 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.

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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).

  • HHS Federal Guidelines (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.

  • Local Guidelines for human investigations have been issued by many medical societies and hospitals.

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Nuremberg Trials

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 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.

Lead to Nuremberg Code

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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

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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.

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The Declaration of Helsinki(1964,2000)

  • Many of the Nuremberg 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

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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

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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

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Food and Drug Administration (FDA)

  • Responsible for approval of new drugs, biologics and devices

  • Created in 1906, Pure Food & Drug Act

  • The FDA has different regulations which apply to products regulated by FDA.

    • Drugs

    • Biologics

    • Devices

  • In spirit they are the same as the HHS regulations with regard to scientific issues

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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

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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

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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

  • Consent must be written & oral (if possible

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Ethical IssuesInforming the Patients

  • 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?

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Basic Contents/Informal Consent (1)

  • Explanation of research study

    • Purpose

    • Duration

    • Procedures

  • Possible risks

  • Possible benefits

    • Patient

    • Other individuals

  • Disclosure of alternative treatment

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Basic Contents/Informal Consent (2)

  • Describe confidentiality of data

  • Compensation in case of injury

  • Patient contacts for questions or injury

  • Participation is voluntary

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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

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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

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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 documentation 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.

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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?

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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.

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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

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Ethical Omniscience


Pregnant Women









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)

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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)

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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.

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New Federal Regulations

  • Health Information Portability and Accountability Act (HIPAA)

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I’m from the Federal Government


I am here to help you

In your clinical research activities

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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


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Health Insurance Portability and Privacy Act (HIPAA) Motivation

  • Increased risk to patient privacy

    • A University had 4000 patient records hacked

    • 400 organ donors have identity released to recipients

  • Health care across state lines – need for standardization

  • Avoid employer & insurance discrimination

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  • Privacy Final Form August 2002

    • Notice of Privacy Practices by April 15, 2003

  • Security Final Form February 2003

    • In effect by April of 2004


  • It may be years before we really understand what this means

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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)

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HIPAA for Clinical Trials

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Public Health Information (PHI)

  • Data, in any form, created, received, and/or held by a Covered Entity (CE) and

  • relates to physical or mental health, provision of care or payment; and

  • identifies individual or can be used to identify individual

  • does NOT include blood and tissue specimens, but information associated with them is PHI

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HIPAA Transition

  • Protocols completed prior to 4/14/03 were “grandfathered”

  • Protocols continuing past 4/14/03 had to receive new IRB review of patient authorization

  • All protocols started after 4/14/03 have to meet one of the HIPAA Privacy Rules options

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HIPAA Privacy Rule Options

  • Obtain written patient authorization

    • Separate document

    • Part of Informed Consent document

  • Apply to IRB for a waiver

  • Develop a Limited Data Set

  • Develop statistical argument of low risk identification

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Obtaining Subject Authorization

  • A description of PHI to be used and disclosed

  • Identification of individuals who will use/disclose PHI

  • Identification of individuals who will receive PHI

  • Purpose of disclosure

  • An expiration date or notice of no expiration

  • Statement of individual’s right to revoke at any time, but that PHI gathered prior to revocation may be used to maintain integrity of the study

  • Signature and date/copy provided

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Waiver of Written Authorization

  • Research on existing database with no contact information

  • IRB must determine:

    1)No more than minimal privacy risk

    a)Proper use plan

    b)Plan to destroy identifiers

    c)Written assurances that PHI not to be

    disclosed to third party (except by law)

    2)Research cannot practically be done without

    waiver and without access to and use of PHI

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Limited Data Use Agreement


  • Specifies two parties (CE and recipient)

  • Specifies what data is requested and how to be used

  • Permitted uses and disclosures

  • Obligation of recipient

  • Effective date, survival and termination

  • Notices and reporting

  • Signatures (including General Counsel of CE)

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  • Authorization: Do patients/subjects really understand Authorization form any more than they understand the Informed Consent?

  • Waivers: Easier/safer to say no than yes

  • LDU’s : Burden may be on recipient but would not want to count on no risk

  • Statistical Assurance: Are you kidding!

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Data sharing: Key point

  • The usual end result of scientific research in a journal

  • Journals publish summary statistics

  • Future researchers may want to analyze data in different ways

  • This can only be achieved by access to raw data

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Three rationales for data sharing

  • The scientific value of data can be maximized by reanalysis and meta-analysis

  • Data obtained with public funds should be shared for the public good

  • All data sets build on prior science and should therefore be made available to optimize future science

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Data Sharing Problems

  • Arguments are logical but this is not a logical arena

  • Not all clinical trial data paid by public funds

  • Patients are suspicious

  • IRBS are uptight

  • Investigators are uptight

  • Data security is getting harder

    (i.e Hackers)

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Final Remarks on HIPAA

  • We have not heard the end of this

  • Data security will be a major topic

  • Biostatistical & clinical trial community needs to get involved at all levels

  • An open field for litigation

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Definition: Clinical Trial

A clinical trial is an experiment on humans for the purpose of evaluating one or more potentially beneficial therapies where the investigator has control of some features of the trial.

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The General Flow of Statistical Inference




Sample Patients On Study

Patient Population

Observed Results




Inference about Population

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Single & Double Blind Clinical Trial

Single Blind: A clinical trial where the participant/patient does not know the identity of the treatment received

Double Blind: A clinical trial in which neither the patient nor the treating physician knows the identity of the treatment being administered.

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Placebo Control Clinical Trial

Placebo: An inert substance made up to physically resemble a treatment being investigated for therapeutic benefit.

Used as a control treatment.

Design may be

1) treatment vs placebo or

2) Best standard of care plus either experimental treatment or a matching placebo

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Types of Clinical Trials

Phase I:

New treatment (usually drugs) is to be tried on humans for the first time. Aim is to find acceptable range of doses and schedules.

Phase II:

Treatment is to be given to humans to determine if it has any beneficial activity. Doses and schedules may not be optimum.

Phase III:

Comparative Trial. To compare experimental or new therapies with standard therapy or competitive therapies.

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Types of Clinical Trials

  • Randomized

  • Non-Randomized

  • Single Center

  • Multi Center

  • Phase I, II, III Trials

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Characterization of TrialsRandomized vs. Non-RandomizedMulti-Center vs. Single Center

Carrying out a multi-center randomized clinical trial is the most difficult way to generate scientific information.

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Why Are Clinical Trials Needed? (1)

1.Most definitive method of determining whether a treatment is effective.

  • Other designs have more potential biases

  • One cannot determine on the basis of uncontrolled observation whether an intervention has made a difference to outcome.

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Observational Studies

  • Issue - Correlation vs. Causation

  • Examples of False Positives

    1.High cholesterol diet and rectal cancer

    2.Smoking and breast cancer

    3.Vasectomy and prostate cancer

    4.Red meat and colon cancer

    5.Red meat and breast cancer

    6.Drinking water frequently and bladder cancer

    7.Not consuming olive oil and breast cancer

  • Replication of Observational Studies

    • E.g. smoking and lung cancer

    • May not overcome confounding and bias

    • Beta-carotene

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Why Are Clinical Trials Needed? (2)

2.Determine incidence of side effects and complications.

Example: Coronary Drug Project

A.Cardiac Arrhythmias







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Why Are Clinical Trials Needed? (3)

3.Therapy accepted with no trial! Later,

  • IPPB Trial no benefit

  • Retrolental Fibroplasia, high [O2] in premature infants  Harmful

  • Tonsillectomy  Reduced use

  • Bypass Surgery  Restricted use

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Why are Trials Needed ? (4)To Evaluate New Frontiers


Diagnostic Trials

Prevention Trials

Gene Therapy




(Speed Up Process)

Selected Targets

Selected Patients

Francis Collins (3/2001)

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Practice Based

On Theory

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Retrolental Fibroplasia Lesson(1)(Silverman, 1977, Scientific American)

  • Search for a cause

    • High dose O2 suspected based on anecdotal evidence of 147 infants

    • Another observational series of 479 infants claimed benefit

  • One study attempted to lower O2 dose

    • But nurses would turn O2 on at night and off in a.m.

    • Felt no or low O2 unethical

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Retrolental Fibroplasia Lesson(2)(Silverman, 1977, Scientific American)

  • 1953 NIH Conference - Two opinions

    1. Need controlled study

    2. No need, O2 already convicted

  • 1953 RCT began on 800 infants

    % Blinded

    - standard O2 dose 23%

    - 50% O2 dose only for clinical indications7%

    Also found a dose response

  • 1954 Results published, high O2 practice stopped and epidemic subsided

    However, not before 10,000 infants had been blinded

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Failure to Use Therapy Based on Theory

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Chronic Heart Failure

  • Not many good therapies in 1980’s

  • Beta blockers known to be effective in post MI patient care

    • Reduces mortality

    • Lowers blood pressure

    • Slows and regulates heart rate

  • Proscribed for heart failure patients

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Beta-Blocker HFTrial Features

  • Class II-IV heart failure

  • Low ejection fraction

  • Beta-blocker vs. placebo

  • Randomized double blind

  • Several thousand patients

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Total Mortality

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Lancet, 1999

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NEJM, 2001

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CIBIS-2 1998

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Long Standing Treatment

Based on Theory and


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Hormone Replacement Therapy (HRT)

  • Hypothesis that HRT reduced coronary heart disease

  • Supportive data

    • Lipid lowering

    • Non-human primate studies

    • Observational studies

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Observational Studies

  • Example – Refs:

    • Stampfer & Coldiz (Prev Med 1991)

      Nurses Health Study

    • Grady (Ann Int Med 1992)

    • Cauley, Cummings, et al. (Am J OB/GYN, 1990)

    • Grodstein, Stempfer, Manson (NEJM 1996)

  • Suggest 40-50% reduction in CHD risk

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  • 1/3 of post-menopausal women use HRT

  • Second most prescribed drugs

  • Year 2000, 46 million prescriptions for Premarin (Estrogen)

  • $1 billion in sales

  • 22 million prescriptions for PremPro (E+P)

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  • Secondary Prevention

    HERS:Hully S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E; for the HERS Research Group: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 28(7):605-13, 1998.

  • Primary Prevention

    WHI:Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative Randomized Controlled trial. JAMA 288:321-333, 2002.

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HERSJAMA 28(7):605-13, 1998

  • Postmenopausal women

  • Secondary prevention, patients had documented cardiovascular disease

  • Estrogen-progestin vs. placebo

  • Randomized double blind

  • Outcomes

    • CVD mortality

    • Fractures

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  • Observed early clotting problems

    • DVTs

    • PEs

  • Fracture trend for benefit

  • Early negative trend in mortality that reverses to neutrality (non-definitive)

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JAMA, 1998

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  • Many believed results only applied in secondary prevention

  • Many interpreted trend reversal as suggesting benefit if longer follow-up

  • No perceptible impact on HRT use since HRT has other benefits

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  • A large factorial trial evaluating HRT, low fat diet and calcium

  • Multiple outcomes for each treatment

  • For HRT

    • Coronary heart disease (MI & CHD death)

    • Invasive breast cancer

    • Global index

    • Fractures

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16,608 Randomized


373,092 Women Initiated Screening

18,845 Provided Consent & Reported No Hysterectomy

8506 Assigned to Receive Estrogen + Progestin

8102 Assigned to

Receive Placebo

  • Status on April 30, 2002

  • Alive & Outcomes Data

  • Submitted in Last 18 Months

  • Unknown Vital Status

  • 231 Deceased

Status on April 30, 2002

7608 Alive & Outcomes Data

Submitted in Last 18 Months

276 Unknown Vital Status

218 Deceased

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Cumulative Dropout and Drop-in Rates by Randomization Assignment and Follow-up Duration


JAMA, 2002

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Kaplan-Meier Estimates of Cumulative Hazards

for Selected Clinical Outcomes

JAMA, 2002

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Kaplan-Meier Estimates of Cumulative Hazards

for Global Index and Death

JAMA, 2002

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Kaplan-Meier Estimates of Cumulative Hazards

for Selected Clinical Outcomes

JAMA, 2002

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Kaplan-Meier Estimates of Cumulative Hazards

for Selected Clinical Outcomes

JAMA, 2002

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HRT: Low But Increased Risk

Rate %HR






Breast CA.38.301.26


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Wisconsin State Journal


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Ann of Int Med 137(4), 2002

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Evidence Based Medicine

  • For important questions with serious mortality/morbidity, need RCTs

  • If RCTs not possible, need to be cautious & vigilant about Treatments only based on observation/association or theory

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When Should a Clinical Trial Be Started?(1)

1.Intervention (knowledge about it)

  • Safety

  • Correct dose/duration

  • Final form (TPA story)

  • Defining study population (PHS)

  • Obsolescence

    2.Trial Design

  • What outcomes to assess

  • Ability to measure

  • Expected effect of intervention


  • Resources

    • Financial

    • Staff

    • Equipment/technology

    • Time

  • Availability of subjects

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When Should a Clinical Trial Be Started?(2)

4. Narrow window in time

  • If done too soon, trial may not be relevant to eventual practice or may be a disaster operationally.

    e.g. VA Bypass Trial (early op deaths)

  • If done too late, intervention may become accepted practice before being properly tested.

    e.g. Bypass Surgery

    -VA Trial




    -PTCA vs. Bypass

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Key Analysis Principle

  • Intent-to-Treat Principle (ITT)

    • Analyze all subjects entered, regardless of compliance to protocol

  • Impacts trial design, sample size, trial conduct & analysis

  • Should be primary analysis for all trials

  • Other analysis, eg per protocol, can be used as secondary

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Organizational Structure

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NHLBI Clinical Trial Model

Policy Advisory




Data Monitoring










  • Clinics

Greenberg Report. Controlled Clinical Trials, 137-148, 1988

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NIH Organizational StructureA Brief Overview (1)

1. Project Office/Funding Agency

  • Responsible for providing organizational, scientific & statistical direction through Project Officer

  • Contract Officer is responsible for all administrative matters related to award and conduct of contracts

  • Responsible for most of the pre-award development; RFP, sample size, etc.

    2.Policy Advisory Board (PAB) Data Monitoring Board (DMB)

  • Acts as senior independent advisory board to NIH on policy matters

  • Reviews study design and changes to the initial design

  • Reviews interim study results, by treatment group and recommends early termination for toxicity or beneficial effects

  • Reviews performance of individual clinical centers

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NIH Organizational StructureA Brief Overview (2)

3.Steering Committee

  • Provides scientific direction for the study at the operational level

  • Usually are recommended or elected representatives of the clinical center principle investigators

  • Monitors performance of individual centers

  • Report major problems to PAB and P.O.

  • May have several subcommittees which are responsible for various aspects such as recruitment, endpoints, publications, quality control, etc.

    4.Assembly of Investigators (may be same as Steering Committee)

  • Each operational unit (clinic, laboratory, data center) has a representative

  • Elects from its membership representative on Steering Committee

  • Reviews operational progress of study

  • Represents individual clinical centers

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NIH Organizational StructureA Brief Overview (3)

5.Coordinating Center

  • Responsible for collecting, editing, analyzing & storing all data collected

  • Develop and test forms

  • Develop randomization procedure

  • Monitor quality control of clinics and labs

  • Periodic analysis for potential risks and benefits

  • Perform final analysis at end of the trial

    6.Central Labs

  • Provide standardized results across centers to insure comparability

  • Examples are EKG, Biochemistry, Pathology

    7.Clinical Centers

  • Recruit patients, administer treatment, coordinate patient care & collect data required

  • Grass Roots of any clinical trial

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A Trial Protocol

  • Required for all trials

  • Basis of Review

    • IRB/Ethics

    • Funding

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Purposes of a Protocol

  • To assist the investigator in thinking through the research.

  • To insure that both patient and study management are considered at the planning stage.

  • To provide a “sounding board” for external comments.

  • To orient the staff for the preparation of forms and data processing procedures.

  • To guide the treatment of the patient on the study.

  • To provide a document which can be used by other investigators who wish to “confirm” the results or use the treatment in practice.

    Reference: Dana-Farber Cancer Institute: Outline to Writing a Protocol

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Protocol Outline: “A Blueprint” (1)

A.Background & Rationale


1.Primary Question

2.Secondary Question

3.Subgroup Questions


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Protocol Outline: “A Blueprint” (2)



-Inclusion criteria

-Exclusion criteria

2.Sample Size Rationale


-Recruitment strategy

-Informed consent

-Eligibility assessment

-Baseline exam



6.Follow-up Schedule

7.Outcome Ascertainment

-Data collection

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Protocol Outline: “A Blueprint” (3)

D.Data Monitoring

1.Quality Control



4.Early Termination

E.Data Analysis/ Reporting




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Protocol Outline: “A Blueprint” (4)


  • Definitions

  • Combined Outcomes

    • Examples

      • fatal or non fatal MI

      • CHD or stroke

      • ARC or AIDS or Death

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Manual of Operations

Describes in detail how to implement the protocol at the clinic, laboratories, and Coordinating Center

Generally includes:

1.Design portion of protocol,

possibly in more detail

2.Definitions of criteria

3.Standardization of procedures

  • Laboratory (chemical or mechanical)

  • Equipment

  • Clinical

    4.Forms and instructions for completion

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UW Hospital and Clinics

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