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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

STATISTICS 542STATISTICS 542Introduction to Clinical TrialsIntroduction to Clinical Trials

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STATISTICS 542 - REFERENCESSTATISTICS 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.

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Clinical Trials Research(human, comparative)

Basic Research(bench, animal)

Observational Research(human, epidemiological)

Research Cycle

Translational Research

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Evidence-Based MedicineEvidence-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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TYPES OF EVIDENCE (1)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

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TYPES OF EVIDENCE (2)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

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TYPES OF EVIDENCE (3)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

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Types of Clinical ResearchTypes of Clinical Research1. 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”

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Definition of a Clinical TrialDefinition of a Clinical TrialA 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

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Clinical TrialsClinical TrialsNatural ExperimentNatural 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 TrialsClinical TrialsPlanned ExperimentPlanned 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 TrialsClinical TrialsConcurrent ControlConcurrent 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 TrialsClinical Trials The Numerical Method 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 TrialsClinical Trials

• Concept of Randomization in designed experiments, introduced by Fisher into agriculture in 1926

• First randomized clinical trial 1931 by Amberson in tuberculosis patients

Sano crysin(gold compound)

Control salineinjection

blinded

randomized12 12

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Clinical TrialsClinical TrialsUse of RandomizationUse 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 The General Flow of Statistical InferenceStatistical Inference

Patient Population

Sample* Protocol

Patients On Study

Observed Results

Inference about Population

*Sample of Opportunity: random or non-random?

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Ethics and Clinical TrialsEthics and Clinical Trials

• Background

• History

• Code of federal regulations

• Ethical issues informing the patient

• Recent developments

• Ethical omniscience

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EthicsEthics

• 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 HistorySome 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.

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Nuremberg CodeNuremberg 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.

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The Nuremberg Code The Nuremberg Code (1)(1)Some PrinciplesSome 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 CodeThe Nuremberg Code (2) (2) Some Principles 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 HelsinkiThe Declaration of Helsinki(1964,2000)(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

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Belmont Report (1979)Belmont Report (1979)Ethical Principles & GuidelinesEthical Principles & Guidelines

Sponsored by NIHSponsored 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)Code of Federal Regulations (HHS)Design IssuesDesign 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 Food and Drug Administration (FDA)(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

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Federal RegulationsFederal RegulationsProtection of Human SubjectsProtection 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)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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Ethical IssuesEthical IssuesInforming the Patients (1)Informing 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

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Ethical IssuesEthical IssuesInforming the Patients (2)Informing 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?

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Recent Developments (1)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.

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Recent Developments (2)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)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 TrialsMonitoring 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 OmniscienceEthical Omniscience• 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

Sero-PositivePregnant Women

AndInfant

RAND

AZT

Placebo

• Requires consent from both mother and father (if available)

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Ethical ImperialismEthical 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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Ethical OmniscienceEthical OmniscienceMedical Journal PoliciesMedical 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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Institutional Review Institutional Review Boards ( IRBs)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

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Informed Consent ProcessInformed Consent Process

1. Effective informal consent must be obtained from subject or their legally authorized representative

2. Investigator may exert no coercion

3. Information must be understandable

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Basic Contents/Informal Basic Contents/Informal Consent (1)Consent (1)

1. Explanation of research study• Purpose • Duration• Procedures

2. Possible risks3. Possible benefits

• Patient• Other individuals

4. Disclosure of alternative treatment

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Basic Contents/Informal Basic Contents/Informal Consent (2)Consent (2)

5. Describe confidentiality of data

6. Compensation in case of injury

7. Patient contacts for questions or injury

8. Participation is voluntary

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Additional Possible Additional Possible Elements/Informal ConsentElements/Informal Consent

1. Risks to fetus2. Investigator may terminate patient

participation3. Costs of additional tests4. Consequences of patient withdrawal5. Sharing of new findings during

course of trial6. Total number of subjects

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Consent WaiverConsent Waiver

1. Approval by local government

2. No other way to carry out research

3. Research involves no more than minimal risk

4. Waiver does not adversely affect subject rights/welfare

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New Federal RegulationsNew Federal Regulations

• Health Information Portability and Accountability Act (HIPAA)

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I’m from the Federal Government

And

I am here to help you

In your clinical research activities

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National Health Information Infrastructure National Health Information Infrastructure (NHII) Task Force Issues(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

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HIPAA MotivationHIPAA 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

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HIPAAHIPAA

• 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

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HIPAA RequiresHIPAA 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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Federal InvolvementFederal 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

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HIPAA for Clinical TrialsHIPAA for Clinical Trials

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Public Health Information (PHI)Public Health Information (PHI)

• Data, in any form, created, received, and/or held by a Covered Entity 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 TransitionHIPAA 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 HIPAA Privacy Rule OptionsOptions

• 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 AuthorizationObtaining 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 AuthorizationWaiver of Written Authorization

• Research on existing database with no contact information

• IRB must determine:1) No more than minimal privacy risk

a) Improper use planb) Plan to destroy identifiersc) Written assurances that PHI not to be

disclosed to third party (except as law requires)2) Research cannot practically be done without

waiver and without access to and use of PHI

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Limited Data Use Agreement Limited Data Use Agreement

Includes: • 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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IssuesIssues

• 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 pointData 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 Three rationales for data sharingsharing

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

2. Data obtained with public funds should be shared for the public good

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

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Data Sharing ProblemsData 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 HIPAAFinal 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 TrialDefinition: 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 The General Flow of Statistical InferenceStatistical Inference

Patient Population

Sample* Protocol

Patients On Study

Observed Results

Inference about Population

*Sample of Opportunity: random or non-random?

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Single & Double Blind Single & Double Blind Clinical TrialClinical 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 TrialPlacebo 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 TrialsTypes 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 TrialsTypes of Clinical Trials

• Randomized

• Non-Randomized

• Single Center

• Multi Center

• Phase I, II, III Trials

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Characterization of TrialsCharacterization of TrialsRandomized vs. Non-RandomizedRandomized vs. Non-Randomized

Multi-Center vs. Single CenterMulti-Center vs. Single Center

Phase Single Center Multi Center

Randomized Non-Rand. Randomized Non-Rand.

I Never Yes Never Sometimes

II Rare Yes Yes Sometimes

III Yes Use of Historical Controls

Yes Use of Historical Controls

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)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 StudiesObservational Studies• Issue - Correlation vs. Causation

• Examples of False Positives

1. High cholesterol diet and rectal cancer2. Smoking and breast cancer3. Vasectomy and prostate cancer4. Red meat and colon cancer5. Red meat and breast cancer6. Drinking water frequently and bladder cancer7. 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)Why Are Clinical Trials Needed? (2)

2. Determine incidence of side effects and complications.

Example: Coronary Drug Project

A. Detection of side effect (Cardiac Arrhythmias)Clofibrate 33.3%Niacin 32.7% p>.05Placebo 38.2%

B. Natural occurring side effects (nausea)Clofibrate 7.6%Placebo 6.2%

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Why Are Clinical Trials Needed? (3)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)Why are Trials Needed ? (4)To Evaluate New FrontiersTo Evaluate New Frontiers

Drug Development

Gene Therapy Trials

Prevention TrialsDiagnostic Trials

Selected Targets

Selected Patients

Francis Collins (3/2001)

(Speed Up Process)

Genomics

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Practice Based

On Theory

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

• In early 1940’s, epidemic of retrolental fibroplasia began in premature infants

Case reviews indicated “state of the art” care, including high concentration of O2

• Suspicion arose that cause occurred after birth resulting in progressive changes in retina blood vessels

• Early 1950’s, ACTH treatment proposed and RCT tested

Arm Results

ACTH 1/3 Blind

vs. ACTH = adrenocorticotrophic

hormone

Placebo 1/5 Blind

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Retrolental Fibroplasia Lesson(2)Retrolental Fibroplasia Lesson(2) (Silverman, 1977, (Silverman, 1977, Scientific AmericanScientific 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(3)Retrolental Fibroplasia Lesson(3)(Silverman, 1977, (Silverman, 1977, Scientific AmericanScientific American))

• 1953 NIH Conference - Two opinions1. Need controlled study2. 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 Failure to Use Therapy Based on TheoryBased on Theory

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Chronic Heart FailureChronic 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 HFBeta-Blocker HFTrial FeaturesTrial Features

• Class II-IV heart failure

• Low ejection fraction

• Beta-blocker vs. placebo

• Randomized double blind

• Several thousand patients

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MERITMERIT

Total Mortality

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CIBIS-IICIBIS-II

Lancet, 1999

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COPERNICUSCOPERNICUS

NEJM, 2001

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Long Standing Treatment

Based on Theory and

Observation/Association

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• Hypothesis that HRT reduced coronary heart disease

• Supportive data– Lipid lowering– Non-human primate studies– Observational studies

Hormone Replacement Therapy (HRT)

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Observational StudiesObservational Studies

• Example – Refs:1) Stampfer & Coldiz (Prev Med 1991)

Nurses Health Study

2) Grady (Ann Int Med 1992)

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

4) Grodstein, Stempfer, Manson (NEJM 1996)

• Suggest 40-50% reduction in CHD risk

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HRT POPULARHRT POPULAR

• 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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HORMONE REPLACEMENT THERAPY HORMONE REPLACEMENT THERAPY FOR POSTMENOPAUSAL WOMENFOR POSTMENOPAUSAL WOMEN

• Secondary PreventionHERS: 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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HORMONE REPLACEMENT THERAPY HORMONE REPLACEMENT THERAPY FOR POSTMENOPAUSAL WOMENFOR POSTMENOPAUSAL WOMEN

• Secondary PreventionHERS: 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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HERSHERS JAMA 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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HERSHERS• 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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HERS MORTALITYHERS MORTALITY

JAMA, 1998

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HERS IMPACTHERS IMPACT

• 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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WOMEN’S HEALTH INITIATIVEWOMEN’S HEALTH INITIATIVEJAMA 288(3):321-33, 2002

• 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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WHIWHI373,092 Women Initiated Screening

18,845 Provided Consent & Reported No Hysterectomy

8506 Assigned to Receive Estrogen + Progestin

8102 Assigned to Receive Placebo

16,608 Randomized

Status on April 30, 2002

7968 Alive & Outcomes Data Submitted in Last 18 Months307 Unknown Vital Status231 Deceased

Status on April 30, 2002

7608 Alive & Outcomes Data Submitted in Last 18 Months276 Unknown Vital Status218 Deceased

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WHIWHI

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

JAMA, 2002

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Wisconsin State Journal2002

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WHIWHI

JAMA, 2002

Kaplan-Meier Estimates of Cumulative Hazards for Selected Clinical Outcomes

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WHIWHI

JAMA, 2002

Kaplan-Meier Estimates of Cumulative Hazards for Global Index and Death

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WHIWHIKaplan-Meier Estimates of Cumulative Hazards

for Selected Clinical Outcomes

JAMA, 2002

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WHIWHIKaplan-Meier Estimates of Cumulative Hazards

for Selected Clinical Outcomes

JAMA, 2002

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HRT: Low But Increased RiskHRT: Low But Increased Risk

Rate % HR

Outcome HRT PLBO

CHD .37 .30 1.29

Stroke .29 .21 1.41

DVT .26 .13 2.07

PE .16 .08 2.13

Breast CA .38 .30 1.26

Death .52 .53 .98

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Ann of Int Med 137(4), 2002

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Evidence Based MedicineEvidence 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)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

3. Feasible– Resources

• Financial• Staff• Equipment/technology• Time

– Availability of subjects

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When Should a Clinical Trial Be Started?(2)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-NIH CASS

PTCA-NIH BARI-PTCA vs. Bypass

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TrialTrial

Organizational Structure

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NHLBI Clinical Trial ModelNHLBI Clinical Trial Model

Policy Advisory Board

Data Monitoring Committee

Central Lab(s)

Data Center

ClinicsWorking

Committees

Steering Committee

Funding Agency

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

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NIH Organizational StructureNIH Organizational StructureA Brief Overview (1)A 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 StructureNIH Organizational StructureA Brief Overview (2)A 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 StructureNIH Organizational StructureA Brief Overview (3)A 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 ProtocolA Trial Protocol

• Required for all trials

• Basis of Review– IRB/Ethics– Funding

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Purposes of a ProtocolPurposes of a Protocol

1. To assist the investigator in thinking through the research.

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

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

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

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

6. 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)Protocol Outline: “A Blueprint” (1)

A. Background & Rationale

B. Objectives

1. Primary Question

2. Secondary Question

3. Subgroup Questions

4. Toxicities

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Protocol Outline: “A Blueprint” (2)Protocol Outline: “A Blueprint” (2)C. Design

1. Population-Inclusion criteria-Exclusion criteria

2. Sample Size Rationale

3. Enrollment-Recruitment strategy-Informed consent-Eligibility assessment-Baseline exam

4. Randomization

5. Intervention

6. Follow-up Schedule

7. Outcome Ascertainment-Data collection

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Protocol Outline: “A Blueprint” (3)Protocol Outline: “A Blueprint” (3)D. Data Monitoring

1. Quality Control

2. Recruitment

3. Benefit/Risk

4. Early Termination

E. Data Analysis/ Reporting

F. Organization

1. Investigators

2. Committees

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Protocol Outline: “A Blueprint” (4)Protocol Outline: “A Blueprint” (4)

Appendix

• Definitions

• Combined Outcomes

– Examples• fatal or non fatal MI• CHD or stroke• ARC or AIDS or Death

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Manual of OperationsManual 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