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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: demets@biostat.wisc.edu

542-01-#1
STATISTICS 542 - REFERENCES
1. Friedman, Furberg & DeMets (3rd edition, 1998) Fundamentals of Clinical Trials.
Springer-Verlag, NY, NY.

2. Pocock (1986) Clinical Trials - A Practical Approach. Wiley and Sons, New York, NY.

3. Meinert (1986) Clinical Trials - Design, Conduct & Analysis. Oxford University Press,
New York, NY.

4. Hill (1962) Statistical Methods of Clinical and Preventive Medicine. Oxford University
Press, New York, NY.

5. Tygstrup, Lachin & Juhl (1982) The Randomized Clinical Trial and Therapeutics
Decisions. Marcell Dekker, New York, NY.

6. Shapiro & Louis (1983) Clinical Trials - Issues and Approaches. Marcell Dekker, New
York, NY.

7. Mike & Stanley (1982) Statistics in Medicine Research. Wiley and Sons, New York.

8. Bulpitt (1983) Randomized Controlled Clinical Trials. Martinus Nijhoff, Boston, MA.

9. Peto, Pike, Armitage, et al. (1976) Design and Analysis of Randomized Clinical Trials
Requiring Prolonged Observation of Each Patient. British Journal of Cancer.

542-01-#2
Research Cycle

Clinical Trials Research


(human, comparative)

Translational Research

Basic Research Observational Research


(bench, animal) (human, epidemiological)

542-01-#3
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
542-01-#4
TYPES OF EVIDENCE (1)

Randomized Clinical Trial (RCT) is


gold standard
RCT minimizes bias
Cant do RCTs for all important
questions (time, funding, ethics)
Must make choices on what evidence
to use for clinical guidelines

542-01-#5
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

542-01-#6
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

542-01-#7
Types of Clinical Research
1. Case Report
Anecdotal Problem

2. Observational
a. Case-Control/Retrospective (lung cancer)
b. Cross Sectional (WESDR) Beaver Dam
c. Prospective (Framington) WESDR-II
Associations

3. Drug Development Phase 0, Phase I, and Phase II

4. Experimental
a. Historical Controls
b. Concurrent (Non-randomized)
c. Randomized
Effect
542-01-#8
Definition of a Clinical Trial
A prospective study comparing the effect and value of intervention(s)
against a control in human subjects

NOTE:
Prospective not retrospective

Intervention/Equipment
preventive -drug
therapeutic -device
diagnostic -procedure
-biologic

Control Group
no intervention -current standard therapy
placebo (Diehl, 1938) -previous standard

Humans not animals


ethics
informed consent
542-01-#9
Clinical Trials
Natural Experiment
General Lancaster (1600)

East Indian Shipping Co.

4 ships - Lancasters ship fortuitously


had lemon juice on board

Lancasters ship remained free of


scurvy

Natural Experiment, not planned


542-01-#10
Clinical Trials
Planned 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

542-01-#11
Clinical Trials
Concurrent 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
542-01-#12
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. 542-01-#13
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
12 12 randomized

Sano crysin Control saline blinded


(gold compound) injection

542-01-#14
Clinical Trials
Use 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


542-01-#15
The General Flow of
Statistical Inference

Patient Sample* Observed


Population Protocol Results
Patients On
Study

Inference about Population

*Sample of Opportunity: random or non-random?


542-01-#16
Ethics and Clinical Trials

Background
History
Code of federal regulations
Ethical issues informing the patient
Recent developments
Ethical omniscience

542-01-#17
Ethics

Moral quality of a course of action


Rules or standards governing the
conduct of a profession
Societys 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.

542-01-#18
Some History
Nuremberg Code (1947): Set of standards for judging
physicians and scientists who had conducted biomedical
experiments on concentration camp prisoners.
Helsinki Declaration (1964, 1975 rev).
Various Guidelines issued by HHS (latest revision 1991).
FDA Guidelines (similar to HHS, revised 2000).
Uniform Federal Policy for protection of human subjects
was adopted by 16 Federal departments and agencies.
Guidelines for human investigations have been issued by
many medical societies and hospitals.

542-01-#19
Nuremberg Code
Formulated in 1947 in Nuremberg, Germany by American
judges sitting in judgment of Nazi doctors accused of
conducting murderous and torturous human experiments in
the concentration camps. Examples:

Approximately 200 internees placed in vacuum chamber


40% died-anoxia, ruptured lungs.

Approximately 300 internees immersed for hours in tubs of


ice water, others fed nothing but salt water for days;
others outside, in sub-freezing weather 30% died.

Experiments involving battlefield medicine-deliberate


gunshot wounds, amputations, chemical and biological
exposures, etc.

542-01-#20
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
542-01-#21
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.
542-01-#22
The Declaration of Helsinki
(1964,2000)

Many of the Nurenberg Principles


became formalized in the Helsinki
Declaration in 1964
Declaration has been modified or updated

Most recent modification addresses use


of placebo controls when a proven
therapy exists
542-01-#23
Belmont Report (1979)
Ethical Principles & Guidelines
Sponsored 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
542-01-#24
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

542-01-#25
Food and Drug Administration
(FDA)
Responsible for approval of new drugs,
biologics and devices

The FDA has different regulations which


apply to products regulated by FDA.
In spirit they are the same as the HHS
regulations with regard to scientific issues

542-01-#26
Federal Regulations
Protection 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

542-01-#27
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

542-01-#28
Ethical Issues
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
542-01-#29
Ethical Issues
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?
542-01-#30
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.
542-01-#31
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?

542-01-#32
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.
542-01-#33
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

542-01-#34
Ethical 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-Positive R AZT
Pregnant Women A
And N
Infant D Placebo

Requires consent from both mother and father


(if available)
542-01-#35
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.

542-01-#36
Ethical Omniscience
Medical Journal Policies
Journal will not publish reports of unethical research
regardless of scientific meritthe 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)
542-01-#37
Institutional Review
Boards ( IRBs)
Review all protocols for ethical aspects
and informal consent
May provide limited scientific review
Design
Population studied
Adequacy of sample size
Must review each protocol progress
annually
Responsible for monitoring patient safety
542-01-#38
Informed 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


542-01-#39
Basic Contents/Informal
Consent (1)

1. Explanation of research study


Purpose
Duration
Procedures
2. Possible risks
3. Possible benefits
Patient
Other individuals
4. Disclosure of alternative treatment
542-01-#40
Basic Contents/Informal
Consent (2)

5. Describe confidentiality of data


6. Compensation in case of injury
7. Patient contacts for questions or injury
8. Participation is voluntary

542-01-#41
Additional Possible
Elements/Informal Consent
1. Risks to fetus
2. Investigator may terminate patient
participation
3. Costs of additional tests
4. Consequences of patient withdrawal
5. Sharing of new findings during
course of trial
6. Total number of subjects
542-01-#42
Consent 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

542-01-#43
New Federal Regulations

Health Information Portability and


Accountability Act (HIPAA)

542-01-#44
Im from the Federal Government
And
I am here to help you
In your clinical research activities

542-01-#45
National Health Information Infrastructure
(NHII) Task Force Issues
Lack of Standards
prevents interoperability and sharing of data
Lack of Incentives
value of collecting data electronically not appreciated at
the point of care
Insufficient Funding
of projects that lead to improved health care delivery
using measures of better quality, improved patient
safety and reduced costs based on evidence.
Privacy concerns
security and confidentiality
SO NEED FOR STANDARDS IMPLIES A NEED
FOR PRIVACY AND SECURITY
BUT CONGRESS DID NOT ACT SOON ENOUGH
542-01-#46
HIPAA Motivation

Increased risk to patient privacy


A University has 4000 patient records
hacked
400 organ donors have identity released to
recipients
Health care across state lines need
for standardization
Avoid employer & insurance
discrimination
542-01-#47
HIPAA
Privacy Final Form August 2002
Notice of Privacy Practices by April 15,
2003
Security Final Form February 2003
In effect by April of 2004
DEVIL IS IN THE DETAILS
It may be years before we really
understand what this means

542-01-#48
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)

542-01-#49
Federal Involvement

Federal Government now involved in


Health Information Standards
Simultaneously
National Health Information Infrastructure
(NHII) Sponsoring thoughtful deliberation
Consolidated Health Informatics (CHI)
Moving in like a bull and just doing it
WITH NO PUBLIC PARTICIPATION

542-01-#50
HIPAA for Clinical Trials

542-01-#51
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
542-01-#52
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

542-01-#53
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

542-01-#54
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 individuals 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


542-01-#55
Waiver of Written Authorization
Research on existing database with no contact
information

IRB must determine:


1) No more than minimal privacy risk
a) Improper use plan
b) Plan to destroy identifiers
c) 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

542-01-#56
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)

542-01-#57
Issues
Authorization: Do patients/subjects really
understand Authorization form any more
than they understand the Informed
Consent?
Waivers: Easier/safer to say no than yes
LDUs : Burden may be on recipient but
would not want to count on no risk
Statistical Assurance: Are you kidding!

542-01-#58
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

542-01-#59
Three rationales for data
sharing
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
542-01-#60
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)

542-01-#61
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

542-01-#62
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.

542-01-#63
The General Flow of
Statistical Inference

Patient Sample* Observed


Population Protocol Results
Patients On
Study

Inference about Population

*Sample of Opportunity: random or non-random?


542-01-#64
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.
542-01-#65
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
542-01-#66
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.
542-01-#67
542-01-#68
Types of Clinical Trials
Randomized

Non-Randomized

Single Center

Multi Center

Phase I, II, III Trials 542-01-#69


Characterization of Trials
Randomized vs. Non-Randomized
Multi-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 Yes Use of


Historical Historical
Controls Controls

Carrying out a multi-center randomized clinical trial is the most difficult


way to generate scientific information. 542-01-#70
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.
542-01-#71
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
542-01-#72
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>.05
Placebo 38.2%

B. Natural occurring side effects (nausea)


Clofibrate 7.6%
Placebo 6.2% 542-01-#73
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

542-01-#74
Why are Trials Needed ? (4)
To Evaluate New Frontiers

Genomics

Gene Therapy Drug


Diagnostic Trials Prevention Trials
Trials Development
(Speed Up Process)
Selected Targets

Selected Patients

Francis Collins (3/2001)


542-01-#75
Practice Based

On Theory

542-01-#76
Retrolental Fibroplasia Lesson(1)
(Silverman, 1977, Scientific American)
In early 1940s, 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 1950s, ACTH treatment proposed and RCT tested

Arm Results
ACTH 1/3 Blind
vs. ACTH = adrenocorticotrophic
hormone
Placebo 1/5 Blind
542-01-#77
Retrolental Fibroplasia Lesson(2)
(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

542-01-#78
Retrolental Fibroplasia Lesson(3)
(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 indications 7%
Also found a dose response
1954 Results published, high O2 practice stopped
and epidemic subsided
However, not before 10,000 infants had been blinded
542-01-#79
Failure to Use Therapy
Based on Theory

542-01-#80
Chronic Heart Failure

Not many good therapies in 1980s


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

542-01-#81
Beta-Blocker HF
Trial Features

Class II-IV heart failure


Low ejection fraction
Beta-blocker vs. placebo
Randomized double blind
Several thousand patients

542-01-#82
MERIT
Total Mortality

542-01-#83
CIBIS-II

Lancet, 1999
542-01-#84
COPERNICUS

NEJM, 2001
542-01-#85
Long Standing Treatment

Based on Theory and

Observation/Association

542-01-#86
Hormone Replacement Therapy
(HRT)

Hypothesis that HRT reduced


coronary heart disease
Supportive data
Lipid lowering
Non-human primate studies
Observational studies

542-01-#87
Observational 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

542-01-#88
HRT 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)

542-01-#89
HORMONE REPLACEMENT THERAPY
FOR POSTMENOPAUSAL WOMEN
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 Womens Health Initiative
Investigators: Risks and benefits of estrogen plus progestin
in healthy postmenopausal women. Principal results from
the Womens Health Initiative Randomized Controlled trial.
JAMA 288:321-333, 2002.

542-01-#90
HORMONE REPLACEMENT THERAPY
FOR POSTMENOPAUSAL WOMEN
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 Womens Health Initiative
Investigators: Risks and benefits of estrogen plus progestin
in healthy postmenopausal women. Principal results from
the Womens Health Initiative Randomized Controlled trial.
JAMA 288:321-333, 2002.

542-01-#91
HERS
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

542-01-#92
HERS
Observed early clotting problems
DVTs
PEs

Fracture trend for benefit

Early negative trend in mortality that


reverses to neutrality (non-definitive)

542-01-#93
HERS MORTALITY

JAMA, 1998
542-01-#94
HERS 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

542-01-#95
WOMENS HEALTH INITIATIVE
JAMA 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

542-01-#96
WHI
373,092 Women Initiated Screening

18,845 Provided Consent &


Reported No Hysterectomy

16,608 Randomized

8506 Assigned to Receive 8102 Assigned to


Estrogen + Progestin Receive Placebo

Status on April 30, 2002 Status on April 30, 2002

7968 Alive & Outcomes Data 7608 Alive & Outcomes Data
Submitted in Last 18 Months Submitted in Last 18 Months
307 Unknown Vital Status 276 Unknown Vital Status
231 Deceased 218 Deceased
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Cumulative Dropout and Drop-in Rates by
Randomization Assignment and Follow-up Duration

WHI

JAMA, 2002
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Wisconsin State Journal
2002

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542-01-#100
WHI

Kaplan-Meier Estimates of Cumulative Hazards


for Selected Clinical Outcomes

JAMA, 2002
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WHI
Kaplan-Meier Estimates of Cumulative Hazards
for Global Index and Death

JAMA, 2002 542-01-#102


WHI
Kaplan-Meier Estimates of Cumulative Hazards
for Selected Clinical Outcomes

JAMA, 2002 542-01-#103


WHI
Kaplan-Meier Estimates of Cumulative Hazards
for Selected Clinical Outcomes

JAMA, 2002 542-01-#104


HRT: 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 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

3. Feasible
Resources
Financial
Staff
Equipment/technology
Time
Availability of subjects 542-01-#108
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 542-01-#109
Trial

Organizational
Structure

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NHLBI Clinical Trial Model

Policy Advisory Funding


Board Agency

Data Monitoring
Committee Steering
Committee

Data Central Working


Clinics
Center Lab(s) Committees

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


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NIH Organizational Structure
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 Structure
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 Structure
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 Protocol

Required for all trials

Basis of Review
IRB/Ethics
Funding

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Purposes 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)

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)
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 542-01-#118
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)
Appendix

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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