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David L. DeMets, Ph.D.

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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 – PowerPoint PPT presentation

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Title: David L. DeMets, Ph.D.


1
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_at_biostat.wisc.edu

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

3
Research Cycle
Clinical Trials Research (human, comparative)
Translational Research
Basic Research (bench, animal)
Observational Research (human, epidemiological)
4
Evidence-Based Medicine
  • Ideally based on data from clinical trials
  • Need to understand fundamentals of good design
    and analysis
  • Not all published data of same quality

5
TYPES OF EVIDENCE (1)
  • Randomized Clinical Trial (RCT) is gold standard
  • RCT minimizes bias
  • Cant do RCTs for all important questions (time,
    funding, ethics)
  • Must make choices on what evidence to use for
    clinical guidelines

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

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

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

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

10
Clinical 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

11
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

12
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

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

14
Clinical Trials
  • Concept of Randomization in designed experiments,
    introduced by Fisher into agriculture in 1926
  • First randomized clinical trial 1931 by Amberson
    in tuberculosis patients

randomized
12
12
blinded
Control saline injection
Sano crysin (gold compound)
15
Clinical 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

16
The General Flow of Statistical Inference
Sample Protocol Patients On Study
Patient Population
Observed Results
Inference about Population
Sample of Opportunity random or non-random?
17
Ethics and Clinical Trials
  • Background
  • History
  • Code of federal regulations
  • Ethical issues informing the patient
  • Recent developments
  • Ethical omniscience

18
Ethics
  • Moral quality of a course of action
  • Rules or standards governing the conduct of a
    profession
  • 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.

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

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

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

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

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

24
Belmont Report (1979) Ethical Principles
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

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

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

27
Federal 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

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

29
Ethical 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

30
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?

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

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

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

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

35
Ethical Omniscience
  • 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 Pregnant Women And Infant
R A N D
AZT Placebo
  • Requires consent from both mother and father (if
    available)

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

37
Ethical 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)

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

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

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

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

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

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

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

45
Im from the Federal Government And I am here
to help you In your clinical research activities
46
National Health Information Infrastructure (NHII)
Task Force Issues
  • Lack of Standards
  • prevents interoperability and sharing of data
  • Lack of Incentives
  • value of collecting data electronically not
    appreciated at the point of care
  • Insufficient Funding
  • of projects that lead to improved health care
    delivery using measures of better quality,
    improved patient safety and reduced costs based
    on evidence.
  • Privacy concerns
  • security and confidentiality
  • SO NEED FOR STANDARDS IMPLIES A NEED FOR PRIVACY
    AND SECURITY
  • BUT CONGRESS DID NOT ACT SOON ENOUGH

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

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

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

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

51
HIPAA for Clinical Trials
52
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

53
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

54
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

55
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

56
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

57
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)

58
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!

59
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

60
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

61
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)

62
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

63
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.

64
The General Flow of Statistical Inference
Sample Protocol Patients On Study
Patient Population
Observed Results
Inference about Population
Sample of Opportunity random or non-random?
65
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.

66
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

67
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.

68
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69
Types of Clinical Trials
  • Randomized
  • Non-Randomized
  • Single Center
  • Multi Center
  • Phase I, II, III Trials

70
Characterization of Trials Randomized vs.
Non-Randomized Multi-Center vs. Single Center
Carrying out a multi-center randomized clinical
trial is the most difficult way to generate
scientific information.
71
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.

72
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

73
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 pgt.05
  • Placebo 38.2
  • B. Natural occurring side effects (nausea)
  • Clofibrate 7.6
  • Placebo 6.2

74
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

75
Why are Trials Needed ? (4) To Evaluate New
Frontiers
Genomics
Drug Development
Gene Therapy Trials
Prevention Trials
Diagnostic Trials
(Speed Up Process)
Selected Targets
Selected Patients
Francis Collins (3/2001)
76
  • Practice Based
  • On Theory

77
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

78
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

79
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

80
Failure to Use Therapy Based on Theory
81
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

82
Beta-Blocker HF Trial Features
  • Class II-IV heart failure
  • Low ejection fraction
  • Beta-blocker vs. placebo
  • Randomized double blind
  • Several thousand patients

83
MERIT
Total Mortality
84
CIBIS-II
Lancet, 1999
85
COPERNICUS
NEJM, 2001
86
  • Long Standing Treatment
  • Based on Theory and
  • Observation/Association

87

Hormone Replacement Therapy (HRT)
  • Hypothesis that HRT reduced coronary heart
    disease
  • Supportive data
  • Lipid lowering
  • Non-human primate studies
  • Observational studies

88
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

89
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 (EP)

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 288321-333, 2002.

91
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 288321-333, 2002.

92
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

93
HERS
  • Observed early clotting problems
  • DVTs
  • PEs
  • Fracture trend for benefit
  • Early negative trend in mortality that reverses
    to neutrality (non-definitive)

94
HERS MORTALITY
JAMA, 1998
95
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

96
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

97
WHI
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
98
WHI
Cumulative Dropout and Drop-in Rates by
Randomization Assignment and Follow-up Duration
JAMA, 2002
99
Wisconsin State Journal 2002
100
(No Transcript)
101
WHI
Kaplan-Meier Estimates of Cumulative Hazards for
Selected Clinical Outcomes
JAMA, 2002
102
WHI
Kaplan-Meier Estimates of Cumulative Hazards for
Global Index and Death
JAMA, 2002
103
WHI
Kaplan-Meier Estimates of Cumulative Hazards for
Selected Clinical Outcomes
JAMA, 2002
104
WHI
Kaplan-Meier Estimates of Cumulative Hazards for
Selected Clinical Outcomes
JAMA, 2002
105
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

106
Ann of Int Med 137(4), 2002
107
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

108
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

109
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

110
Trial
  • Organizational Structure

111
NHLBI Clinical Trial Model

Policy Advisory Board
Funding Agency
Data Monitoring Committee
Steering Committee
Central Lab(s)
Working Committees
Data Center
Clinics
Greenberg Report. Controlled Clinical Trials,
137-148, 1988
112
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

113
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

114
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

115
A Trial Protocol
  • Required for all trials
  • Basis of Review
  • IRB/Ethics
  • Funding

116
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

117
Protocol Outline A Blueprint (1)
  • A. Background Rationale
  • B. Objectives
  • 1. Primary Question
  • 2. Secondary Question
  • 3. Subgroup Questions
  • 4. Toxicities

118
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

119
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

120
Protocol Outline A Blueprint (4)
  • Appendix
  • Definitions
  • Combined Outcomes
  • Examples
  • fatal or non fatal MI
  • CHD or stroke
  • ARC or AIDS or Death

121
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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