Introduction to Clinical Trials PartII

1
Introduction to Clinical TrialsPart-II
2
Research Cycle
Clinical Trials Research (human, comparative)
Translational Research
Basic Research (bench, animal)
Observational Research (human, epidemiological)
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

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

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

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

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

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Definition of a Clinical Trial

• A prospective study comparing the effect and
  value of intervention(s) against a control in
  human subjects
• 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 Trials The Numerical Method

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

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Clinical Trials

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

randomized
12
12
blinded
Control saline injection
Sano crysin (gold compound)
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Clinical TrialsUse of Randomization

• Multicenter Trials (1944) - Common Cold
• Medical Research Council
• Treatment of common cold
• Different sites all using common protocol
• Patulin vs. Placebo
• MRC Tuberculosis Trial (1948) - Grandfather Trial
• (Ref British Medical Journal, 1948)
• Randomized (by random numbers)
• Streptomycin vs. Placebo
• Based on work of Bradford Hill, founder of modern
  day clinical trial
• Supported Concept of Randomization

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The General Flow of Statistical Inference
Sample Protocol Patients On Study
Patient Population
Observed Results
Inference about Population
Sample of Opportunity random or non-random?
13
Ethics and Clinical Trials

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

14
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.

15
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.

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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.

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The Nuremberg Code (1)Some Principles

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

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The Nuremberg Code (2) Some Principles

• Degree of risk should never exceed humanitarian
  importance of problem to be solved.
• Protect subject against remote possibility of
  injury.
• Experiments conducted only by scientifically-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.

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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

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Belmont Report (1979)Ethical Principles
GuidelinesSponsored by NIH

• Respect for Persons
• Persons with diminished autonomy are entitled to
  protection (e.g. children, prisoners)
• Beneficence
• Maximize possible benefits and minimize possible
  harm.
• Justice
• Fairness in distribution access to experimental
  treatment

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Code of Federal Regulations (HHS)Design Issues

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

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Food and Drug Administration (FDA)

• Responsible for approval of new drugs, biologics
  and devices
• 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 RegulationsProtection of Human Subjects

• The Office for Protection of Research Risks
  (OPRR), now Office of Human Research Protection
  (OHRP) in HHS ultimate authority
• Issues, requirements and policies
• Reviews, IRBs for compliance
• May shut down research at an institution for
  non-compliance

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Institutional Review Boards (IRB)

• Required for each research institution by Federal
  regulations
• Must review each new protocol for
• Merit and ethics
• Consent process/document
• Must conduct annual review
• Responsible for patient safety

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Ethical IssuesInforming 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 IssuesInforming 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)

• 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)

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

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Recent Developments (3)

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

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Monitoring of Clinical Trials

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

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Ethical Omniscience

• 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)

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Ethical Imperialism

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

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Ethical OmniscienceMedical 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)

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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

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Informed Consent Process

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

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Basic Contents/Informal Consent (1)

• Explanation of research study
• Purpose
• Duration
• Procedures
• Possible risks
• Possible benefits
• Patient
• Other individuals
• Disclosure of alternative treatment

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Basic Contents/Informal Consent (2)

• Describe confidentiality of data
• Compensation in case of injury
• Patient contacts for questions or injury
• Participation is voluntary

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Additional Possible Elements/Informal Consent

• Risks to fetus
• Investigator may terminate patient participation
• Costs of additional tests
• Consequences of patient withdrawal
• Sharing of new findings during course of trial
• Total number of subjects

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Consent Waiver

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

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New Federal Regulations

• Health Information Portability and Accountability
  Act (HIPAA)

41
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

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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

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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

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HIPAA Requires

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

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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

46
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

47
HIPAA Transition

• Protocols completed prior to 4/14/03 were
  grandfathered
• Protocols continuing past 4/14/03 had to receive
  new IRB review of patient authorization
• All protocols started after 4/14/03 have to meet
  one of the HIPAA Privacy Rules options

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HIPAA Privacy Rule Options

• Obtain written patient authorization
• Separate document
• Part of Informed Consent document
• Apply to IRB for a waiver
• Develop a Limited Data Set
• Develop statistical argument of low risk
  identification

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Obtaining Subject Authorization

• A description of PHI to be used and disclosed
• Identification of individuals who will
  use/disclose PHI
• Identification of individuals who will receive
  PHI
• Purpose of disclosure
• An expiration date or notice of no expiration
• Statement of 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

50
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

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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!

52
Data sharing Key point

• The usual end result of scientific research in a
  journal
• Journals publish summary statistics
• Future researchers may want to analyze data in
  different ways
• This can only be achieved by access to raw data

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Three rationales for data sharing

• The scientific value of data can be maximized by
  reanalysis and meta-analysis
• Data obtained with public funds should be shared
  for the public good
• All data sets build on prior science and should
  therefore be made available to optimize future
  science

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Data Sharing Problems

• Arguments are logical but this is not a logical
  arena
• Not all clinical trial data paid by public funds
• Patients are suspicious
• IRBS are uptight
• Investigators are uptight
• Data security is getting harder
• (i.e Hackers)

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Definition Clinical Trial

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

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Single Double Blind Clinical Trial

• Single Blind A clinical trial where the
  participant/patient does not know the identity of
  the treatment received
• Double Blind A clinical trial in which neither
  the patient nor the treating physician knows the
  identity of the treatment being administered.

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Placebo Control Clinical Trial

• Placebo An inert substance made up to
  physically resemble a treatment being
  investigated for therapeutic benefit.
• Used as a control treatment.
• Design may be
• 1) treatment vs placebo or
• 2) Best standard of care plus either experimental
  treatment or a matching placebo

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Types of Clinical Trials

• Phase I
• New treatment (usually drugs) is to be tried on
  humans for the first time. Aim is to find
  acceptable range of doses and schedules.
• Phase II
• Treatment is to be given to humans to determine
  if it has any beneficial activity. Doses and
  schedules may not be optimum.
• Phase III
• Comparative Trial. To compare experimental or new
  therapies with standard therapy or competitive
  therapies.

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Types of Clinical Trials

• Randomized
• Non-Randomized
• Single Center
• Multi Center
• Phase I, II, III Trials

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Characterization of TrialsRandomized vs.
Non-RandomizedMulti-Center vs. Single Center
Carrying out a multi-center randomized clinical
trial is the most difficult way to generate
scientific information.
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Why Are Clinical Trials Needed? (1)

• 1. Most definitive method of determining whether
  a treatment is effective.
• Other designs have more potential biases
• One cannot determine on the basis of uncontrolled
  observation whether an intervention has made a
  difference to outcome.

63
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

64
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

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Why Are Clinical Trials Needed? (3)

• 3. Therapy accepted with no trial! Later,
• IPPB Trial ? no benefit
• Retrolental Fibroplasia, high O2 in premature
  infants ? Harmful
• Tonsillectomy ? Reduced use
• Bypass Surgery ? Restricted use

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Failure to Use Therapy Based on Theory
67
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

68
Beta-Blocker HFTrial Features

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

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MERIT
Total Mortality
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CIBIS-II
Lancet, 1999
71
COPERNICUS
NEJM, 2001
72

• Long Standing Treatment
• Based on Theory and
• Observation/Association

73

Hormone Replacement Therapy (HRT)

• Hypothesis that HRT reduced coronary heart
  disease
• Supportive data
• Lipid lowering
• Non-human primate studies
• Observational studies

74
Observational Studies

• Example Refs
• Stampfer Coldiz (Prev Med 1991)
• Nurses Health Study
• Grady (Ann Int Med 1992)
• Cauley, Cummings, et al. (Am J OB/GYN, 1990)
• Grodstein, Stempfer, Manson (NEJM 1996)
• Suggest 40-50 reduction in CHD risk

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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)

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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.

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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.

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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

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HERS

• 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 MORTALITY
JAMA, 1998
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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

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WOMENS 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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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
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WHI
Cumulative Dropout and Drop-in Rates by
Randomization Assignment and Follow-up Duration
JAMA, 2002
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Wisconsin State Journal 2002
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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
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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
Selected Clinical Outcomes
JAMA, 2002
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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
93
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

94
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)

• 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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Trial

• Organizational Structure

97
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
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NIH Organizational StructureA Brief Overview (1)

• 1. Project Office/Funding Agency
• Responsible for providing organizational,
  scientific statistical direction through
  Project Officer
• Contract Officer is responsible for all
  administrative matters related to award and
  conduct of contracts
• Responsible for most of the pre-award
  development RFP, sample size, etc.
• 2. Policy Advisory Board (PAB) Data Monitoring
  Board (DMB)
• Acts as senior independent advisory board to NIH
  on policy matters
• Reviews study design and changes to the initial
  design
• Reviews interim study results, by treatment group
  and recommends early termination for toxicity or
  beneficial effects
• Reviews performance of individual clinical centers

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NIH Organizational StructureA Brief Overview (2)

• 3. Steering Committee
• Provides scientific direction for the study at
  the operational level
• Usually are recommended or elected
  representatives of the clinical center principle
  investigators
• Monitors performance of individual centers
• Report major problems to PAB and P.O.
• May have several subcommittees which are
  responsible for various aspects such as
  recruitment, endpoints, publications, quality
  control, etc.
• 4. Assembly of Investigators (may be same as
  Steering Committee)
• Each operational unit (clinic, laboratory, data
  center) has a representative
• Elects from its membership representative on
  Steering Committee
• Reviews operational progress of study
• Represents individual clinical centers

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NIH Organizational StructureA Brief Overview (3)

• 5. Coordinating Center
• Responsible for collecting, editing, analyzing
  storing all data collected
• Develop and test forms
• Develop randomization procedure
• Monitor quality control of clinics and labs
• Periodic analysis for potential risks and
  benefits
• Perform final analysis at end of the trial
• 6. Central Labs
• Provide standardized results across centers to
  insure comparability
• Examples are EKG, Biochemistry, Pathology
• 7. Clinical Centers
• Recruit patients, administer treatment,
  coordinate patient care collect data required
• Grass Roots of any clinical trial

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A Trial Protocol

• Required for all trials
• Basis of Review
• IRB/Ethics
• Funding

102
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

103
Protocol Outline A Blueprint (1)

• A. Background Rationale
• B. Objectives
• 1. Primary Question
• 2. Secondary Question
• 3. Subgroup Questions
• 4. Toxicities

104
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

105
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

106
Protocol Outline A Blueprint (4)

• Appendix
• Definitions
• Combined Outcomes
• Examples
• fatal or non fatal MI
• CHD or stroke
• ARC or AIDS or Death

107
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