PWA Advisory Group: Clinical Trials

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PWA Advisory Group Clinical Trials

• Tracy Swan
• January 2004
• Informacion adicional Rob Camp agosto 2006

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WHAT IS A CLINICAL TRIAL?

• An experiment in human beings
• to determine
• SAFETY, EFFICACY
• ACTIVITY
• of a drug, an intervention or a
• treatment for a given condition
• or disease

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PHASES OF CLINICAL TRIALS

• PRE-CLINICAL test tube studies
• and studies in rats, dogs
• monkeys-- looks at toxicities
• PHASE I safety activity, dose-
• finding, phamacokinetics (how
• much drug gets in and how long it
• lasts)--small short-term

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PHASES OF CLINICAL TRIALS

• PHASE II safety efficacy, 48 weeks,
• randomized, uses HIV RNA and CD4
• count as endpoints, larger (gt100 people)
• PHASE IIIefficacy/effectiveness,
• randomized, surrogate or clinical
• endpoints, can be 1000s of people

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PHASES OF CLINICAL TRIALS

• PHASE IV post-approval studies,
• can answer many important ?s
• long-term effectiveness, toxicities,
• which regimen is best to start with..
• We arent getting the answers to
• questions that havent been asked

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ACCELERTATED VS. TRADITIONAL APPROVAL

• Accelerated approval changes in HIV
• RNA at week 24
• Traditional approval changes in HIV
• RNA at week 48

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PARTICIPATING IN A TRIAL

• PHASE I for HIV volunteers, high risk
• for getting wrong dose/resistance--often
• use HIV-volunteers, risk of toxicity
• PHASE II if you are interested in HIV
• TX can take a risk might be a good
• idea
• PHASE III a safer entry point more is
• known about the drug

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US HISTORY OF CLINICAL TRIALS HIGHS LOWS

• 1906 original Food Drugs Act passed by
  Congress.
• 1914 Harrison Narcotics Act regulates opiates
  and cocaine
• 1932 infamous Tuskeegee Study of
• Untreated Syphilis in the Negro Male Begins

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US HISTORY OF CLINICAL TRIALS HIGHS LOWS

• 1938 The Federal Food, Drug, Cosmetic (FDC)
  Act passes Congress, (after 100 people die taking
  an elixir containing ethylene glycol) starting a
  new system of drug regulation-new drugs need to
  be shown safe before marketing
• 1947 Nuremberg, The voluntary consent of the
  human subject is absolutely essential.

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US HISTORY OF CLINICAL TRIALS HIGHS LOWS

• 1951 Durham Humphrey Amendment to create
  prescription drugs
• 1961 Thalidomide widely used in Europe approval
  blocked in U.S.
• 1962 Thalidomide found to cause birth defects
  US application withdrawn.
• Kefauver-Harris Amendments pass- drugs to
  prove efficacy before marketing

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US HISTORY - CLINICAL TRIALS HIGHS LOWS

• 1964 World Medical Assembly adopts Declaration
  of Helsinki Recommendations Guiding Medical
  Doctors in Biomedical Research Involving Human
  Subjects (distinguishes therapeutic research from
  non-therapeutic)
• 1966 NIH develops Policies for the Protection of
  Human Subjects

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US HISTORY - CLINICAL TRIALS HIGHS LOWS

• 1972 NYT headlines on Tuskeegee
• 1974 Regulations protecting human subjects
  passed
• 1975 Additional Protections Pertaining to
  Research, Development, and Related Activities
  Involving Fetuses, Pregnant Women and Human in
  Vitro Fertilization" becomes final

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US HISTORY - CLINICAL TRIALS HIGHS LOWS

• 1977 FDA recommends premenopausal women capable
  of becoming pregnant be excluded from early drug
  trials
• 1979 Belmont Report-Ethical Principles and
  Guidelines for the Protection of Human Subjects
  of Research
• (respect for persons, beneficence, and justice)

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US HISTORY - CLINICAL TRIALS HIGHS LOWS

• 1980 Rutherford vs US, patients do not have a
  right to unapproved drugs
• 1983 Orphan Drug Act to promote research
  marketing of rare disease drugs
• 1986 NIH policy urges inclusion of women in
  trials
• 1987 Investigational Drug Regulations revised to
  expand access to experimental drugs for patients
  with serious diseases with no alternative
  therapies.

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US HISTORY - CLINICAL TRIALS HIGHS LOWS

• 1987 NIH guideline encourages inclusion of
  minorities
• 1989 NIH Memorandum requires rationale for
  exclusion of women/minorities
• 1990 Cruzan vs Missouri patients have right to
  refuse medical treatment
• 1991 FDA accelerated review for
  life-threatening diseases
• 1992 FDA Modernization Act, including
  accelerated review and advertising guidelines
• 1993 FDA ends restrictions on women of
  childbearing age

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US HISTORY - CLINICAL TRIALS HIGHS LOWS

• 1994 NIH Guidelines for Inclusion of Women and
  Minorities
• 2001 DHHS revised regulations on participation
  of women (to enhance the opportunity for pregnant
  women to participate in research)--implementation
  delayed by president bush
• 2005 Gonzales vs Raich, dispensing of new drugs
  must always have federal approval