CLINICAL TRIALS FOR DEPARTMENT ADMINISTRATORS

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CLINICAL TRIALS FOR DEPARTMENT ADMINISTRATORS

• Barbara Longmire, RN, MSN
• April 20, 2004

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BASICS OF CLINICAL TRIALS

• Common Terminology
• Phases of Clinical Trials
• Regulatory Oversight

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COMMON TERMS

• IND Application
• Investigational or experimental
  drug/device/biologic
• Placebo
• Protocol

• Informed consent
• Experimental group
• Control group
• Blinded study
• Randomization
• Efficacy

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COMMON TERMS (cont)

• FDA (Food and Drug Administration)
• OHRP (Office of Human Research Protection)

• Institutional Review Board (IRB)
• Sponsor
• Principal investigator

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PHASES OF CLINICAL TRIALS

• Phase I
• Phase II
• Phase III

• Post-Marketing
• Phase IV
• Phase V

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PHASE I STUDIES

• Small numbers, 20-80 subjects
• Usually healthy volunteers
• Typically pharmacokinetic studies
• Testing for safety and dose only
• Duration weeks to several months

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HUMAN SUBJECTS

• A "human subject" is a living individual about
  whom an investigator obtains either (1) data
  through interaction or intervention with the
  individual, or (2) identifiable private
  information.
• 45 CFR 46.102(f)

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PHASE II STUDIES

• 100 to 300 subjects with the disease/condition
• Continued monitoring of safety
• Pilot efficacy studies
• Most are randomized trials
• Duration several months to two years

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PHASE III STUDIES

• 500 3000 subjects for whom the
  drug/device/biologic is intended
• Multicenter studies
• Most randomized and blinded
• Additional safety and efficacy data
• Duration 1 to 4 years

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PHASE III STUDIES (cont)

• Phase IIIB may be done between NDA submission and
  FDA approval
• Provide info for package insert and labeling
• 70 - 90 of drugs that enter Phase III
  successfully completed

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PHASE IV STUDIES

• Post-marketing
• Provide additional long-term safety and efficacy
  data on general population
• Additional information obtained
• compare approved drug with others on the market
  for the same indication
• evaluate cost-effectiveness compared to
  traditional therapies

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PHASE V STUDIES

• Further post-marketing
• Seldom used designation

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REGULATORY OVERSIGHT
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WHERE DID ALL THIS COME FROM?

• Regulations help to maintain quality standards
• Important to have independent evaluation of
  medical products
• Regulations protect from exploitation and abuse,
  but legislation can not solve all the problems

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NUREMBERG TRIALS

• Verdict delivered August 19, 1947 against German
  physicians for human research atrocities
• At time of Nuremberg trials there was no formal
  code of ethics in medical research to which the
  judges could hold the physicians accountable

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NUREMBERG CODE

• Judgment by the war crimes tribunal listed ten
  standards for permissible human experimentation
  covering
• Voluntary Participation
• Consent
• Benefit(s) must outweigh risks

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DECLARATION OF HELSINKI

• World Medical Association drafted code in 1961,
  accepted in 1964
• Distinguish ethical from unethical clinical
  research
• Separated clinical research (combined with
  clinical care) from non-therapeutic biomedical
  research involving human subjects
• Most recent revision October, 2000

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BELMONT REPORT

• Resulted from senate hearings in 1970s
• Public Law 93-348 established the National
  Commission for the Protection of Human Subjects.
• Commission issued the Belmont Report after
  holding hearings (1974)

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THE BELMONT REPORT

• Basic Ethical Principals
• Respect for Persons
• Beneficence
• Justice

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PROTECTION OF HUMAN SUBJECTS

• US Federal Regulations
• DHHS
• Office for Human Research Protections (45 CFR 46)
• Food and Drug Administration (21 CFR 50, 21 CFR
  56)
• State Laws
• International Guidelines
• International Conference on Harmonization (ICH)

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CODE OF FEDERAL REGULATIONS

• 21CFR 50 Protection of Human Subjects
• 21CFR 54 Financial Disclosure
• 21CFR 56 Institutional Review Boards
  (IRBs)
• 21CFR 312 IND

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BASIC PROTECTIONS

• The regulations contain three basic protections
  for human subjects
• Institutional Assurances
• IRB Review
• Informed Consent

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GENERAL RESPONSIBILITIES OF SPONSORS

• 21 CFR 312.50Sponsors are responsible
• for selecting qualified investigators
• providing them with the information they need to
  conduct an investigation properly
• ensuring proper monitoring of the
  investigation(s)
• ensuring that the investigation(s) is conducted
  in accordance with the general investigational
  plan and protocols contained in the IND

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GENERAL RESPONSIBILITIES OF SPONSORS
(cont)

• maintaining an effective IND with respect to the
  investigations
• and ensuring that FDA and all participating
  investigators are promptly informed of
  significant new adverse effects or risks with
  respect to the drug

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GENERAL RESPONSIBILITIES OF INVESTIGATORS

• 21 CFR 312.60
• An investigator is responsible
• for ensuring that an investigations is conducted
  according to
• the signed investigator statement (1572)
• the investigational plan
• applicable regulations

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GENERAL RESPONSIBILITIES OF INVESTIGATORS
(cont)

• for protecting the rights, safety, and welfare of
  subjects under the investigator's care
• for the control of drugs under investigation.

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FEDERAL REGUALTIONS AND POLICY OHRP

• 45CFR46 - Protection of Human Research Subjects
• Subpart A Originally adopted January 13, 1981
• The Common Rule - Subpart A Revised June 18,
  1991, becoming federal policy for the protection
  of human subjects by the 17 adopting federal
  agencies

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FEDERAL REGUALTIONS AND POLICY OHRP
(cont)

• Additional Protections Included in 45 CFR 46
• Subpart B - fetuses, pregnant women, and human in
  vitro fertilization
• Subpart C - biomedical and behavioral research
  involving prisoners as subjects
• Subpart D children involved as research
  subjects

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REGULATORY OVERSIGHT BY FDA

• Drugs CDER (Center for Drugs Evaluation and
  Research)
• Biologics CBER(Center for Biologics Evaluation
  and Research)
• Blood, vaccines, gene therapy, tissues, etc.
• Devices and HIV test kits
• Devices CDRH(Center for Devices and
  Radiological Health)

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INTERNATIONAL COOPERATION

• 1980s European Union developed a single market
  for pharmaceuticals
• Success demonstrated feasability of harmonisation
  
• Discussion began between US, Japan and Europe
• 1989 Specific plans for action began at the WHO
  conference

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GENERAL COMMENTS ON ICH GUIDELINES

• ICH Guidelines published in federal register, but
  do not bind FDA
• ICH not concerned with financial disclosures
• ICH not concerned with (NDA), only with
  harmonizing components of phase I-III trials that
  make up IND