Ethical considerations in clinical trials: Drug trials

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Ethical considerations in clinical trialsDrug
trials

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  (bioequivalence)

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Phase I
Animal and/or Laboratory studies
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Phase I human pharmacology trial

• The first stage of testing in human subjects.
• Designed to assess drugs toxicity,
  pharmacokinetics (absorption, distribution,
  metabolism, excretion), duration of action,
  drug-drug interaction or food-drug interaction
• Small (20-50) group of healthy volunteers will be
  selected, except highly toxic drugs (e.g.
  chemotherapy) will be tested in patients.
• Higher risk trials are those categorized as
  first-into-human trial or dose escalating
  trial

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Case study

• TGN1412 (monoclonal antibody) is an
  immunodomulatory drug intended for the treatment
  of B cell chronic lymphocytic leukemia (B-CLL)
  and rheumatoid arthritis.
• In March 2006, The previously healthy young men
  were being paid (up to 150/330 a day) to take
  part in its first human trial.
• The subjects was administered at a sub-clinical
  dose of 0.1 mg per kg 500 times lower than the
  dose found safe in animals.
• Within hours of their first injection, six
  volunteers suffered from multiple organ failure
  and were put in intensive care. The two men
  receiving placebo are fine.
• The problems resulted from "unforeseen biological
  action in humans".

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Lesson learned from the event
Note for bioequivalence trials

• Calculation of initial and subsequent dose
• Using sequential dosing
• One participant dosed on day one, and the rest
  dosed after a review and a go-ahead decision by
  data safety monitoring committee
• First dose in the morning (e.g. 800 am)
• Using dedicated hospital ward or ICU for high
  risk trials
• Doctor standby during the first 24 hours of the
  trial
• Establishment of independent data safety
  monitoring committee to assess the data safety

Guidelines from European Medicine Agency
(EMEA), Association of the British Pharmaceutical
Industry (ABPI)
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Phase II Therapeutic exploratory trial

• Aim to show proof-of-concept, surrogate
  endpoints can be used
• Explore therapeutic efficacy in small target
  patients (20-100)
• Sometimes divided into Phase IIA and IIB.
• Phase IIA designed to assess dosing requirements
  (how much drug should be given).
• Phase IIB designed to study efficacy (how well
  the drug works at the prescribed dose).

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Phase III Therapeutic confirmatory trial

• Randomized controlled multicenter trials on large
  patient groups (3003,000)
• Aim to demonstrate or confirm the therapeutic
  benefit, important clinical endpoints are used,
  in comparison with current 'gold standard' or
  placebo treatment.

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Karlberg and Speers, Reviewing Clinical Trials
a guide for the Ethics Committee, 2010
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Phase IV Therapeutic use trial

• Phase IV trial is also known as Post Marketing
  Surveillance Trial.
• Aim to study the effectiveness of treatment after
  approval to support use under the approved
  indication e.g. safety, drug-drug interaction,
  dose response.
• It is also critical for exploring new use for a
  therapy
• Harmful effects discovered by Phase IV trials may
  result in a drug being no longer sold, or
  restricted to certain uses recent examples
  involve cerivastatin (brand names Baycol and
  Lipobay), troglitazone (Rezulin) and rofecoxib
  (Vioxx).

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  ????? ???????? phase IA, phase IB, Phase I/II
  ???? Phase II/III ???????

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Phase 0 micro dosing trial

• Phase 0 is a new exploratory, first-in-human
  trials.
• Phase 0 trials include the administration of
  single subtherapeutic doses of the study drug to
  a small number of subjects (10 to 15) to gather
  preliminary data on the drugs pharmacokinetics
  (how the body processes the drug) and
  pharmacodynamics (how the drug works in the body).

Phase 0 is conducted based on the US FDA 2006
Guidance on Exploratory IND Studies.
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Dilemma of Phase 0

• Drug development companies use Phase 0 studies to
  rank drug candidates in order to decide which has
  the best pharmacokinetic parameters in humans to
  take forward into further development (using
  human models, instead of relying on inconsistent
  animal data).
• A Phase 0 study gives no data on safety or
  efficacy because the dose is too low.
• Prediction of Phase 0 may be incorrect.
• Are Phase 0 trials useful, ethically acceptable,
  feasible, speed up the drug development process
  or save money?

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Criteria for EC approval of research

1. Risks are reasonable relative to benefits
2. Risks to subjects are minimized
3. Adequate protection of subject privacy
   confidentiality
4. Adequate safety monitoring plan
5. Written informed consent obtained (unless waived)
6. Appropriate consent elements are present
7. Subject selection is equitable
8. Additional safeguards for vulnerable populations
9. Other ethical compliance issues (e.g. conflict
   of interest, quality of investigator/trial
   management etc.)

45 CFR 46.111, OHRP common Rule 21 CFR 56.111,
FDA
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Consideration for reviewing clinical trials

• Science - clinical trials with one standard!
• Ethics
• Quality assurance
• Clinical trial with poor science, poor ethics
  or poor data quality puts participants at
  unnecessary risk of harm and is likely to be
  rejected by regulatory authorities or
  international biomedical scientific community.
• Trials that do not add any new information
  to our body of knowledge put participants at risk
  without any reason.

Declaration of Helsinki and the ICH GCP
guideline
Karlberg and Speers, Reviewing Clinical Trials
a guide for the Ethics Committee, 2010
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Example of unsound protocols - unethical

• Lack of sufficient pre-clinical research
  information
• No obvious clinical value
• The trial will not advance knowledge, put risks
  to participants and consume financial human
  resource for no reason
• Using incorrect endpoint, too small sample size,
  no controls, no randomization, no blinding when
  it could be utilized
• Major considerations for trials with confirmatory
  nature.
• Using a drug that is manufactured without
  evidence of good manufacturing practice (GMP)
• Using placebo control group inappropriately
  withholding standard treatment

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Things to remember when writing a protocol

• Clinical rationale
• What is (are) the expected benefit(s) of the drug
  in normal clinical care?
• Study objectives
• Is (are) objective(s) clearly stated?
• Study outcomes
• Is the study exploratory or confirmatory in
  nature?
• Is the primary outcome a clinical or surrogate
  outcome?
• Is the outcome the valid internationally accepted
  outcome?
• Sample size
• Has a proper assumption sample size calculation
  been made?
• If randomization is used, how will this be
  performed?

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Ethics consideration in clinical trials

• Risk benefit balance
• In medical research involving human
  subjects, the well-being of the individual
  research subject must take precedence over all
  other interests.
• Medical research involving human subjects
  may only be conducted if the importance of the
  objective outweighs the inherent risks and
  burdens to the research subjects.

Declaration of Helsinki
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Consideration for risks benefits

• Risks of harm
• Physical harm (bodily harm or inconvenience)
• Psychological harm (emotional suffering or breach
  of confidentiality)
• Social harm (employment or social discrimination)
• Economic risks (financial costs related to
  participation)

• Potential benefits
• Physical benefit (improvement of disease)
• Psychological benefit (comfort from suffering or
  feeling of helping others in the future)
• Economic benefit (financial benefits related to
  research participation)
• Benefit to science/society (general knowledge,
  effective treatment in the future)

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Risk benefit balance in Phase I trial

• Safety concern is immediate serious adverse
  reaction
• Sufficient preclinical safety data
• Proposed dosing from the relevance animal model
• Sequential manner (for high risk or
  first-into-human trial)
• Appropriate clinical facilities
• Conducted by trained investigators experience
  medical staff
• No benefit for participants (either healthy or
  patients)
• This should be clearly stated in the informed
  consent.
• Volunteer often get compensation for discomfort.
• Payment is not benefit!
• Payment should be appropriate, pay per
  performance (not at the end) and clearly stated
  in the informed consent.
• Evidence of product manufacturing and safety
  (GMP)

European Medicines Agency, 2007
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Risk benefit balance in Phase II/III trial

• Inclusion/exclusion criteria
• Include subjects most likely to yield an answer
• Include subjects equitably (vulnerable subjects
  get benefit?)
• Exclude subjects who could predictably confound
  the answer
• Exclude subjects who might be at increased risk
  in a research
• Not expose subjects to excessive, unnecessary
  risks
• Appropriate risk management
• Appropriate frequency to monitor risk/benefit
• Adequate risk monitoring and stopping rules for
  subject with worsening condition
• If placebo is justified, rescue medication should
  be available
• Has independent data monitoring committee (if
  appropriate)
• Subjects are properly informed of the risks
  involved

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Quality assurance of clinical trials

• EC partially responsible by reviewing
• EC applications protocol
• Qualification of investigators
• Amendments
• Adverse event reports
• Continuing progress reports
• Final reports
• Compliance issues
• Routine or for cause site visits

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Case scenario 1

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  pharmacodynamic parameters ??????????????????????
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Case scenario 2

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Summary Ethical considerations for clinical
drug trials

• Scientifically sound protocol
• Risk benefit balance
• Risks are reasonable relative to benefits
• Appropriate risk management
• Adequate safety monitoring plan
• Subject selection in equitable
• Additional safeguards for vulnerable populations
• Appropriate consent elements are present
• Quality assurance
• Qualification of investigators
• Continuing progress report
• Serious adverse event report
• Compliance issues

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Thank you for your attention