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Title: Ethical considerations in clinical trials: Drug trials


1
Ethical considerations in clinical trialsDrug
trials
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2
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  • ???????????????????? ?????????????????/??????????/
    ????????????? ????????????????????????
  • ?????????????? ???????????????????????????
    (bioequivalence)

3
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Phase I
Animal and/or Laboratory studies
4
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

5
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".

6
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)
7
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).

8
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.

9
Karlberg and Speers, Reviewing Clinical Trials
a guide for the Ethics Committee, 2010
10
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).

11
  • ???????????? ?????????????????????????????????????
    ????? ???????? phase IA, phase IB, Phase I/II
    ???? Phase II/III ???????

12
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13
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.
14
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?

15
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
16
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
17
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

18
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?

19
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
20
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)

21
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
22
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

23
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

24
Case scenario 1
  • Phase I trial ???????????? pharmacokinetics ???
    pharmacodynamic parameters ??????????????????????
    ??? small cell lung cancer
  • ????????????????????????????? advanced
    ???????????? 800 ml ?????????? 2 ???????
  • ???????????????
  • ??????????????????????????????????????????????????
    ????????

25
Case scenario 2
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    ?????????????????
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    ?????????????????????????????????????????????
  • ????????????????????????????????????

26
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

27
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