Title: Ethical considerations in clinical trials: Drug trials
1Ethical considerations in clinical trialsDrug
trials
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(bioequivalence)
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Phase I
Animal and/or Laboratory studies
4Phase 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
5Case 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".
6Lesson 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)
7Phase 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).
8Phase 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.
9Karlberg and Speers, Reviewing Clinical Trials
a guide for the Ethics Committee, 2010
10Phase 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
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13Phase 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.
14Dilemma 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?
15Criteria for EC approval of research
- Risks are reasonable relative to benefits
- Risks to subjects are minimized
- Adequate protection of subject privacy
confidentiality - Adequate safety monitoring plan
- Written informed consent obtained (unless waived)
- Appropriate consent elements are present
- Subject selection is equitable
- Additional safeguards for vulnerable populations
- 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
16Consideration 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
17Example 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
18Things 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?
19Ethics 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
20Consideration 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)
21Risk 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
22Risk 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
23Quality 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
24Case scenario 1
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pharmacodynamic parameters ??????????????????????
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25Case scenario 2
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26Summary 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
27Thank you for your attention