Ethical considerations in clinical trials:
Drug trials
รศ.ภญ.นุจรี ประทีปะวณิช จอห์นส
ประเภทของการทดลองยาทางคลินิก
 ยาใหม่
 ยาที่ ยงั ไม่ได้ขึน
้ ทะเบียนยาในประเทศไทย
 ยาที่ ขึน
้ ทะเบียนแล้ว แต่ทดลองใช้ในขนาด/
วิธีการใช้/กลุ่มตัวอย่าง ที่ต่างจากที่ขึน้ ทะเบียน
 ยาผลิตในประเทศ ทดสอบเปรียบเที ยบกับยา
ต้นแบบ (bioequivalence)
การวิจยั ยาทางคลินิกในระยะต่างๆ
Investigational
new drug application (IND)
Phase IV
FDA
Phase III
Approval
Phase II
Phase I
Animal and/or
Laboratory
studies
New drug
application (NDA)
Phase I: human pharmacology trial
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The first stage of testing in human subjects.
Designed to assess: drug’s 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’
Case study
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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".
Note for bioequivalence trials
Lesson learned from the event
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Calculation of initial and subsequent dose
Using sequential dosing
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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. 8:00 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)
Phase II: Therapeutic exploratory trial
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Aim to show ‘proof-of-concept’, surrogate endpoints can
be used
Explore therapeutic efficacy in small target patients (20100)
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).
Phase III: Therapeutic confirmatory trial
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Randomized controlled multicenter trials on large patient
groups (300–3,000)
Aim to demonstrate or confirm the therapeutic benefit,
important clinical endpoints are used, in comparison with
current 'gold standard' or placebo treatment.
Karlberg and Speers, Reviewing Clinical Trials:
a guide for the Ethics Committee, 2010
Phase IV: Therapeutic use trial
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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).
ในทางปฏิบตั ิ งานวิจยั ทางคลินิกมีหลายวัตถุประสงค์ร่วมกัน จึงอาจพบ
phase IA, phase IB, Phase I/II หรือ Phase II/III เป็ นต้น
Phase 0: micro dosing trial
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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
drug’s 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.
Dilemma of Phase 0
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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?
Criteria for EC approval of research
1.
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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
Consideration for reviewing clinical trials
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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
Example of ‘unsound’ protocols - unethical
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Lack of sufficient pre-clinical research information
No obvious clinical value:
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Using incorrect endpoint, too small sample size, no
controls, no randomization, no blinding when it could be
utilized
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The trial will not advance knowledge, put risks to participants
and consume financial & human resource for no reason
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
Things to remember when writing a protocol
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Clinical rationale
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Study objectives
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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:
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Is (are) objective(s) clearly stated?
Study outcomes:
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What is (are) the expected benefit(s) of the drug in normal
clinical care?
Has a proper assumption & sample size calculation been
made?
If randomization is used, how will this be performed?
Ethics consideration in clinical trials
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Risk benefit balance
“In medical research involving human subjects, the wellbeing 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
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)
Risk benefit balance in Phase I trial
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Safety concern is immediate serious adverse reaction:
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No benefit for participants (either healthy or patients)
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This should be clearly stated in the informed consent.
Volunteer often get compensation for discomfort.
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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
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
Risk benefit balance in Phase II/III trial
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Inclusion/exclusion criteria
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Not expose subjects to excessive, unnecessary risks
Appropriate risk management
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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
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
Quality assurance of clinical trials
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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
Case scenario 1
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Phase I trial เป็ นการศึกษา pharmacokinetics และ
pharmacodynamic parameters ของยาใหม่ในการรักษามะเร็ง
small cell lung cancer
ต้องการเจาะเลือดผูป้ ่ วยในระยะ advanced จานวนไม่เกิน 800 ml
ในช่วงเวลา 2 สัปดาห์
ข้อมูลเบือ้ งต้น
– ต้องศึกษาในผูป
้ ่ วยมะเร็งเนื่ องจากเป็ นยาที่มีความเป็ นพิษสูง
Case scenario 2
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การศึกษาผลของสารสกัดโสมเข้มข้นในการเพิ่มคุณภาพชีวิตใน
ผูป้ ่ วยสูงอายุ
ข้อมูลเบือ้ งต้น
– มีการใช้โสมเป็ นสมุนไพรมาเป็ นเวลานาน และยังไม่มีรายงาน
อาการไม่พึงประสงค์ที่ร้ายแรง
– ยังไม่เคยมีการใช้ในรูปสารสกัดเข้มข้น
Summary:
Ethical considerations for clinical drug trials
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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
Thank you for your attention