Transcript Concepts of Causation - مرکز تحقیقات اخلاق

‫مسائل اخالقي در كارآزمايي باليني‬
‫دكتر اكبر فتوحي‬
‫استاديار اپيدميولوژي‬
‫دانشكده بهداشت و انستيتو تحقيقات بهداشتي‬
‫منابع‬
‫فهرست مطالب‬
‫چرا كارآزمايي باليني؟‬
‫سود و زيان‬
‫مراحل كارآزمايي باليني‬
‫طرحهاي (‪ )design‬كارآزمايي باليني‬
‫مسائل اخالقي در اجراي كارآزمايي باليني (‪)GCP‬‬
‫دارونما‬
‫رضايت نامه‬
‫كارآزمايي باليني در گروه هاي خاص‬
‫تضاد منافع (‪)Conflict of interest‬‬
‫پرداخت غرامت در كارآزمايي باليني‬
‫كميته هاي اخالق و كارآزمايي باليني‬
‫انتشار نتايج كارآزمايي باليني‬
‫چرا كارآزمايي باليني؟‬
Randomized clinical trials are the “gold
standard” of the treatments evaluation.
When is drug development worth pursuing?
When is a clinical trial appropriate?
An example: Hormone Replacement Therapy (HRT)
Four core ethical principals in clinical
trials:
Authonomy
Beneficence
Non-maleficence
Justice
‫بحث سود و زيان در كارآزمايي باليني‬
‫عدالت در سود و زيان‬
‫مراحل كارآزمايي باليني‬
Stage I (preclinical studies)
Stage II (clinical studies)
Phase
Phase
Phase
Phase
1
2
3
4
‫فازهاي كارآزمايي باليني‬
Phase
Participants
Research questions
Number
Characteristics
I
20-80
Usually young,
healthy, male
volunteers
Tolerability
Pharmacokinetics
Pharmacodynamics
II
100-300
Patients rather
than volunteers
Effectiveness
Dosage, Safety
III
1,000-3,000
Approximate
real-life patient
population
Compare to placebo,
current treatments
Effects of compound on
targets, side-effects
)‫(ادامه‬
Phase
‫فازهاي كارآزمايي باليني‬
Research questions
IIIb
Marketing – cost/value
Compares with market leader
Further data on safety and efficacy
IV
New formulations
Identify best patients
Safety assessment
‫طرحهاي (‪ )design‬كارآزمايي باليني‬
‫طرح هايي كه براي كم كردن بار اخالقي كارآزمايي باليني‬
‫پيشنهاد شده اند‪:‬‬
‫‪Zelen design‬‬
‫‪Adaptive design‬‬
‫‪Sequential design‬‬
‫طرح هايي كه داراي جنبه هاي اخالقي خاص هستند‪:‬‬
‫‪Community trials‬‬
‫‪Crossover design‬‬
Zelen design
Adaptive design
Sequential design
Community trials
Crossover design
‫مسائل اخالقي در اجراي كارآزمايي باليني‬
‫( ‪Good Clinical‬‬
‫‪)Practice‬‬
‫پروتكل‬
‫پايش بيماران‬
‫گروه كنترل‬
‫رندميزاسيون‬
‫كورسازي‬
‫قطع زود هنگام كارآزمايي باليني‬
‫بيماريابي و دعوت افراد به شركت در كارآزمايي باليني‬
‫دارونما‬
‫آيا استفاده از دارونما اخالقي است؟‬
‫آيا هميشه به گروه شاهد با دارونما نياز است؟‬
‫چه مواقعي مي توان از دارونما استفاده كرد؟‬
‫دارونما در ناخوشي هاي جزئي و شديد‪.‬‬
‫دارونماي تهاجمي‪.‬‬
‫قوانين مربوط به كاربرد دارونما‪.‬‬
)‫(ادامه‬
‫دارونما‬
When Placebo Controls May be Used:
There is no standard treatment
Standard treatment has been shown to
be no better than placebo
Evidence causes doubt about therapeutic
advantage of standard therapy
)‫(ادامه‬
‫دارونما‬
When Placebo Controls May be Used:
In a population of patients who are
refractory to standard treatment and
for whom there is no standard secondline treatment
Testing add-on treatment to standard
therapy when all subjects in the trial
receive all treatments that would
normally be prescribed
)‫(ادامه‬
‫دارونما‬
When Placebo Controls May be Used:
(Controversial Conditions)
Many argue that persons with conditions
with a low risk of harm (understand as
low probability or low magnitude of
harm) may be entered into a placebo arm
Many argue that placebo controls are
ethical when resources are limited and
standard treatment is not available
)‫(ادامه‬
‫دارونما‬
Declaration of Helsinki (prior to 2000)
In any medical study, every patient-including those of the control group, if
any--should be assured of the best
proven diagnostic and therapeutic
method. This does not exclude the use
of inert placebo in studies where no
proven diagnostic or therapeutic method
exists (emphasis added).
)‫(ادامه‬
Declaration of Helsinki (2000)
‫دارونما‬
The benefits, risks, burdens and
effectiveness of a new method should be
tested against those of the best current
prophylactic, diagnostic, and therapeutic
methods. This does not exclude the use
of placebo, or no treatment, in studies
where no proven prophylactic, diagnostic,
and therapeutic method exists (emphasis
added).
)‫(ادامه‬
‫دارونما‬
Declaration of Helsinki (October 2002 statement)
... a placebo-controlled trial may be ethically
acceptable, even if proven therapy is available,
under the following circumstances:- Where for
compelling and scientifically sound methodological
reasons its use is necessary to determine the
efficacy or safety of a prophylactic, diagnostic or
therapeutic method, or - Where a prophylactic,
diagnostic or therapeutic method is being
investigated for a minor condition and the patients
who receive placebo will not be subject to any
additional risk of serious or irreversible harm.
‫رضايت نامه‬
Consent - legally effective agreement of the
subject or the subject's legally authorized
representative based on information that is
given to the subject or the representative in
language that is understandable
Assent - child’s affirmative agreement to
participate in research
Permission - agreement of parent(s) or
guardian to the participation of their child or
ward in research
)‫(ادامه‬
‫رضايت نامه‬
Objectives of Informed Consent
To Ensure:
Voluntariness
Comprehension
Information
To Demonstrate That:
Person freely gave consent to participate
Consent given by a competent person
Person has been given all information
Person knows this is research – not
treatment
)‫(ادامه‬
‫رضايت نامه‬
Components of Informed Consent
Must Include the Following Information:
Why research being done?
What researchers want to accomplish?
What will be done and for how long?
Risks & benefits of trial
Other treatments available
Can withdraw from trial whenever desire
Compensation for unexpected injuries
‫كارآزمايي باليني در گروه هاي خاص‬
‫داوطلبين سالم (فاز ‪ 1‬كارآزمايي باليني)‬
‫افراد با دانش و آگاهي محدود (كودكان‪ ،‬افراد با اختالالت‬
‫رواني يا اختالالت يادگيري)‬
‫افراد با اختيار محدود (زنداني ها‪ ،‬دانشجويان‪ ،‬كارمندان)‬
‫افراد با توانايي و منابع محدود (بيماران با بيماريهاي شديد‪،‬‬
‫فقرا‪ ،‬كشورهاي فقير‪ ،‬اقليت ها)‬
‫كارآزمايي باليني با داوطلبين سالم‬
‫در کارآزمايي واکسن و فاز ‪ 1‬کارآزمايي دارويي‬
‫غربالگري سالمتي‬
‫حداکثر ميزان نمونه گيري خون‬
‫كارآزمايي باليني در افراد با دانش و آگاهي‬
‫محدود‬
‫محدود به مواردی که اين افراد بيشترين فايده را از‬
‫بهبود شيوه درماني ميبرند‬
‫قبالً حداقل خطر در مطالعات ثابت شده باشد‬
‫رضايت نامه از فرد‬
‫كارآزمايي باليني در افراد با اختيار محدود‬
‫جذب داوطلب از کارمندان و دانشجويان‬
‫زندانيان‬
‫كارآزمايي باليني در كودكان‬
‫موارد خاصی که تنها کودکان را گرفتار ميکند‬
‫تعيين اثر بخشی و دوز مناسب در اطفال‬
‫قبالً در بالغين اثر بخشی و عوارض قابل قبول ثابت‬
‫شده باشد‪.‬‬
‫رضايت والدين ‪ +‬رضايت کودک‬
‫رازداری‬
‫كارآزمايي باليني در افراد با توانايي و منابع‬
‫محدود‬
‫تضاد منافع (‪)Conflict of interest‬‬
‫محققين‬
‫مراكز تحقيقاتي‬
‫شركتهاي دارويي‬
‫تضاد منافع‬
‫(محققين و مراكز تحقيقاتي)‬
)‫(شركتهاي دارويي‬
‫تضاد منافع‬
Does the for-profit motivation of
industry create un-ethical research?
Cost of developing one drug from
discovery to market: $250-500 million
Average development time- 10 years
3000 drugs in clinical testing each year
60-75 new drugs filed in NDA each year
6-12 new drugs approved each year
)‫(شركتهاي دارويي‬
‫تضاد منافع‬
Do companies design studies likely to
favor their products?
Protections for
Financial Conflicts of Interest
Disclosure
To institution/IRB/COI committee
To patients
In journals
Management
Data safety and monitoring boards (DSMBs)
Independent consent monitors
Prohibitions
Against types/amounts of financial interests
By removing researchers from study
‫پرداخت غرامت در كارآزمايي باليني‬
‫كميته هاي اخالق و كارآزمايي باليني‬
IRB responsible for such tasks:
Review research to ensure that potential benefits outweigh
risks
Develop and issue written procedures
Review research for risk/benefit analysis & proper
protection of subjects
Issue written notice of approval/disapproval to the
Investigator
Review and respond to proposed protocol changes
submitted by the Investigator
Review reports of deaths, and serious and unexpected
adverse events received from the Investigator
Conduct periodic continuing review of the study, study
risks, selection of subjects, privacy of subjects,
confidentiality of data, and the consent process
‫انتشار نتايج كارآزمايي باليني‬
‫‪International Committee of Medical Journal Editors‬‬
‫نويسندگان‬
‫سپاسگذاري‬
‫نامه روی مقاله‬
‫ويراستار‪ ,‬مرورکننده و ناشر‬
‫مالکيت نتايج‬
Authorship
conception and design, or analysis and
interpretation of data, or both
drafting the article or revising it for
critically important intellectual
content
final approval of the version to be
published.
Acknowledgements
contributions that need acknowledging but do
not justify authorship (advice, critical review
of study proposal, data collection,
participation in clinical trial)
acknowledgements of technical help
acknowledgements of financial and material
support
financial relationships that may constitute a
conflict of interest.
covering letter
information on prior duplicate publication
or submission elsewhere of any part of the
work
statement of financial or other
relationships that might lead to a conflict
of interests
statement that the manuscript has been
read and approved by all authors
the name, address, and telephone number
of the corresponding author
Editors, peer reviewers and publishers
Acceptance or rejection of articles
should be on scientific grounds only
Peer reviewers must respect and
maintain the confidentiality of the
unpublished information to which they
have privileged access
Ownership of results
original data must be held by the
sponsoring institution
Copies of all data may be taken by the
researcher