Essential Elements of Clinical Trial
Essential Elements of Clinical Trial
Essential Elements of Clinical Trial
13 – Essential Elements in
Clinical Trial Assessment
L1 Lourenco; 28.01.2008
Disclaimer: the information within
this presentation is based on the
presenter's expertise and
experience, and represents the
views of the presenter for the
purposes of a training workshop
2
Overview
• Sufficient evidence (safety, efficacy,
and quality)
• Enabling regulatory framework
• Good review practices when
assessing a clinical trial
• Challenges & strategies
• Lessons learned from the Canadian
experience
3
Sufficient Evidence
• Sufficient evidence signifies a positive benefit-
to-risk ratio based on a sum of all of the
following:
– Acceptable Quality (CMC) for the phase of
development
– Acceptable supporting nonclinical and clinical data
(as applicable) for the phase of development, type of
drug and/or disease target
– Acceptable protocol and informed consent form for
the proposed trial
– Maintenance of the positive benefit/risk ratio during
the conduct of the trial through safety monitoring of
the trial as well as other ongoing trials with the drug
(‘product life-cycle’ approach) 4
•SUADRs
•Other
2 - CTA Review
and
3 - Trial is information
conducted
Documentation
5 - Trial
completed
Regulatory Framework must be Enabling of
Sound Benefit / Risk Assessment
Regulatory Framework
• Regulations must aim to protect clinical trial
subjects and enable sound benefit / risk
assessment, without unduly restricting research
and access
• Regulatory requirements should take into
consideration the global context
• Gobalization: adopt international guidelines
where possible
• Address regional-specific issues by developing
region-specific guidelines
• Guidance documents on process, format, and
content, of clinical trial applications should be
available 6
Good Review Practices Overview
• Regulatory expertise
• Scientific expertise
• Time management
• Documentation
• Systematic approach to review
• Review of subsequent
information – life cycle approach
7
Good Review Practices (1)
• Regulatory expertise:
– Know the applicable regulations
– Know the applicable guidelines
– Know the difference between regulations and
guidelines
• Regulations are mandatory requirements
• Guidelines are supported by regulations but allow flexibility in
requirements when acceptable scientific rationales are
presented
– Check prior decisions that were precedence-setting and
ensure consistency
– Use a case-by-case approach for infrequent scenarios
8
Good Review Practices (2)
• Time management:
– A good review takes time, therefore, do the
preliminary assessment as soon as possible taking
into consideration the time available
– Prioritize applications that may present problems
following initial overview / screen
– Major issues should be communicated to the sponsor
as early as possible to allow time for discussion and
resolution
– Strive for issuing requests for additional information
once the entire data package has been reviewed
11
Good Review Practices (5)
• Documentation:
– Documentation of the review of the clinical
trial should be accurate and concise,
including information about the drug, sponsor
and manufacturer, protocol number, title of
the study, and the regulatory tracking
number(s) assigned to the clinical trial
application
12
Good Review Practices (6)
• Documentation (continued):
– Both the clinical and quality (CMC) review reports
should include a section where the reviewer
summarizes the essential quality and clinical
elements in the proposed clinical trial presented by
the sponsor, along with the reviewer’s comments and
thought processes in the analysis of the information
13
Good Review Practices (7)
• Documentation (continued):
– Any deficiencies identified during review
should be described along with the outcome
of all discussions with colleagues, managers,
experts, or communications with the sponsor
to resolve the deficiencies
22
Good Review Practices (16)
• Review of amendments:
– The amendment should be supported by a sound
rationale from the sponsor
– Protocol text changes should be clearly identified
– Changes to CMC should be supported by the
necessary data
– Review should assess
• overall impact on safety, including monitoring
• altered statistical analyses plans, including interim
analyses
• impact on evaluation of efficacy
• impact on informed consent form
• any SUADRs that have been reported
23
Good Review Practices (17)
• Review of notifications:
– Changes to the protocol or CMC should be
clearly identified, and include a rationale for
the notification
– Assess impact on:
• safety of trial subjects, including monitoring
• evaluation of efficacy
• informed consent form
• A review of SUADRs may be warranted
24
Good Review Practices (18)
• Review of SUADRs:
– Integrate clinical trial reports with post-market
reports
27
Good Review Practices (21)
– Premature discontinuations should include a
sound rationale from the sponsor and indicate:
• The impact on planned or ongoing trials
• That all investigators, including those of other
ongoing trials, have been informed
• That all left-over trial drug has been retrieved
– The review is aimed at assessing:
• Impact on the safety of trial subjects from the
discontinued trial, as well as patients in ongoing or
planned trials
• Impact on informed consent forms
• Whether the sponsor fulfilled the regulatory
requirements as stated above 28
Challenges
• A variety of types of clinical trials signifies that a
small group of clinical reviewers have to cover a
broad knowledge base on different disease
areas, which has the potential to lead to ill-
informed decisions: “ignorance of ignorance”
• Increased complexity in science, types of
products, and treatment of disease (e.g., gene
therapies, product combinations,
nanotechnologies)
• Despite the degree of complexity, reviewers
have a short time frame to arrive at a review
recommendation 29
Strategies (1)
• Always approach a review with a perspective of
safety
– Regulatory requirements must be met
– Alternate approaches to guidelines could be
acceptable, however, the reviewer should ask for a
rationale from sponsors if there is inconsistency
between the sponsor’s proposal and the guidelines
• Question your knowledge, and discuss issues
with colleagues and managers: do not work
alone!
• Maintain, and make use of, internal expertise or
established external expertise such as scientific
advisory committees
30
Strategies (2)
• Review the decisions by other regulators
• Discuss issues or concerns with sponsors
• Others will also be reviewing the trial, including,
but not limited to:
– REBs
– Qualified investigators
– DSMB
• Record decisions for future reference
• Keep-up with the science
31
New Clinical Trial Regulations:
Canadian Experience (1)
• New regulations typically go through extensive internal
and external consultations before implementation
• Important to:
– Develop and release guidance documents at the time of
implementation of the regulations
– Be aware and address new scope of the regulations
32
Canadian Experience (2)
• Division 5 of the Canadian regulations is only 6 ½ years
old; previous regulations were from the early 60’s:
– Main changes brought by new regulations were:
• Incorporating GCP into regulations
• Broader scope, encompassing off-label trials
• Inspection program
37
Thank You!
38