profile of the overall trial design. Good Quality
Schedule of Assessments sections also include
acceptable time windows around the variables
being collected that can minimize protocol
deviations.
The inclusion and exclusion criteria are
described in the Subject Selection part of the pro-
tocol. To a large extent, the success or failure of a
particular clinical trial can often be traced back to
how well these criteria were developed. Good pro-
tocol authors strive to include the most appropriate
patient population to satisfy the study objective
and still include those kinds of patients who will
ultimately receive the drug. Therefore, selection
criteria can be unreasonable and unnecessary in
some cases and vague and not specific in other
cases. The management of concomitant medica-
tions is particularly problematic. The protocol
must attempt to define those medications that are
permitted for intercurrent illnesses and those that
are prohibited as they will interfere with the inter-
pretation of the test medication. Although there are
noeasyanswers, qualityprotocolsare abletojustify
with some precision the rationale for each inclusion
and criteria. How these criteria are applied is
handled in the Screening for Study Entry section.
The efficacy and safety parameters describe how
and when the variables are going to be recorded,
usually in relation to drug administration and
follow-up periods. How adverse events are mana-
ged and recorded are particularly important to the
sponsor and to regulatory authorities. Protocol
authors should ensure that the study defines the
criteria for success or failure of treatment. End
points should be clear and defined. As many
clinical phenomena are open to interpretation,
protocols should provide definitions of variables
and timewindows for their collection. If the assess-
ments are purely subjective, provision for observer
truing must be provided. Addressing these issues
will improve the quality and meaningfulness of the
results of the study. Training on such assessments
at investigator meetings before the trial starts
proves a valuable investment.
The description of the management of trial med-
ication is often a source of confusion. Protocols
must include clear directions for dosing intervals
and adjustments. Because patients will never fol-
low a protocol precisely in all cases, provisions for
missing doses or ‘what if’ situations should be
anticipated. Good protocols always include, in
addition, adequate compliance checks of drug con-
sumption by the subjects of the study.
Protocols should predetermine how subjects will
be replaced following dropping out of the study.
This is important because the means by which
subjects are replaced can adversely affect the sta-
tistical analysis. Similarly, a decision concerning
the conditions under which a subject would not be
evaluable must be stated explicitly before the study
starts. This is intended to minimize intentional or
unintentional data manipulation.
TheQuality Control/Assurancesectionaddresses
the sponsor’s conduct of periodic monitoring visits
to ensure that the protocol and GCPs are being
followed. The sponsor’s representatives (monitors
or Clinical Research Associates; CRAs will review
source documents to confirm that the data recorded
on CRFs are accurate – this is a fundamental
requirement of quality clinical research. This sec-
tion also alerts the investigator and clinical institu-
tion that the sponsor’s representatives (for
monitoring and/or audit purposes) and possibly
appropriate regulatory authorities (for inspections)
will require direct access to source documents to
perform this verification. It is important that the
investigator(s) and his or her relevant personnel
are available during the monitoring visits and pos-
sible audits or inspections, and that sufficient time is
devoted to the process.
The Data Handling and Record Retention sec-
tion of the protocol will address the requirement to
maintain data (whether on a paper CRF or using an
electronic data collection tool (DCT)) of each trial
subject. It will address expectations of ownership
of the completed CRF data, the investigator’s
responsibility to ensure accuracy and complete-
ness of data recording. This section will also
address the requirements for retention of records
at the trial site in accordance with relevant guide-
lines and regulatory requirements.
The Ethics section of the protocol deals with the
fundamental requirement for prospective IRB/IEC
approvalofthetrialprotocol,protocolamendments,
informed consent forms and other relevant docu-
ments (e.g. subject recruitment advertisements).30 CH3 CLINICAL RESEARCH EDUCATION AND TRAINING FOR BIOPHARMACEUTICAL STAFF