120514P - REVIEW OF THE STUDY PROTOCOL

Presentation at the Workshop on Research Ethics held at Jazan University 14-15^th  May 2012 by Professor Omar Hasan Kasule Sr. MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Chairman Institutional Review Board and Department of Bioethics King Fahad Medical City Riyadh EM: omarkasule@yahoo.com

1.0 SCOPE:

• The study protocol details the medical and administrative aspects of the study.
• Protocol covers: definition of objectives, the background to the study, definition of the sample and the treatments, methods of data collection and data analysis.

2.0 CHAPTERS OF THE PROTOCOL I:

• Title page, background and Introduction;
• Objectives of the trial;
• Patient Selection Criteria;
• Trial design;
• Therapeutic regimen: dose and toxicity; required evaluations: clinical, laboratory, and follow-up; criteria of evaluation; registration and randomization of patients;
• Forms and procedure for data collection;
• Statistical procedures;

3.0 CHAPTERS OF THE PROTOCOL II

• Administrative responsibilities;
• Informed consent;
• References;
• Regulatory regulations,
• Drug ordering,
• Appendices (consent form etc).

4.0 DEFINITION OF OBJECTIVES AND LITERATURE REVIEW:

• A clinical trial is a serious and expensive undertaking that must not be started before defining clear, specific, and attainable objectives.:
• Once objectives are set, literature review is carried out for similar studies or similar outcomes.

5.0 DEFINITION OF PATIENTS:

• Method of randomization,
• Inclusion and exclusion criteria: criteria should not be too rigid to ensure a homogenous population
• Treatment allocation, and withdrawals.
• Registration procedures must be defined explicitly.
• Rigorous enrollment procedures should ensure that the subject does not have the outcome at the time of enrollment.

6.0 DESCRIPTION OF TREATMENT:

• Treatment response assessment (single-blind & double-blind),
• Protocol departures,
• Definition of end-points and criteria of efficacy,
• Duration and frequency of treatment.
• Type of treatment: single agent, combined modality, or adjuvant therapy.
• Treatment administration includes what to do in case of side effects or adverse drug reactions.
• A schema is a treatment plan in graphic form.

7.0 SAMPLE SIZE:

• The sample size is fixed in advance in fixed sample studies.
• In sequential sample trials no fixed sample size in advance
• What really matters is the number of events and not number of subjects: a study of 1000 patients with 5 events is a weak study.

8.0 DATA COLLECTION I

• The exact methods of data collection must be described in such detail that any knowledgeable person will be able to carry out the protocol without further instructions.
• Measurement of effects and end-points must be defined.
• The data collection section must define the items of data to be collected.

9.0 Data Collection II: Data Items Usually Needed:

• Identification data (patient identifier, trial identifier, and institution identifier),
• Administrative data (names of physicians and research associates),
• Regulation data (institution review board approval, informed consent),
• The case record form (who fills the form and when, standard layout of the form including standard header, number of items, designation of decimal points, unit of measurement used, and definition of alternative responses of unknown, not available or not applicable, not done)
• Coding of the CRF responses (multiple choices, numeric self-coding, non-numeric self coding),

10.0 DATA COLLECTION III: CRF

• The design of the case record form is important for accuracy of data collection.
• In computerized CRF data is entered directly into the data-base
• the choice between online and offline data entry depends on the nature of the study and preferences of the institution.
• Online data entry has the problem that there is no paper record to check for mistakes.
• Sometimes direct data capture is possible from laboratory and clinical measuring instruments.

11.0 DATA-BASE:

• The design of the study data-base includes details of data retrieval and security features.
• The database should be designed such that automatic editing checks are made for eligibility criteria and data inaccuracies as data is entered.
• The system must also be able to check for timely submission of data from the clinical centers.
• The relational data-base is more commonly used than the hierarchical. Attention must be paid to data security.
• Audit trails for changes made to the data must be updated and available.
• Three groups of study files are maintained: the protocol file with all protocol changes, the regulatory file, and the patient file.

12.0 METHOD OF ANALYSIS:

• The statistical analytic philosophy must be determined in advance.
• The Bayesian approach which requires having a prior probability. The prior probability may be subjective or could be objective based on previous data
• The likelihood approach in which the inference is drawn as the trial progresses. The study is terminated as soon as a significant result is obtained.

10.0 REGULATORY MEASURES:

• Information must be obtained on whether the institution where the research is undertaken is in good standing.
• Is the investigator authorized?
• Are regulatory requirements met?
• Are patients eligible?
• Demographic data.
• Measures to ensure protocol compliance.

11.0 QUALITY CONTROL:

• Quality control measures must be put in place.
• The local clinical site is responsible for ensuring timeliness, completeness, and consistency of data. It must also make sure that patient identifiers are correct and that the necessary privacy measures have been taken.
• The coordination center is responsible for systematic review of the data and making sure it is complete.
• The following are QA responsibilities of the central data coordination center: eligibility checks, logging data receipt, checking for correct identifiers, checking for data completion, range sand field type checks, logical and consistency checks carried out manually or computerized, assessment of study end-points, clinical review, and feedback to participants.
• A data monitoring committee whose members are independent of the study investigators will monitor issues such as safety data and carry out interim analyses.

12.0 GCP Responsibilities Of The Local Participating Site:

• Ethics committee approval
• Patient recruitment
• Patient informed consent
• Collection and record of data required by the protocol
• Reporting of adverse effects
• Ensuring protocol compliance
• Ordering and storing study drugs.

13.0 GCP Responsibilities Of The Study Coordination Center:

• Confirmation of the ethics committee approval,
• Confirming informed consent,
• Confirming the accuracy of the data by regular visits to the study site,
• Screening qualifications of study personnel,
• Quality control of CRF,
• Monitoring adverse effects,
• Analysis of the trial and report of results.

14.0 LENGTH OF PROTOCOL REVIEW: Department of Anaesthesia, College of Medicine, University of Ibadan, Nigeria

• A 6-year (2002-2007) retrospective audit of the protocols submitted to the HREC was performed to determine the profile of the lead investigator, sources of funding for the research and the duration for review using a 25 item questionnaire.
• A total of 752 protocols were submitted, 618 protocols (82%) were approved while 38 protocols were not approved.
• The principal investigators were mainly postgraduate students (67.1%) while academic staff constituted 21.3%.
• The average time from submission to approval was approximately 21 weeks (95% CI: 20-23 weeks).
• The period from submission to approval is significantly affected by the number of revision required and the funding agent (p < 0.05); it took a shorter time to review internationally funded research.

Source:  Eyelade OR etAn appraisal of the process of protocol review by an ethics review conmmittee in a tertiary institution in Ibadan.  Afr J Med Med Sci. 2011 Jun;40(2):163-9.

15.0 VARIATIONS AMONG IRBs: A Dilemma For Multi Center Trials

• We obtained the institutional review board response from 6 of the 7 participating institutions after initial submission of the Minimally Invasive Surgical Therapies study protocol and classified the responses.
• We then redistributed the approved protocols to an institutional review board at another participating institution and analyzed that review of these protocols.
• We found that the number and type of responses required for institutional review board approval of an identical study protocol varied significantly among participating institutions.
• We also found that institutional review board responses were inconsistent in the second review, although all protocols were ultimately approved.
• Conclusions: The current system of local institutional review board review in the context of a multicenter surgical trial is inefficient in the review process and may not provide expertise for overseeing surgical trials.
• Based on these results a central surgical institutional review board may be needed to improve the ethical review process in multicenter trials.

Source: Helfand BT et al. Variation in institutional review board responses to a standard protocol for a multicenter randomized, controlled surgical trial.

J Urol. 2009 Jun;181(6):2674-9.