A clinical trial is an interventional clinical study, in which participants are recruited for the administration of a specific intervention (use of a study drug, a procedure with a medical device, an educational intervention, etc.). Planning for a clinical research trial includes the development of a clinical protocol document. There are several reasons to have a clear and well-written protocol:
- So that the research plan is clearly defined to everyone who will participate in conducting the study, and all processes and procedures are clearly and completely described to avoid variation in procedures and the introduction of assessment bias into the study conduct
- So that oversight committees and agencies (Institutional Review Boards (IRBs)/Research Ethics Committees, scientific review committees, radiation safety or other committees, and regulatory agencies such as the Food and Drug Administration (FDA)) can review the research proposal in enough detail to ensure that it meets regulatory requirements to grant approval for the research conduct
- So that the endpoints, study design, data collection parameters, and the data analysis plan are prospectively defined prior to the research being conducted, and bias cannot be introduced by changing the design or analysis plan during the study (for this reason, many journals now require public posting of the full research protocol along with the publication of study results).
There are many ways to outline and describe the necessary components of the research protocol and plan, and there are many protocol templates that are available to serve as guidelines for protocol development. In this paper, we are addressing these requirements from the perspective of the IRB. Federal regulations dictate specific criteria against which the IRB must review all protocol submissions, to make an independent determination regarding whether the prospective research plan can be approved. If the protocol (or other documents such as the IRB submission form and consent documents that accompany the protocol in the submission) does not provide adequate or complete information for the IRB to make a determination that all criteria have been met, the IRB cannot approve the research plan. This document is intended to assist investigators and research teams by providing a list of the necessary information that they can use as a writing guide, or use as a checklist against the protocol and submission document package, to ensure that all the necessary information is included prior to submitting the protocol and plan for review by an IRB.
TABLE 1 lists the criteria for the approval of research (paraphrased here from the full regulatory language in 21 CFR 56.111) by an IRB, and describes the information that is necessary for the clinical protocol (or elsewhere in the research plan submitted for review), for the IRB to be able to make determinations regarding whether a research plan can be approved.
TABLE 2 describes additional components or documents that may need to be included, based on specifics of the study product or the study plan.
In addition, all protocol documents should:
- Be final documents. Draft protocols or other study documents should not be submitted for IRB review as the IRB must review final and complete study plans. If edits or changes are made after IRB review, the amended protocol must be resubmitted for approval of the changes.
- Include page numbers and/or section or outline numbering so that the location of content can be identified
- Include a table of contents
- Include some kind of version control notation (either a version number or version date) so that revisions of the documents can be clearly tracked.
TABLE 1: Necessary Information for All Protocol Submissions
Criterion for Approval of the Research Proposal:
That risks to participants are minimized by using procedures that are consistent with sound research design and that do not unnecessarily expose subjects to risk, and whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
Corresponding Information required in the Protocol/Research Plan:
- A clear and detailed list of all study procedures, including screening and follow-up procedures (often in tabular format, describing the procedures to be conducted at each study visit). “Procedures” includes (but is not limited to) study visits; interviews for the collection of safety or other data; vital sign measurements; surveys, questionnaires, or diary completion; study drug administration or other investigational study intervention; invasive and non-invasive procedures including blood draws, radiologic tests or other diagnostic testing.
- The protocol should very clearly define what visits, assessments and procedures would be occurring as part of standard care
- If participants need to leave the study early or suddenly, the protocol should include any specific testing or follow-up that may need to occur for safety purposes.
Criterion for Approval of the Research Proposal:
That risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.
Corresponding Information required in the Protocol/Research Plan:
- Study background that clearly describes the scientific basis for the study, the unmet need, the research question, the rationale for the endpoint selection, and a summary of supporting literature to explain
- the scientific knowledge expected to result from the research project
- the potential direct benefits to individual research participants in the study
- The protocol should also contain a clear and complete description of the study drugs/study intervention including (as appropriate) dosing information, storage information, and criteria for dose modification or dose adjustments.
Criterion for Approval of the Research Proposal:
That the selection of subjects is equitable.
Corresponding Information required in the Protocol/Research Plan:
- Complete and detailed list of all criteria that would make a participant eligible to participate in the research study, and all criteria that would make a participant ineligible to participate in the research study. These are usually provided as two separate lists. If not clear from the background information, the rationale for each criterion should be explained. If a specific population is being included or excluded because of a regulatory requirement or request (for example, a pharmacokinetic study that will enroll only persons of a certain racial or ethnic background) it is helpful to explain that in the protocol.
- Eligibility criteria should be designed to make the study as inclusive as possible while excluding persons with factors or conditions that unacceptably increase the potential risks, or unreasonably confound the measurement of study endpoints
- Consider demographics, medical history and co-morbidities, concomitant medications, and whether the protocol must include testing for the presence or absence of conditions specified in the criteria
- It is not necessary to specify opposite factors in both lists, i.e., if inclusion criterion is age ≥ 18, the exclusion does not need to specify age < 18.
Criterion for Approval of the Research Proposal:
Informed consent will be sought from each prospective subject or the subject’s legally authorized representative.
Informed consent will be appropriately documented or appropriately waived.
Corresponding Information required in the Protocol/Research Plan:
- While the protocol submission must include a written informed consent document, it should also describe the process of obtaining informed consent from participants; how they will be identified and contacted, who will approach them about the study, and how they will be given adequate opportunity to ask questions during the consent discussion
- The written informed consent document must provide all of the elements required by federal regulations
- If potential participants may be incapable of providing informed consent and consent must be provided by legally authorized representatives, the consent process must describe this and the consent form must have appropriate signature spaces
- While there are circumstances in which the regulations allow either a waiver of documentation of consent (no signature) or a waiver of obtaining consent for standard or for emergency research, if a waiver is requested the submission should describe how the proposed research meets the specific requirements for these waivers, and how participants’ rights and privacy will be protected if the waiver is granted.
Criterion for Approval of the Research Proposal:
When appropriate, the research plan makes adequate provisions for monitoring the data collected to ensure the safety of subjects.
Corresponding Information required in the Protocol/Research Plan:
- The protocol should include an adequate description of the safety and efficacy data points that will be collected, including how adverse events will be collected, recorded, graded, and assessed
- How will safety data be monitored on an ongoing basis to identify any unanticipated safety issues during the study? Who will review the data, and will the study include a Data Safety Monitoring Committee, Data Monitoring Committee, or Adjudication Committee?
Criterion for Approval of the Research Proposal:
When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.
Corresponding Information required in the Protocol/Research Plan:
- The protocol or associated documents should describe how the privacy of participants will be protected (including if appropriate how people will be approached about the study and given the opportunity to ask questions in a private setting), as well as how the data being collected will be anonymized or de-identified, stored, transferred and analyzed to maintain confidentiality.
Criterion for Approval of the Research Proposal:
When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, individuals with impaired decision making capacity, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects.
Corresponding Information required in the Protocol/Research Plan:
- Note that federal regulations have specific sections for additional precautions required in the research when research is conducted on children, pregnant persons, and prisoners. Inclusion or exclusion of these groups should be specified in the eligibility criteria.
- Consideration should also be given to whether the protocol should include specific steps for the protection of participants who may be unable to make consent decisions (temporarily or permanently).
TABLE 2: Additional Components to Include when Appropriate
Circumstance or Condition:
If the protocol is evaluating the safety and/or efficacy of a drug, biologic or medical device (even if the drug, biologic or medical device is already FDA approved).
Additional information or documents that must be provided:
The regulatory status of the drug/device must be provided to the IRB, either via
- a description in the protocol,
- the submission form, or
- a copy of a letter from the FDA.
For drugs or biologics, the documentation must include an (Investigational New Drug (IND) number or a regulatory-based rationale for why the product is considered IND-exempt (21 CFR 312.2).
For medical devices, the documentation must specify whether the device is used ‘on label’ (for exactly the same indication and circumstances for which is has already been FDA-cleared or approved) or is investigational. If the device
is investigational, the documentation must include an Investigational Device Exemption (IDE), an NSR justification, or a regulatory-based rationale for why the device is considered IDE-exempt.
When the protocol is evaluating interventions for foods, herbal products, dietary and other supplements, vitamins, and cosmetics, a regulatory-based justification for why that agent is not considered a drug or biologic as used in the research must be provided. Remember that foods that are being researched for possible use as drug products (looking for evidence of action in diagnosing, treating or mitigating a disease or condition) are regulated as drugs.
The IRB must ensure that research is being conducted in compliance with FDA regulations, so submitting appropriate documents or explanations may prevent questions during the review process. If the IRB cannot confirm documentation, or if the IRB is not completely sure that the FDA would agree with the justification for why certain research would not need FDA oversight (i.e., would be IND- or IDE- exempt), the IRB must ask the researcher/sponsor to consult with FDA and obtain documentation that FDA agrees that their oversight is not indicated.
Circumstance or Condition:
Some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant persons, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons.
Additional information or documents that must be provided:
When persons from vulnerable populations may be enrolled in the research the research plan must always specify this and consideration should also be given to whether the protocol should include specific steps for the protection of participants who may be unable to make consent decisions (temporarily or permanently).
Note that federal regulations have specific sections for additional precautions required in the research when research is conducted on children, pregnant persons, and prisoners.
Circumstance or Condition:
The study includes the use of surveys, questionnaires or other instruments (quality of life assessments, etc.).
Additional information or documents that must be provided:
If the protocol includes the use of surveys, all survey questions must be submitted as part of the protocol, an attachment to the protocol, or a supplemental document. If standardized questionnaires or instruments are being used, these must also be submitted. The IRB is required to review all participant-facing materials, including participant diaries and participant recruitment materials [note: some IRBs, including WCG IRB, do not require submission of common, standard instruments such as the SF-36, but if there is any doubt about whether submission is required it is better to add it and avoid possible delays].
Circumstance or Condition:
Study participants must provide written informed consent.
Additional information or documents that must be provided:
The informed consent document must be provided for review and must have all the elements required by regulations.
Circumstance or Condition:
A waiver of informed consent documentation is being requested.
Additional information or documents that must be provided:
In addition to the regulatory-based justification for the waiver (see Table 1), a Participant Information Sheet must be included in the submission.
Circumstance or Condition:
A waiver or alteration of HIPAA requirements is being requested.
Additional information or documents that must be provided:
A regulatory-based justification must be provided specifying how the research is eligible for the waiver or alteration.
Conclusion
For researchers new at conducting clinical research or writing protocols, developing a new clinical trial protocol that is complete and sufficient for the purposes for which it will be needed is often a larger and more time-consuming project that was initially expected. While IRBs are generally happy to provide information and to answer specific regulatory questions in advance of a protocol being submitted, most do not have the resources or capacity to provide one-on-one guidance to researchers who have protocols that need major revisions to meet the criteria for approval.
Researchers may find it best to work with an experienced medical writer or clinical research consultant; while the cost of these services can be significant, this may be the most cost-effective plan when balanced against the time saved by the researcher and the facilitation of the review and approval process when guided by someone who is familiar with clinical research regulations.
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