Office of Human Research
SOP No.: 301 CLINICAL PROTOCOL DEVELOPMENT, IMPLEMENTATION AND COMPLIANCE
Author: Office of Human Research
Effective Date: October 1, 2007
Supercedes document dated: N/A
Last Reviewed on: N/A
Results of Review: N/A
This SOP pertains to: All clinical protocols that are developed, reviewed, approved and implemented for FDA-regulated human subject research by Investigators within the Thomas Jefferson University.
Responsibility for executing this SOP: Investigator and Designated Research Personnel
J. Bruce Smith, MD
Associate Vice President for Research
(signature on file at OHR)
Steven E. McKenzie, MD, Ph.D.
Vice President for Research
(signature on file at OHR)
This procedure describes the process for developing, reviewing, approving and implementing clinical protocols and includes all human subject research that is conducted using an FDA-regulated product whether or not there is an IND in place.
2. GENERAL INSTRUCTIONS AND RESPONSIBILITIES
The Investigator is responsible for:
- Supervising the implementation of this procedure. The Investigator may delegate the responsibility for writing the clinical protocol and its associated documents to a designated qualified individual.
- Preparing the initial draft of the protocol, in conjunction with participating Investigator(s), biostatisticians, information technology/database experts and others as appropriate.
- Consulting with the Office of Human Research (OHR) in ascertaining which internal and external regulatory authorities must be included in the overall protocol approval process.
- Forwarding final, internally approved protocols to the FDA (alone or as part of another document) and other applicable external regulatory authorities for their review and approval as required.
- Obtaining all internal and external regulatory authority approvals before enrolling the first participant.
- Ensuring that all participating Investigators comply with the approved clinical protocol.
- Registration of trial at ClinicalTrials.gov
3. SPECIFIC PROCEDURES
3.1 Writing the Clinical Protocol
- General Instructions:
- In general, the FDA permits protocols for phase 1 studies to be less detailed and more flexible than protocols for phase 2 and 3 studies.
- Phase 1 protocols should provide an outline of the investigation and the FDA suggests those protocols specify in detail only those elements that are critical to safety (Reference 21 CFR 312.23(a)(6)(i)).
- For phase 2 and 3 protocols, the FDA requires detailed protocols
- The Investigator will determine who will write the clinical protocol, and who is required to review and approve the clinical protocol.
- Because the protocol is a controlled document, the Investigator will follow the general procedures in SOP 102, Document Development and Change Control to draft the protocol.
- The Investigator will develop a protocol that materially conforms to the protocol template (See SOP 301 Attachment A).
- For investigational medical device protocols, the same format as above should be followed to the extent possible, except that some sections may not be applicable. For example, it may not be possible to perform blinding or randomization procedures for an investigational device study (See SOP 301 Attachment A).
3.2 Review and Approval of the Clinical Protocol
- The Investigator should complete SOP 102 Attachment A, Document Control Form, identifying the draft with the protocol number and a draft version number and date.
- The Investigator will circulate the draft protocol to designated individuals and other experts (e.g., statistician, database developer) to ensure that the proposed clinical protocol is scientifically and ethically sound, and meets all applicable regulations and guidelines.
- The Investigator will repeat the review process until all comments are addressed.
- The final draft protocol will be reviewed and approved by all previously designated individuals by the Investigator and in accordance with departments and University policies (Reference SOP 102).
- Once reviewed and approved internally, the Investigator will give the protocol a version number and approval date. The Investigator will sign the final approved protocol (Reference SOP 102).
- Further changes made to the protocol after approval of the original version requires sequential numbering from the original.
- The Investigator will include the protocol version number and effective date in the Footer of the protocol.
- Certain protocols must be submitted to other external and/or internal regulatory authorities (e.g., the NIH Office of Biotechnology Activities or OBA, the Institutional Biosafety Committee, Radiation Safety Committee) for review before or concurrently with IRB/FDA submission. All protocols involving subjects with cancer must be submitted for approval to the Clinical Cancer Research Review Committee (CCRRC) prior to submission to the IRB.
- For NIH Requirements for OBA-Reviewed Research, and for specific FDA and OBA submission requirements to these agencies. (Reference to SOP 201, Contacts and Submissions for FDA, and SOP 203).
- Protocols for Investigational New Drug (IND) and Investigational Device Exemption (IDE) clinical studies may be submitted to FDA for formal review as part of those IND or IDE submissions, or the protocol may be sent informally for preliminary review (pre-IND or pre-IDE) prior to an IND or IDE submission (Reference SOP 201 for specific procedures).
- When appropriate, the Investigator will distribute the final approved protocol to all prospective participating Investigators.
- The Investigator should access the IRB website for detailed instructions on IRB submission preparation
- The Investigator will submit the final protocol and informed consent form to their local IRB of record, and other applicable regulatory authorities and ensure that other participating Investigators do the same at their institutions.
- The Investigator must obtain a copy of the IRB approval letter from each participating Investigator and place it in the appropriate section of the Regulatory Master File (Reference SOP 503, Documentation and Records Retention).
- The Investigator will not implement the protocol until final IRB approval is obtained, the protocol has been submitted to the FDA and the Investigator is in receipt of the FDA's IND determination either assigning an IND or granting an exemption from filing an IND. (Reference SOP 201).
- If the FDA, the OHRP, the IRB, the Dean of School or any regulatory authority issues a clinical hold the Investigator will not implement the protocol until all issues have been resolved and the clinical hold has been removed.
- Once an IND is in effect, additional new protocols added to the IND may proceed once the IRB approval has been obtained on the new protocol(s) and the OHR has been notified.
- A new IRB-approved significant risk (SR) IDE must be submitted to the FDA. The Investigator must be in receipt of the FDA's IDE determination either assigning an IDE or granting an exemption from filing an IDE.
- Subject enrollment may begin after all regulatory authorizations have been obtained and the OHR has been notified.
- The Investigator may make any editorial or typographical changes to the protocol, as described in the definition for Minor Protocol Changes, at the time of the next protocol amendment submission.
- Changes such as expanding the age of eligibility to participate or capturing new data not previously specified in the protocol or changing other inclusion/exclusion criteria do not qualify as minor protocol changes. These changes are significant changes to the protocol and must be resubmitted to all appropriate internal and external regulatory authorities (Reference SOP 302, Clinical Protocol Amendments).
- The Investigator will retain approved clinical protocols and their attachments, as well as subsequent revisions and any associated correspondence with regulatory authorities and other documents as described in SOP 503.
3.3 Protocol Violations and Waivers
- Any deviation from an approved clinical protocol will be considered a protocol violation.
- Any deviation from the protocol requires an IRB approved protocol waiver prior to implementation. The waiver will describe the nature of the deviation and a rationale for its implementation.
- A deviation to eliminate a hazard or otherwise protect the life or well-being of a participant may be implemented immediately, with IRB, and Sponsor (if applicable) notification of the deviation occurring within five (5) days after the event. For protocols under an IND/IDE such deviations must be reported to the FDA in a protocol amendment submission within five (5) days of the event.
- A protocol for a phase 2 or 3 study (or pivotal device study) should be designed such that, if the Investigator anticipates that some deviation from the study design may become necessary as the investigation progresses, alternatives or contingencies to provide for such deviations are built into the original protocol at the outset.
- If changes to the protocol are determined to be necessary, then the changes should be managed in the form of a protocol amendment (Reference SOP 201 and SOP 303).
- The Investigator must notify the IRB in a timely manner if a protocol violation occurs and the justification for the violation.
- If the protocol waiver is approved by the IRB, the deviation from the approved protocol may be implemented on a one-time basis only, and it should be reported to the IRB as soon as possible.
- If the deviation is considered a necessary change to the protocol and/or likely to reoccur, the Investigator should immediately initiate an amendment to the protocol and an amendment (or supplement if for a medical device) to the IND/IDE (Reference SOP 302 and SOP 201).