Guidance for Multi-site Protocols
Guidance to Investigators Submitting Multi-site Trials for NYSPI IRB Approval
In a multi-site trial, there will be a national protocol. The local NYSPI protocol, the PSF, should be used to create a record of the local protocol that is both an accurate reflection of the national protocol, and that operationalizes judgments or procedures that need clarification. Specific examples follow:
1. Eligibility criteria. Eligibility criteria in multi-site trials sometimes include somewhat vaguely worded criteria, such as: “No serious, unstable medical or psychiatric disorders that in the opinion of the Investigator would preclude safe participation in the study.” The NYSPI IRB often accepts that this is ultimately a clinical judgment, but the NYSPI IRB typically wants the basis upon which this judgment is made to be more clearly operationalized. So, for example, the PSF might add to this stated criterion something like the following: “Examples include schizophrenia, bipolar disorder, untreated major depression, or current moderate to severe substance use disorders.”
2. Discontinuation criteria. Similarly, national protocols often have vague discontinuation criteria, something like: “In the opinion of the investigator the participant is not safe to continue in the study.” The PI IRB is typically concerned that participants not continue in protocols if the participant is either not improving after a reasonable trial of therapy in the study, or if the participant is worsening. Participants who are unimproved or worsening should not be prevented from accessing other effective treatments because of study participation. The NYSPI IRB, again, often accepts that this is ultimately a complicated clinical judgment, but typically asks that criteria be operationalized that would trigger an evaluation as to whether a patient should continue. For example: “A CGI severity improvement score of 4 or greater (no improvement) after at least 6 weeks of treatment, or a CGI improvement score of 6 or greater (much worse or very much worse) on any occasion, will trigger a clinical evaluation regarding whether the patient should continue in the study, or be removed and started on or referred to other treatment.”
3. Lay Summary and Background sections. Comprehension of the PSF is enhanced by Lay Summary and Background Sections that clearly and in plain language explain the scientific and public health importance of the proposed study. National protocols do not always read this way, as they are sometimes written in a more technical way for Sponsor or regulatory agencies. Thus, Investigators are encouraged to take the time to write a Lay Summary and Background section that translate the summary and background in clear language (non-scientific audience).
4. Consent Form. Consent forms (CFs) need to contain NYSPI-IRB required language in certain sections, and need to conform to the NYSPI-IRB format. However, beyond that, the CFs provided by the sponsor of a multi-site trial sometimes contain elements that NYSPI-IRB does not usually favor. For example, CFs sometimes contain lists of all the procedures carried out for each study visit, going on for many pages. The NYSPI-IRB typically favors shorter consent forms. The NYSPI-IRB’s main concern is that overlong CFs interfere with the informed consent process, by providing a document where the main important issues of risk and alternatives and so forth can get lost in all the details. However, NYSPI-IRB will consider accepting such elements (such as long lists of procedures) if it is justified and offset by other features. For example, a clearly worded Cover Summary Sheet helps to provide potential participants an overview before launching into the details of the main consent. Also helpful are explicit details in the PSF about the consent process and how sufficient time will be allotted for review and discussion of the CF.
5. Risks and Protections. Risks, particularly of new medication treatments, will already have been assessed by sponsors and agencies such as FDA. However, the NSYPI IRB needs to make its own assessment of risks and protections. To this end, PIs should be sure to review the Investigators’ Brochure and ensure that all significant potential risks are addressed in the PSF. The risks should be reasonable and the protections adequate. It is helpful to include a discussion clarifying the PI’s thinking on the rationale for why the risks are reasonable and the protections adequate.