Some years ago, the CRO I worked with (Emmes) developed a standardized form as a starting point for so-called Transfer of Regulatory Obligations (TORO) agreements between a Sponsor and the CRO. Our basic TORO form outlined those possible responsibilities in a long table, any one of which could be transferred to us at the CRO under our contract or other agreements. It cited both ICH GCP (E6, Section 5.2), and U.S. Federal regulations. As a template form, it got updated as needed for individual sponsor needs as well as the CRO's expectations and current regulations and guidance. The TORO form could even include reference to 3rd parties, like another co-sponsor or coordinating center, with whom some contractural agreements mixed with TORO elements assigned to the CRO. The TORO table cited each applicable regulation element by element, e.g., 312.56(a). The list also included a few items not listed in the 312 regulations per se, like who was responsible for submitting the study information to clinicaltrials.gov or another applicable registry (
42USC282(j)) and completing Form FDA 3674.
A separate version of the TORO form was developed for device trials, in consideration that the same TORO idea is not expressed in the 812 regulations. Of course, the same issues exist in terms of who was expected to be responsible for doing what in a device trial as they would in a drug trial. (Please don't argue that a Sponsor cannot do this transfer in device trials. They obviously do it all the time with the understanding that the Sponsor is always ultimately "responsible" for anyone they contract as a vendor for services.) The same can be said about drug trials, in that the ultimate responsibility lies with the Sponsor, and the Sponsor has an unending obligation of oversight for their vendors, including everything they assign to a CRO or other entity.
For each element on the TORO tabular listing, we had default columns to mark for "Retained by Sponsor," "Transferred to CRO," or "Shared." If any item was considered Shared, some explanation was required to annotate the agreement and clarify what sharing meant. E.g., CRO finds, qualifies and nominates investigators, and the Sponsor approved the selections (or not). Alternately in that example, the Sponsor, who may know nothing about how to find and select qualified investigators (this happens more often that you might think!), leaves all that to the CRO per the TORO agreement, including the approval of those selected. Same goes for who writes the clinical protocol, the investigator's brochure, the statistical analysis plan, who selects monitors and performs adequate monitoring activities, who develops the database and collects the data, writes the annual reports, safety reports, supplies the Medical Monitor and manages a DSMB, etc. (Sounds like what most CROs do.) The TORO form itself could be an addendum to, or a separate item with, other contractural agreements the CRO has with the Sponsor. As a clear TORO summary, signed by both (all) parties, the tabular form itself would be included in an IND submission to let FDA know who was responsible for what. (The IND submissions themselves would be just another task that could have been transferred to the CRO to perform independently, or prepared by the CRO and subsequently approved by a Sponsor representative, of course.)
In some cases, yes, the Sponsor may simply transfer "all" regulatory obligations to another entity (e.g, the CRO). If this is so, a tabular TORO agreement form may not really be needed (though it remains a useful checklist). Notification about this to FDA is stated simply by checking the Box 15 on the Form FDA 1571 in an IND submission and identifying the TORO details on the Continuation Page as, "All responsibilities transferred to..." the CRO named there, or other language to that effect. The Continuation Page alternately would state the name of the CRO and refer to the TORO form like we used that would be attached with the IND submission, giving the details of what was retained, transferred or shared. For a device submission, an IDE application or supplement would deliver similar information to FDA.
In our many years of experience with this TORO agreement method, FDA has never expressed problems with such agreements. It also helped assure that BIMO inspectors were heading to the correct entity location, should a Sponsor inspection visit be scheduled. In many ways, the TORO was a tool to help direct FDA to the specific places that actually had the data they might want to examine. It meant FDA was informed about who held the collected clinical study data, Sponsor data about the investigators, drug distribution centers, IND regulatory files, specialty testing laboratories, monitoring records, etc., as opposed to just "the Sponsor." Sometimes, all this is managed and kept by the CRO, sometimes not. A good TORO agreement should detail who does what and who retains specific Sponsor records for inspection as required by the regulations and GCP.
Hope that helps.
Best regards,
Jan
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Jan S. Peterson, MS, CCRA, RAC, ASQ CBA, ACRP-CP
Consultant and
VP of Regulatory Affairs and Quality
Global Regulatory Partners, Inc.
United States
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Original Message:
Sent: 08-Apr-2020 16:33
From: Tom Stothoff
Subject: CTD section 1.3.1.4 Transfer of Obligations
We are in the process of drafting the Transfer of Obligations for the CRO's we've contracted to handle our clinical studies and there is some difference of opinion regarding whether a few of the responsibilities should be considered transferred to the CRO.
312.53(a) - Selecting qualified investigators. In my limited experience I've seen this checked as a transferred responsibility to the CRO, but the argument here is that while a CRO may identify investigators it is up to the sponsor to ultimately approve (i.e. select) the investigators.
312.56(a) - The sponsor shall monitor the progress of all clinical investigations being conducted under its IND. I typically see this checked as a transferred responsibility to the CRO. The argument here is that if a sponsor is conducting multiple studies under an IND, then the sponsor is responsible.
312.56(c) - The sponsor shall review and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from the investigator. The sponsors shall make such reports to FDA regarding information relevant to the safety of the drug as are required under 312.32. The sponsor shall make annual reports on the progress of the investigation in accordance with 312.33. I typically see this checked as a transferred responsibility to the CRO. The argument here is that the sponsor is responsible for submitting "such reports to FDA" and therefore this is not the responsibility of a CRO.
I think some of these are open to interpretation (especially 312.53(a)). I also believe that if the responsibility is shared by both the sponsor and CRO then it should be checked as a transferred responsibility.
Would appreciate any feedback by my regulatory colleagues in regards to what they've experienced.
Thank you.
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Tom
Senior Director, Regulatory Affairs CMC
Chicago
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