| Comment Record|
Dr. Kevin Anderson ||
2002-02-19 18:11:33 |
Axio Research |
| Comments for FDA General |
1. General Comments
To: Documents Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
From: Axio Research Corporation
2601-4th Avenue, Suite 200
Seattle, WA 98121
Contact: Kevin Anderson, Ph.D., Director of Biostatistics
Date: February 15, 2002
Re: Docket # 01D-0489
On behalf of Axio Research Corporation, we enclose the following comments and questions that relate to the recently published draft guidance by the Agency entitled 'On the Establishment and Operation of Clinical Trial Data Monitoring Committees'. We fully support the Agency’s commitment to the safety and integrity of clinical trials, as reflected in the recommendations for DMCs in the draft guidance. We thank the Agency for its consideration of the points below and hope they are addressed in the final version of the guidance.
1. In the first paragraph, it is stated that “references to the sponsor with regard to trial management and decision-making should be understood to refer also to any individual or group to which the sponsor has delegated the relevant management responsibilities”, which includes Contract Research Organizations (CROs). While CRO could be substituted for sponsor in some statements in the guidance and under some circumstances, it is typical for a sponsor to delegate some specific study responsibilities but little decision-making authority to CROs. For example, it is unlikely that a CRO would have the authority to amend a protocol or discontinue enrollment in an ongoing study. Similarly, although a CRO has an interest in the successful completion of the study (and perhaps financial benefits if a study continues rather than stops early), the CRO and its employees are not typically compensated based on a study’s results or their market implications. Potential conflicts of interest or biases may exist for a CRO, but may not be of the same nature as those of a sponsor. Therefore, we suggest removing the last sentence of this paragraph. Wording such as the following could be substituted: “In some cases, references to the sponsor may also refer to these groups if they have been delegated equivalent responsibility and authority. The responsibilities delegated to Steering Committees or CROs can vary considerably across clinical trials and sponsors. It is important that the responsibilities and authority of the sponsor and any other entity be clearly defined and understood at the start of this relationship. Potential conflicts of interest of each party should be carefully considered when determining roles and responsibilities.”
2. The draft guidance does not address open-label studies. Should a sponsor assume that any or all of the document applies to this situation?
3. Under Section 220.127.116.11, it would be helpful if the guidance would clarify the amount of information about an interim analysis that is necessary to include in the protocol. Under what circumstances would a protocol amendment be necessary if a change is made either to the protocol or the accompanying detailed analytical plan? For example, is an amendment required if the timing of interim analyses is varied?
4. A recommendation on the method and timing for the disposal of closed reports would be helpful.
5. The Guidance appears internally inconsistent on the issue of what material will be included in the open section of the DMC report. Specifically, should safety and event rate data be presented in the aggregate in the open section? Guidance Section 4.2.2 states the open section presents trial conduct issues such as accrual and dropout rates, timeliness of data submission, eligibility rates and reasons for ineligibility and implies that outcome data is only contained in the closed section. This is in disagreement with Guidance Section 18.104.22.168 which states that the open section may include status of recruitment, baseline characteristics, ineligibility rate, accuracy and timeliness of data submissions, and AGGREGATED SAFETY AND OUTCOME DATA [capitals added]. Guidance Section 6.2 states that the open section may include data such as enrollment, compliance, and EVENT RATES [capitals added]. There could be valid reasons why safety and event rate data is or is not included in the aggregate in the open section. At the minimum, the decision for whether to include this aggregated safety and event rate data in the open section should be thought over carefully and the DMC SOPs should very clearly identify whether or not this data is to be presented.
6. We suggest that the Agency briefly address the issue of the use of electronic media (email/the Web) for dissemination of DMC materials (reports, minutes, charters, etc). For example, “Electronic media may be used for transmission, dissemination and archiving of materials used in support of DMCs. In addition to the requirements set forth in 21CFR11 for e-records and e-signature, particular care should be taken to insure restricted access to the unblinded and other sensitive documents.”
7. With a relatively limited pool of qualified experts to serve on DMCs, it is likely that individuals may be asked to serve on DMCs for multiple sponsors investigating therapeutics in the same disease. This could present an apparent conflict of interest since that individual may be privy to confidential information regarding a related or competing product. Opinions differ regarding the appropriateness of an individual accepting responsibility to serve on multiple DMCs in this situation. The simplest approach may be to recommend disclosure by the individual allowing the sponsors to assess the potential conflict and the associated risks. Similar issues arise in the standing DMCs established for therapeutic study groups (e.g., cancer, HIV, and the newer CF and Parkinson's Disease study groups) where the entire Board reviews protocols for potentially competing products. In these situations, study group leadership should be particularly vigilant in selecting DMC members and routinely reviewing potential conflicts of interest.
8. We applaud the Agency's support of traineeship/apprenticeship programs to develop a larger pool of qualified individuals to serve on DMCs. We strongly recommend that the NIH and FDA set aside career development grant funding specifically for this purpose.