December 18, 2001

Office of Information and Regulatory Affairs
Office of Management and Budget
New Executive Office Bldg.
725 17th Street, N.W.
Room 10235
Washington, D.C., 20503

Attn: Desk Officer for NIH

Dear Sirs,

The American Society of Gene Therapy (ASGT) has reviewed the Notice of Actions under the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) which appeared in the Federal Register: November 19, 2001 (Volume 66, Number 223). Responding to the request for comments, the Society would like to address the following points raised in the changes.

The Notices makes certain changes to the NIH Guidelines which are well reasoned and will enhance the development of gene therapy. Most notably, the goals of public disclosure and rapid identification of trends in adverse events reporting improves patient protection from research risk and is an objective the Society remains firmly dedicated to. Nevertheless, the Society continues to have considerable concerns regarding the proposed changes. Specific areas which are of concern include:

Inclusion of new sections not present in the initial Proposed changes. A new appendix, Appendix M-I-C-5. Confidentiality has appeared in the November 19, 2001 Guideline changes that has been added since the publication of the Proposed changes of December 12, 2000. This section is highly controversial and we believe this section should be open to public comment before implementation. As written, it appears that OBA will have the ability to release information designated by a sponsor as confidential commercial or trade secrets. The decision to release this information will be based on OBA's own interpretation of the confidential nature of the information or on OBA's assessment of the public interest. There is also no stipulation for mediation when sponsors disagree with OBA decisions to release information labeled as confidential. The ASGT shares with NIH the view that patient safety is the highest priority. However, it is critical both for patient safety and for continued progress in the field to maintain the voluntary participation of industry in OBA oversight activities, and it appears that the new guidelines would be a significant disincentive to that participation. Therefore, we urge proper public comment be sought on these changes.

Change of wording which confuses reporting requirements: The proposed changes of December 12, 2000 were modified so that Section I-E-10 now reads "risk information available in the current investigator's brochure." where the term investigator's brochure replaced protocol. According to FDA requirements, all studies will have a protocol but not all studies are required to have an investigator's brochure (only those studies performed at multiple sites). In order to submit severe adverse events (SAEs), investigators not currently required to submit an investigator's brochure to the FDA will now be required to develop such a document to be in compliance with OBA. This adds additional reporting burden that was not outlined in the original Proposed changes.

Animal studies; The Notice requires that "Any finding from tests in laboratory animals that suggests a significant risk for human research participants..." be reported in an expedited fashion. The Society is very concerned about the lack of definition of "Any finding". The Society agrees that prospective studies aimed at assessing the safety of gene therapy should be supplied to OBA. Also, data which become available from well designed studies which document a significant safety concern should be reported. Furthermore, data obtained from such studies which suggest risk should be reported in an expedited manner. Our concern relates to studies which are not designed to assess safety. Animal studies are performed for a variety of different reasons. There is precedence where anecdotal reports, performed without appropriate controls, provided animal data which was misleading. Public disclosure of the initial information without the proper context could have resulted in major harm to the field.

As written, the Notice could be interpreted that each unanticipated animal death must be reported in an expedited manner. Furthermore, the level of analysis required to determine the cause of death is not specified. Understanding trends in toxicity that occur in the course of animal work is important and should be reported. Determining the cause of an isolated toxicity during preclinical experiments presents an onerous task to basic researchers which will hinder development. As written, compliance with the reporting of animal studies will be difficult and may be misleading unless further clarification is provided. The potential amount of additional paperwork generated from this poorly worded stipulation is overwhelming.

As these Guideline changes are new and will require significant reporting burden, we ask that an assessment be performed so that the estimated impact of these regulations be available prior to implementation.

Length of Reporting Requirements; The proposed changes indicate that reporting is required "until the trial is completed". This term requires further definition. In general, a completed trial is one closed with the institutional IRB. Nevertheless, some investigators have been asked to conduct lifelong monitoring of patients for adverse events. For example, lifelong monitoring for replication competent retrovirus has been required in a number of retroviral gene transfer protocols. Clarification of "completed" is requested to determine endpoints for the reporting burden.

Reporting Requirements - Phase of Study: The Notice does not specify what type of study will be monitored by OBA. For example, will post-licensure trials or clinical data collected on licensed products be monitored and subject to the same reporting as Phase I and II gene therapy trials? The requirements must be stated clearly in order to insure compliance.

Submission of a technical and non-technical abstract and current protocol on a yearly basis. The requirement to resubmit these documents on a yearly basis is not in harmonization with FDA requirements and appears to be duplicative. Our understanding of current guidelines indicates that all amendments, including a copy of the revised protocol, must be submitted to OBA. Therefore, the most up-to-date documents will already be on file with your office. An alternative is to indicate the date of the last protocol amendment on the annual report. Amendments which require revision of the technical and non-technical abstract could be submitted when the amended protocol is supplied to OBA. A statement in the annual report indicating the abstracts are current would appear to be sufficient.

"Reports from laboratory animal studies must be submitted in a narrative format." While submission of a narrative summary will aid in interpreting animal data, restricting all data to a narrative format may hinder data review by OBA. Clarification of this point is requested.

The Society also wishes to comment in general terms regarding the increased regulatory role OBA is proposing. The Society strongly supports an oversight structure which assures that trials will not proceed until all elements of the risk-benefit ratio are addressed and approved. Nevertheless, we are very concerned that investigators in this field are faced with overlapping systems of oversight. The reporting requirement proposed by OBA and other federal agencies are onerous. By default, investigators are forced to contend with multiple organizations within the NIH, with the FDA, and with OHRP. For example, a serious adverse event (SAE) related to a gene transfer protocol must be sent to OHRP and the institutes local IRB. It must also be reported to the FDA. Both requirements are covered in the Code of Federal Regulations. A Drug Safety Monitoring Board is also now required and must review SAEs. Individual NIH Institutes also has a variety of reporting requirements that must be adhered to by NIH-funded Institutions. In the Guidelines which cover recombinant DNA research, these SAEs must be supplied to OBA and the institutions local Institutional Biosafety Committee (which are overseen by OBA). If the study uses the General Clinical Research Center (GCRC), the National Center for Research Resources of the NIH requires submission and review of the SAE by the institutions GCRC Advisory Committee. Many individual NIH Institutes have requirements of grantees. For example, if the study is performed within a National Cancer Institute Comprehensive Cancer Center, a separate committee required by the NCI must also be notified (the local Scientific Review Board). Other NIH institutes require similar reporting burdens of their grantees. These requirements are not uniform and a centralized, uniform reporting is needed. Also, it is not clear that this additional burden proves any added value to enhancing patient safety in human clinical trials. Developing goals for monitoring, and assessing the effectiveness of regulations will help improve the safety profile for patients entering clinical trials.

In summary, the American Society of Gene Therapy applauds the efforts of OBA in the areas of patient protection and public access of information regarding gene therapy trials. We wish to express our deep concern with the poor coordination between NIH agencies wishing to oversee gene transfer clinical trials. While OBA has recognized the need for such coordination, a greater effort should be made by other Offices and Institutes within the NIH to develop a single reporting structure that is harmonized with FDA reporting requirements. Reporting to the NIH, as opposed to individual Institutes and Offices, will improve compliance, decrease the current onerous reporting requirements, and ultimately improve the development of clinical gene therapy.

Sincerely,

Kenneth Cornetta Chair, ASGT Clinical & Regulatory Affairs Committee	Malcolm Brenner President, ASGT

CC: Amy Patterson, MD