ASGT Official Response

February 10, 2001

Dr. Amy Patterson
Office of Biotechnology Activities
National Institutes of Health
Building 1, Room 103
Bethesda, Maryland 20892

Dear Dr. Patterson,

The American Society of Gene Therapy has reviewed the Notice of proposed actions under the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) which appeared in the Federal Register: December 12, 2000 (Volume 65, Number 239). Responding to the call for public comments, the Society would like to address the following points raised in the proposed changes.

The Notices proposes 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. The Society is in full support of the following important modifications:

Public access to information about serious adverse events. The Society agrees with OBA that adverse events, in general and collectively, should be made public and not kept confidential. We also believe that reporting can and should be performed without the release of trade secrets.

Protection of individually identifiable patient information as it relates to serious adverse event reporting. The Society is in full agreement that identifiable patient information should be deleted from OBA submissions to protect patient privacy.

A new mechanism for the review and assessment of data on serious adverse events and other relevant safety information. The general goal of the NIH Gene Transfer Safety Assessment Board, to identify trends in vector toxicity, is an important one.

While the Society agrees with a number of the proposed changes, other issues require further clarification or additional efforts at harmonization. Specific areas which are of concern include:

Interpreting adverse event reporting While the Society strongly favors public disclosure of adverse events, we believe adverse events must be reported in the clinical context in which they occurred. Patient protection is not served if the data presented is preliminary or out of context and therefore prone to misinterpretation. Disclosure of erroneous information can result in extreme distress for study participants and their families. All reasonable safeguards must be in place to prevent such occurrences. We recommend OBA serve an interpretive role, providing linkage between fully investigated adverse event reports and the clinical trial.

Serious adverse event reporting. The Society applauded the efforts of your office to harmonize the reporting requirements for OBA with those of other government agencies, most notably the Food and Drug Administration (FDA). Nevertheless, the use of the term "possibly" related to gene therapy is not harmonized with the FDA. Without strict definition of the term "possibly", there remains the potential for further confusion in reporting. We ask that, if there are to be reporting requirements, the reporting requirements be worded as they are in 21 CFR 312.32 to foster compliance and harmonize completely with FDA reporting requirements.

Harmonization of Submitted Data. OBA proposes a complex format for expedited and annual reporting which differs from that submitted to the FDA. Therefore, uniform reporting will not be achieved with the guidelines as written. We ask that the OBA strive to harmonize reporting with the FDA so that a uniform reporting format be developed and accepted by both organizations. Such harmonization will improve compliance and assist investigators in meeting the ever increasing complexity and cost of clinical gene therapy research.

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.

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.

The Society also asks that OBA work with the FDA to revisit the very onerous task of lifelong monitoring. The Society believes that issues such as the scientific basis for lifelong reporting, patient compliance and inconvenience, and investigator funding and mobility have not been adequately addressed. The Society is willing to bring its expertise and experience to any discussions of this matter.

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 your office. 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.

NIH Gene Transfer Safety Assessment Board The general goal of the safety board, identifying trends in adverse event reporting, is a laudable goal. Nevertheless, the goals of the Board appear somewhat diffuse and better definition would increase the likelihood of the Board contributing to improved safety for gene therapy research participants. The Society believes this Board will provide the greatest impact if there work focuses on (1) long-term horizontal monitoring for trends in safety issues; (2) providing a timely, contextual review of adverse event reporting; (3) providing interpretation of individual events and trends in adverse events based on sound clinical and scientific expertise.

One area which requires clarification is the role of the Board in "developing information that will enhance the development, design, and conduct of human gene transfer clinical trials". Information developed by the Board will be an important resource for investigators in designing clinical trials. Nevertheless, the Society is very concerned if the proposed changes suggest that the Board will take an active role in the design of clinical trials. Design of investigational trials has been a collaborative effort between investigators and the FDA. Trial design is complex and the addition of an another, potentially conflicted, organization is not in line with the ACD Working Group recommendations for harmonization.

The Society also wishes to comment in general terms regarding the increased regulatory role OBA is proposing. ASGT is committed to the ethical conduct of clinical trials with an appropriate emphasis on patient safety. Adherence to these general principles assures that the field will maintain a necessary level of credibility as it develops and advances. 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 two distinct systems of oversight. While some aspect of the proposed Notice attempt to improve harmonization, other proposed changes only solidify the distinct features of the oversight organizations. By default, investigators are forced to contend with two varying sets of requirement and it is not clear that this additional burden proves any added value to enhancing patient safety in human clinical trials.

As you are likely aware, the FDA has also recently proposed changes which affect the oversight of gene therapy trials (Federal Register, Publication Date 1/18/01). It is of great concern to the Society that neither the OBA nor FDA proposals address conflict resolution. Both organizations plan to interpret adverse event reports and influence the design of clinical trials, yet the investigator has no recourse when conflicting directives are given from the oversight organizations.

The reporting requirement proposed by OBA are onerous. Since only NIH-funded institutions are required to comply with these regulations, the proposal may place burdens selectively on academic investigators. It might also serve to decrease or inhibit the use of such institutions as clinical trial sites. While the Society believes the complicated reporting system proposed by OBA is important for public disclosure, it questions whether this significant burden in warranted should the FDA make the information public (as proposed in their recent notice). Public disclosure was a major factor in establishing the requirement for OBA reporting, but the need for such reporting is greatly diminished if the FDA performs this function. The goals of OBA and the NIH Gene Transfer Safety Assessment Board could proceed as the information is public. FDA-based data collection also increases the information available to OBA, as the FDA will presumably be reporting gene therapy information from both NIH-funded and industrial sources. If the FDA is going to adopt a major role in the matter of public discussion of gene transfer, then it is appropriate for the NIH to reconsider its position with regard to oversight.

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 apparent lack of harmonization between OBA and the FDA. The potential for conflicting regulatory bodies jeopardizes compliance, may present onerous regulatory requirements for gene therapy investigators, and could negatively effect development. We remain committed to excellence in gene therapy clinical trials, patient protection, and public disclosure and offer the scientific and technical expertise of the Society as OBA strives to meet the challenges of monitoring gene therapy clinical development.

Sincerely,

Inder M. Verma, PhD
President
American Society of Gene Therapy
611 East Wells Street
Milwaukee, WI 53202