ASGT RESPONSE TO FDA PROPOSED RULE: APRIL 16, 2001 

Dockets Management Branch (HFA-305)
U.S. Food and Drug Administration
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Rockville, MD 20852
301/827-6880

Dear Sir or Madam,

The American Society of Gene Therapy has reviewed the Proposed Rule "Availability for Public Disclosure and Submission to FDA for Public Disclosure of Certain Data and Information Related to Human Gene Therapy or Xenotransplantation" (Display Date: 1-17-01, Publication Date: 1-18-01) and has the following response.

The Society wishes to acknowledge the invaluable role the FDA has played in the design and oversight of gene therapy trials. The Agency is uniquely qualified and experienced to provide this oversight function. The growth and complexity of gene therapy warrants increased resources for the Agency to continue its vital function. Nevertheless, the Society questions the assumption that the Proposed Rule will provide added value to existing regulatory oversight. Furthermore, the Proposed Rule may have serious negative impact on research subjects by the release of incomplete data. In addition, the Proposed Rule has the potential to seriously impede the commercial development of gene therapy products, thereby delaying the introduction of novel and more effective therapies.

The Society's objection to the Proposed Rule is best illustrated in the following statement contained within the document:

"Thus, information of the kind FDA proposes to disclose concerning clinical trials on human gene therapy and xenotransplantation is already widely disclosed. This disclosure has not impeded commercial development of these products".

First, the Society does not believe the FDA can support the claim that disclosure has NOT impeded commercial development. The absence of commercial gene therapy products on the market makes this assessment all but impossible, and what limited surrogate data are available in fact suggest that disclosure does indeed adversely affect development, as illustrated by the decreased number of IND submissions following the disclosures surrounding the death of a patient receiving adenoviral vectors. Of note, this incident affected all gene therapy protocols, including those using entirely distinct gene transfer technologies. Hence the Society believes that placing all gene therapy products under one umbrella will prove misleading to the public and will impede the development of new therapies. Any Proposed Rules should not needlessly impose cumbersome and expensive reporting requirements on all gene therapy products, regardless of their inherent risk, but should rather seek to ensure product related safety and efficacy are assessed as accurately as possible.

Secondly, the FDA is correct that the information to be disclosed by the FDA is widely available. It is therefore unclear how the FDA's duplication of pre-existing disclosure requirements from other government agencies will add value to the process. The Proposed Rule alters a well-tested system for product development and oversight. Confidentiality between investigators and the FDA has provided the basis for successful drug development for all manner of therapeutic agents. Unlike other government agencies, the FDA is an active participant is study design. It is also uniquely qualified to review toxicology and adverse events, placing them in the context of the product risks and clinical situation. The Proposed Rule may adversely affect the collaborative relationship the FDA has fostered with academic investigators and industry for no obvious benefit.

Of greatest concern, the proposed disclosure does not provide an interpretive context in which to view the information. 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. By releasing preliminary findings without interpretation, the FDA will circumvent the standard statistical methodology used in assessing toxicities. The Proposed Rule has the potential to supply misleading data that may prove detrimental rather than informative to patients and the public at large. The Agency has not provided significant data or rationale to indicate that the Proposed Rule will enhance the informed consent process.

Part of the rationale for the Proposed Rule is to allow the FDA to participate in discussion of a specific IND. But as the Proposed Rule itself points out, the information is in large part available through other forums, such as the Office of Biotechnology. Hence, the FDA is already free to comment on this public information.

The Proposed Rule will greatly complicate the data submission required by investigators. The Society believes the estimates provided by the Agency substantially underestimate the cost and manpower requirements to implement the Proposed Rule. As the Proposed Rule provides no added value to the public, the significant financial and logistical burdens on developers of gene therapy products does not appear to be justified.

Finally, the Agency's decision to group gene therapy with xenotransplantation under similar regulations appears to have little objective basis. The safety concerns associated with each of these processes are unique. Risks associated with transient expression of well-characterized plasmids cannot be equated with xenotransplantation procedures which have the potential to introduce novel pathogens into immunocompromised patients and even into the environment. Imposing requirements on low risk products will inhibit their development. Moreover, the Proposed Rule ignores other products which have similar or greater risk for individual and societal adverse events. For example, blood products can transmit infectious agents. Even conventional small molecule therapeutics, such as those used for cancer, may have mutagenic effects on patients themselves, and on their germ line. It is not clear why gene therapy has been targeted in this way, while other FDA regulated products that pose equal or greater individual and public health concerns have been ignored.

In summary, the Society views the FDA as an invaluable partner in the development of safe and effective gene therapy products. We strongly support increased resources for the Agency to facilitate its oversight mission. However, we do not believe the Proposed Rule provides added value to existing reporting requirements. It misleads the public by asserting that all gene therapy products share similar- and exceptional - risks compared to other therapeutics. The onerous requirements proposed will place additional burdens on gene therapy investigators and are not harmonized with other NIH mandated reporting. They will needlessly impede the development of safe and effective therapies. We urge the Agency to continue its current product-based approach to oversight and to avoid implementing a process-based system, which will ultimately prove costly to the community we all serve.

Sincerely,

Inder M. Verma, Ph.D. President	Kenneth Cornetta, Ph.D. Chair, Clinical and Regulatory Affairs Committee

 cc:  Steven F. Falter (via e-mail 4/17/01)

CBER (HFM-17), FDA
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