International Conference on Harmonisation; Draft Guidance on E2F Development Safety Update Report (DSUR)

Re: Docket No. FDA-2008-D-0386: International Conference on Harmonisation; Draft

Guidance on E2F Development Safety Update Report; Availability.

Dear Sir/Madam:

The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments supporting the International Conference on Harmonisation’s (ICH) Draft Guidance on E2F Development Safety Update Report (DSUR). BIO welcomes the DSUR guidance which will help to harmonize global safety reporting requirements for ongoing clinical trials and provide valuable, consolidated safety information for regulatory bodies, investigators, patients, and industry. However, BIO encourages the FDA and ICH to minimize duplication among the DSUR and other reporting requirements and to implement the DSUR in the context of broader changes to the U.S. Investigational New Drug (IND) adverse event (AE) reporting regulations.

BIO represents more than 1,200 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.

BIO SUPPORTS THE APPROPRIATE IMPLEMENTATION OF THE DSUR:

BIO supports this much needed guidance which will help to harmonize the U.S. IND Annual Report and the EU CT Directives Annual Safety Report into one annual report for all participating health regulatory authorities. The guidance establishes a sensible template which will serve as a valuable instrument for reporting pertinent safety information from ongoing clinical trials in a consolidated format that promotes consistency and efficiency. If implemented appropriately, the compatibility of the structure and content of the DSUR with the Periodic Safety Update Report (PSUR) will help health regulatory authorities, investigators, ethics committees and industry access important safety information in a timely and efficient manner.

If the DSUR is universally accepted for aggregate clinical trial safety reporting, this important global standard will promote transparency and efficiency regarding evolving safety data.

Additionally, the information included in the DSUR may help to facilitate developing risk mitigation strategies early on during the premarketing period. We encourage FDA to continue to work towards final agreement among global regulators that the DSUR should be used as a common standard, in order to eliminate redundancy and duplication of efforts.

THE GUIDANCE SHOULD AVOID DUPLICATION WITH OTHER SAFETY REPORTING REQUIREMENTS:

However, the scope of the DSUR is overly broad as currently drafted and the guidance proposes to include information that is usually included in the PSUR, as the guideline itself acknowledges.

Submitting duplicative information does not contribute to patient safety and well-being and places an unnecessary burden on the sponsor.

In order to avoid or minimize significant overlap and duplication of report content between the DSUR and PSUR, BIO recommends that the DSUR be limited to data from investigational sources. It is not clear why non-interventional/post marketed trial information is being included in DSUR, when it is already submitted as part of the PSUR. Additionally, it is unclear why post market data would be included if the main focus of the DSUR is data from interventional clinical trials. The overlap of information could cause some safety signals to be overestimated.

If the DSUR is not to be totally limited to data from investigational sources only, then there will continue to be considerable content overlap between the two documents. In that case, we request that further guidance be included on the relationship between a DSUR and PSUR and whether cross reference between the documents is a possibility.

THE DSUR SHOULD SERVE AS THE PRIMARY MEANS FOR REPORTING SUSARS TO INVESTIGATORS:

Implementation of the DSUR guidance is an important step towards harmonizing reporting requirements internationally, but BIO believes that the DSUR should be viewed as one element of a larger effort to streamline domestic IND safety reporting regulations. BIO strongly supports ongoing efforts to improve adverse event data collection in clinical trials, reduce the soaring volume of individual case safety reports (ICSRs) that sponsors and clinical investigators file with institutional review boards (IRBs) and independent ethics committees (IECs), and harmonize adverse event reporting requirements. It could be unduly burdensome to industry if the DSUR is implemented on top of other inconsistent or conflicting domestic regulations governing sponsor adverse event reporting obligations during clinical trials, without reducing other current requirements.

Since the DSUR is intended to represent a more efficient and meaningful method to inform investigators, regulatory authorities and ethics committees of emerging safety information during clinical trials, BIO would like to see the U.S. IND requirement to routinely, expeditiously submit suspected unexpected serious adverse reactions (SUSARs) to all investigators harmonized with EU non-IND requirements. The current IND safety report requirement, which is outdated, is overwhelming investigators and institutional review boards with individual case safety reports that are difficult to interpret. Inconsistent or confusing requirements can lead sponsors to adopt the most conservative reporting practice and send SUSARs from nearly any source to all investigators without the important denominator context, such as SUSARs from different studies, spontaneous SUSARs, literature SUSARs, etc.

It is our understanding that EU sponsors of non-IND, interventional studies are only required to submit applicable SUSARs to the concerned competent authorities and to the Ethics Committee concerned, and not routinely to all investigators. When a global trial is conducted under a U.S. IND, however, the IND safety report requirement trumps other requirements and makes it necessary to send all applicable SUSARs to all global investigators.

BIO believes that the DSUR should serve as the primary mechanism to inform investigators of relevant, cumulative safety information with some sponsor interpretation.

If a significant safety issue is identified, either upon receipt of an individual SUSAR or upon review of aggregate data, the sponsor should then issue an expedited communication to all investigators. A safety issue that impacts upon the course of the clinical study or development project, including suspension of the study program or safety-related amendments to study protocols should also be communicated to investigators expeditiously.

In short, DSUR should replace routine expedited reporting of all SUSARs to all investigators with a few exceptions.

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CONCLUSION:

BIO appreciates this opportunity to comment in support of the International Conference on Harmonisation’s Draft Guidance on E2F Development Safety Update Report. We would be pleased to provide further input or clarification of our comments, as needed.

Sincerely,

/S/

Andrew J. Emmett

Director for Science and Regulatory Affairs

Biotechnology Industry Organization