Moving from Investigational New Drug Application Annual Reporting to Development Safety Update Reports (DSURs) – A Step in the Right Direction

12 June 2023

The FDA proposed a regulation change on 09 Dec 2022 for Investigational New Drug (IND) annual reporting. They suggested accepting Development Safety Update Reports (DSURs; ICH E2F DSUR) instead of the current IND Annual reports (governed by 21 CFR 312.33). This proposal aims to improve public health, reduce risks, and align with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) initiative. The goal is to harmonize report content and format for the development of safe, effective, and high-quality medicines in an efficient manner. This blog aims to provide a comprehensive understanding of the proposed FDA regulation changes for Investigational New Drug (IND) annual reporting. Through this exploration, readers will gain insights into the proposed regulation and its implications for the pharmaceutical industry.

The new regulation will require IND sponsors to submit annual DSURs that are more comprehensive and informative than the IND Annual Reports currently required under FDA regulations.

The proposed § 312.33(a) regulation states that the annual FDA DSUR is intended to provide a thorough annual assessment of the clinical investigations conducted and safety information collected during the reporting period for an investigational new drug with the intent to:

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Cover the entire scope of a large-scale, international development program designed to support applications for marketing in multiple countries and regions

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Capture data from all clinical investigations (completed and ongoing) conducted on behalf of the sponsors evaluating the drug, including investigations not conducted under an IND (refer § 312.33(a)(1)).

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Facilitate the Sponsor to submit the same annual FDA DSUR for each IND held by the sponsor for that drug.

Divergence between the current IND annual report and the proposed FDA DSUR

E2F DSUR provides important advantages for safety evaluation as compared to FDA's IND annual report as it offers a more comprehensive assessment of the product under development. The table below highlights the major differences between the current regulatory requirements for the IND annual report and those for the proposed FDA DSUR.

Examples of major differences between the current regulatory requirements for the IND annual report and the regulatory requirements for the proposed FDA DSUR *
§ 312.33 topics	Current IND annual report requirements	Proposed FDA DSUR requirements
Scope of information on clinical investigations	■ Requires information about clinical investigations of the investigational drug	■ Expands the scope to require comprehensive information about clinical investigations conducted anywhere in the world
Cumulative exposure	■ Not required	■ Adds the requirement to include the cumulative number of subjects exposed to the investigational drug and comparators.
Safety findings from other sources	■ Not required	■ Adds the requirement that a sponsor submit a brief summary of relevant safety findings from other sources, if known, including noninterventional studies of the drug; pooled or meta-analyses of randomized clinical investigations of the drug.
Serious adverse experiences	■ Requires a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system.	■ Requires a list of all serious suspected adverse reactions as defined in § 312.32(a) that occurred during the reporting period,
Event otherwise omitted from safety tabulations because it is a study endpoint	■ Not required	■ Requires identifying each event omitted from the listings and tabulations of safety data because the event is a study endpoint or a component of a study endpoint.
Summary of important risks	■ Not requied	■ Requires providing a cumulative listing and a brief description of all important known and potential risks associated with the drug identified by the sponsor during the course of studies of the drug conducted on behalf of the sponsor.
Exceptions for sponsor-investigators	■ Provides no distinction between sponsor-investigators and other sponsors	■ States that a sponsor-investigator for a clinical investigation not intended to support a marketing application is required to submit only information obtained from the clinical investigation conducted by the sponsor-investigator

*Although current annual reporting practices may go further than that required by the current regulations to be more consistent with the E2F DSUR, this table only highlights the regulatory requirements and not common practices.

Benefits of this Proposed Regulation

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Enabling FDA to more efficiently identify and review new safety signal information

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Creating a more efficient reporting process for certain sponsors by supporting a more comprehensive format for submission to FDA and multiple regulatory authorities worldwide

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Allowing regulatory authorities worldwide to have access to the same data within the same timeframes.

Impact on Sponsors

If the proposed FDA DSUR requirements are implemented, sponsors would need to submit an annual DSUR that adheres to both the proposed FDA regulations and the E2F DSUR guidelines. These requirements aim to provide detailed information for the FDA to assess clinical investigations conducted by IND sponsors. This includes sponsors of large, multinational clinical development programs seeking marketing approval in multiple countries and regions.

In addition, estimated benefits would include reduced efforts by sponsors who may no longer have to prepare a different type of periodic safety report for submission to certain countries or regions in which a drug might be studied. The need of the hour for sponsors would be to demonstrate agility to adopt the new format, which involves gathering, compiling, and reviewing additional data for inclusion in the DSUR.

As you embrace the new requirements basis this regulation, we would be happy to partner with you in this journey. Indegene’s team of safety writers is abreast with the current ICH E2F regulations and guidelines as well as with the newly proposed FDA’s DSUR requirements while being adept at supporting global pharma companies with the end-to-end activities for DSUR - authoring, reviewing, and submissions in various markets across the globe.

References

US Food and Drug Administration. Investigational New Drug Application Annual Reporting (Proposed Rule) Regulatory Impact Analysis FDA. Last updated: 09 Dec 2022. Available: https://www.fda.gov/about-fda/economic-impact-analyses-fda-regulations/investigational-new-drug-application-annual-reporting-proposed-rule-regulatory-impact-analysis. Accessed: 01 Jun 2023.

Department of Health and Human Services, Food and Drug Administration. Investigational New Drug Application Annual Reporting. Available: https://www.fda.gov/media/163795/download. Accessed: 01 Jun 2023.

Federal Register: Investigational New Drug Application Annual Reporting. Last updated: 09 Dec 2022. Available: https://www.federalregister.gov/documents/2022/12/09/2022-26731/investigational-new-drug-application-annual-reporting. Accessed: 01 Jun 2023.

US Food and Drug Administration. E2F Development Safety Update Report. Last updated: 09 Apr 202. Available: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e2f-development-safety-update-report. Accessed: 01 Jun 2023.

Author

Dr. Shubha Rao

Dr. Aditi Nadkarni

Naveen Kumar Pawar