FDA Final Rule: Postmarketing Safety Reports for Human Drug and Biological Products

 FDA released a final rule amending postmarketing safety reporting regulations for drugs and biologics so those subject to mandatory reporting must submit safety reports in an “electronic format that FDA can process, review and archive.” The agency says the provisions will enable it to “more rapidly review postmarketing safety reports, identify emerging safety problems and disseminate safety information,” while “harmonizing FDA’s postmarketing safety reporting regulations with international standards for the electronic submission of safety information.” The rule goes into effect June 10, 2015.

Additionally, along with the final rule, FDA also released draft guidance, Providing Submissions in Electronic Format–Postmarketing Safety Reports (available here) in order to “help persons required to submit postmarketing safety reports comply with the final rule.” Comments may be submitted at any time but are due within 60 days of Federal Register publication to be considered before the FDA begins work on final guidance.

I. Final Rule: Postmarketing Safety Reports for Human Drug and Biological Products; Electronic Submission Requirements

The Food and Drug Administration (FDA) is amending its postmarketing safety reporting regulations for human drug and biological products to require that persons subject to mandatory reporting requirements submit safety reports in an electronic format that FDA can process, review, and archive. FDA is taking this action to improve the Agency’s systems for collecting and analyzing postmarketing safety reports. The change will help the Agency to more rapidly review postmarketing safety reports, identify emerging safety problems, and disseminate safety information in support of FDA’s public health mission. In addition, the amendments will be a key element in harmonizing FDA’s postmarketing safety reporting regulations with international standards for the electronic submission of safety information. This rule is effective June 10, 2015.

This document is scheduled to be published in the Federal Register on 06/10/2014 and available online at http://federalregister.gov/a/2014-13480.

For information concerning human drug products: Jean Chung, Center for Drug Evaluation and Research (CDER), Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, rm. 7268, Silver Spring, MD 20993-0002, 240-402-7911.

For information concerning human biological products: Stephen Ripley, Center for Biologics Evaluation and Research (CBER) (HFM-17), Food and Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-827-6210.

II. Summary of the Final Rule

A. Electronic Submission of Postmarketing Safety Reports

The final rule revises current §§ 310.305, 314.80, 314.98, and 600.80 to require that manufacturers, packers, and distributors, and applicants with approved NDAs, ANDAs, and BLAs and those that market prescription drugs for human use without an approved application submit postmarketing safety reports to the Agency in an electronic format that FDA can process, review, and archive. The final rule also adds part 329 to address safety reports required by section 760 of the FD&C Act. Section 329.100 requires that reports required to be submitted to the Agency under section 760 of the FD&C Act be submitted in an electronic format that FDA can process, review, and archive.

Under the final rule, the following reports must be submitted to FDA in an electronic format: Postmarketing 15-day Alert report ICSRs and any ICSR attachments; periodic adverse (drug) experience reports (including the ICSRs, any ICSR attachments, and the descriptive information portion); and section 760 reports. A separate ICSR is to be submitted for each individual patient report of an adverse drug experience, just as separate paper forms have been submitted for each individual patient report of an adverse drug experience. Information on the formats the Agency is able to process, review, and archive is described in FDA guidance and associated technical specifications documents available on FDA’s Web site.

For marketed products with an approved application, manufacturers, packers, or distributors that do not hold the application continue to have the option of submitting 15-day Alert reports directly to FDA or to the application holder under §§ 314.80(c)(1)(iii) and 600.80(c)(1)(iii). If they opt to submit reports directly to FDA, they are required to do so in electronic format. If they choose to report to the applicant, they may submit the report in any format acceptable to the reporter and applicant. The applicant, however, is required to use electronic reporting when it subsequently reports the information to FDA. Similarly, for marketed prescription drug products without an approved application, initial safety reports submitted to the manufacturer by packers and distributors under § 310.305 may be sent in any format agreeable to the reporter and the manufacturer, but all safety reports submitted to FDA must be in electronic format. Under section 760 of the FD&C Act, a retailer whose name appears on the label of a nonprescription (OTC) drug product marketed in the United States without an approved application, as a distributor, may, by agreement, authorize the manufacturer or packer of the nonprescription drug to submit the required reports to FDA (as long as the retailer directs to the manufacturer or packer all adverse events associated with the drug that are reported to the retailer as specified in section 760). The retailer may direct serious adverse event reports to the manufacturer or packer in any agreed-upon format. However, the manufacturer or packer must then send the required reports to FDA in an electronic format that the Agency can process, review, and archive.

This rule will apply to any new postmarketing safety reports for drug or biological products that are implemented in the future (e.g., once finalized, new postmarketing safety reports in the proposed rule to amend safety reporting requirements published in the Federal Register of March 14, 2003, 68 FR 12406). The rule also revises § 600.81, requiring the electronic submission of biological lot distribution reports.

The specific references to submission of postmarketing safety reports in paper format in §§ 310.305, 314.80, 600.2, and 600.80 have been deleted, and language has been added to these sections which states that FDA will issue guidance on how to provide the electronic submissions (e.g., method of transmission, media, file formats, preparation, and organization of files).

In the proposed rule, FDA stated that the agency was developing a Web-based submission portal (for submission of reports to FAERS) that FDA believed might be preferred by entities that submit a small number of safety reports. The Safety Reporting Portal (SRP) (available at http://www.safetyreporting.hhs.gov) allows the secure electronic submission of ICSRs for drug and nonvaccine biological products directly into the FAERS database once information is typed into the Web-based electronic form. The SRP creates a simple and efficient mechanism for electronic reporting that does not require an internal ICH-compatible database. As described in the preamble to the proposed rule, use of the SRP does however require some administrative support to manually enter information for the ICSRs into a Web-based form.

To assist entities that submit a small number of safety reports for vaccines, FDA has made available an eSubmitter tool. The eSubmitter tool is a stand-alone application that can be downloaded free of charge from FDA’s Web site at http://www.fda.gov/forindustry/fdaesubmitter. The eSubmitter application appears as a fillable form, and once the appropriate fields are filled in, an ICSR in electronic format is generated that can be transmitted through the ESG into the VAERS database. FDA believes that the eSubmitter tool generally offers the same benefits as the SRP. As noted in § 600.80(h), FDA will issue guidance providing further information about the electronic submission of vaccine reports.

B. Safety Reports Not Covered by the Final Rule

Postmarketing safety reports for drugs, including vaccines, constitute the largest volume of paper safety reports received by the Agency and, consequently, require the most resources to input electronically. FDA anticipates that this final rule will permit FDA to manage these postmarketing safety reports more efficiently. The final rule only addresses electronic submission of postmarketing safety reports for drugs and biological products.

C. Waivers

Although this final rule requires that all postmarketing safety reports be submitted to FDA in electronic format, new §§ 310.305(e)(2), 314.80(g)(2), 329.100(c)(2), 600.80(h)(2), and 600.81(b)(2) allow for a temporary waiver from the electronic format requirement for “good cause” shown.10 Details for submitting waiver requests, such as where to send the request and any supporting information, are provided in the postmarketing safety reports guidance issued today in conjunction with this final rule. When a temporary waiver has been granted, FDA intends to specify an acceptable alternate format for submitting the safety reports.

FDA anticipates that temporary waivers of the requirement to submit postmarketing safety reports to the Agency in electronic format will be needed only in rare circumstances. Companies experiencing technical difficulties with transmission of their electronic submissions to FDA should consult FDA for technical assistance rather than submitting a waiver request. Companies that normally use the direct database-to-database method to submit reports to FDA could use the SRP as a backup method for FAERS submissions and the eSubmitter tool as a backup method for VAERS submissions during short-term, temporary outages.

D. Individual Case Safety Report (ICSR)–Definition and Required Information

In this final rule, as in the proposed rule, the term “individual case safety report” (ICSR) is used to describe the information contained in either an initial or a follow up report of an individual adverse drug experience, reported on a Form FDA 3500A, on a Council for International Organizations of Medical Sciences (CIOMS) I form, on a VAERS-1 form, or in electronic format. Because FDA is requiring that all postmarketing safety reports be submitted in electronic format, FDA proposed this term to describe the safety reporting vehicle generically, rather than by reference to the associated paper form. In addition, this term in now commonly used in international electronic reporting standards (e.g., ICH E2B, Health Level 7 (HL7)) in reference to such reports.

Accordingly, as proposed, §§ 310.305(b) and 314.80(a) have been revised to define an ICSR as a description of an adverse drug experience related to an individual patient or subject, and § 600.80(a) has been revised to define an ICSR as a description of an adverse experience related to an individual patient or subject. Because the items of information to be reported were specified on the paper reporting forms that will no longer be used for reports covered under this rule, FDA has added a list of the reportable elements to the regulations. Accordingly, §§ 310.305(d), 314.80(f), 329.100(b), 600.80(f), and 600.80(g) provide detailed lists of specific elements (in five broad categories for nonvaccine products and seven broad categories for vaccine products) that are to be reported in an ICSR, derived from the associated paper forms.

The five categories applicable to all products, including vaccines, and examples of some of the types of information in each category, are as follows:

  • Patient information (e.g., age, gender);
  • Information about the adverse experience (e.g., date and description of the adverse drug experience);
  • Information about the suspect medical product (e.g., drug name, dose, indication, National Drug Code (NDC) number);
  • Information about the initial reporter (e.g., name and contact information); and
  • Information about the drug’s applicant or manufacturer or responsible person (e.g., name and contact information)

In addition, the two categories applicable to vaccine products only are as follows:

  • Information about other vaccine(s) administered in the previous 4 weeks; and
  • Information on the facility and personnel where the vaccine was administered (e.g., name of person who administered vaccine, name of responsible physician and facility where the vaccine was administered).

Though there are minor wording differences, the list of information to be reported is derived from the information reflected on Form FDA 3500A and VAERS-1 for postmarketing reporting for drugs and biological products. Codification of the ICSR reporting requirements is not intended to change the obligation of manufacturers, packers, or distributors to exercise due diligence for purposes of completing all of the applicable elements of an ICSR. The obligation to provide all applicable information described in §§ 310.305(d), 314.80(f), 329.100(b), 600.80(f), or 600.80(g) is the same as the obligation to complete Form FDA 3500A or VAERS-1.

E. Removal of Paper Format Provisions

FDA believes that it is no longer necessary to describe procedures for paper format submissions in the regulations because FDA anticipates that a paper format will be used on a limited basis, if at all. Accordingly, as proposed, this final rule removes from the regulations provisions describing the details for submission of safety reports in paper format, such as the number of required paper copies or specific markings or notations required on the paper forms. FDA has deleted in §§ 310.305(d), 314.80(f), and 600.80(f) the provisions specifically describing paper submissions and replaced them with a paragraph (§§ 310.305(e)(1), 314.80(g)(1), and 600.80(h)(1)), which states that ICSRs and any ICSR attachments must be submitted to FDA in an electronic format that FDA can process, review, and archive.

F. Section 745A of the FD&C Act and Electronic Format for Submissions

Section 745A(a) of the FD&C Act (21 U.S.C. 379k-1), added by section 1136 of the Food and Drug Administration Safety and Innovation Act (Public Law 112-144), provides that submissions under section 505(b), (i), or (j) of the FD&C Act or section 351(a) or (k) of the PHS Act shall be submitted in such electronic format as specified by FDA in guidance. In section 745A(a) of the FD&C Act, Congress granted explicit statutory authority to FDA to implement the electronic format for submissions requirement by guidance. This grant of authority, however, does not preclude FDA from implementing such requirements by notice and comment rulemaking (5 U.S.C. 553). At this time, even though FDA concludes that certain submissions that are addressed in this final rule are also within the scope of section 745A(a) of the FD&C Act, FDA has determined that it is appropriate to amend the current regulations on the submission of postmarketing safety reports to remove references to paper submissions and to specify that such reports be submitted in an electronic format that FDA can process, review, and archive. FDA may consider, at a future date, whether certain electronic submission requirements should be specified in guidance pursuant to section 745A(a) of the FD&C Act.

G. Miscellaneous Changes

As proposed, the final rule amends §§ 310.305, 314.80, 314.98, and 600.80 by replacing he word “shall” with the word “must” except in the first sentence of §§ 314.80(c)(1)(iii) and 600.80(c)(1)(iii), from which the word “shall” has been removed for editorial reasons. The final rule revises in § 314.80(c)(2) the paragraph designations that were not in correct format. FDA believes that these minor changes clarify the regulations and make them easier to read. The final rule, as proposed, also changes the term “licensed manufacturer” to “applicant” in §§ 600.80, 600.81, and 600.90.

The mailing addresses for the submission of postmarketing safety reports have been removed from §§ 310.305(c), 314.80(c), 314.98(b), and 600.80(c) because this information is no longer necessary in light of the requirement to submit safety reports electronically. Final § 310.305(c)(1)(i) requires the submission of a current copy of the labeling in electronic format unless it is already on file with FDA. Previously, under § 310.305(c)(1)(i), each report was to be accompanied by a copy of the labeling. However, if the Agency already has the current labeling on file, FDA does not believe it is necessary for a current copy of the labeling to be submitted with each report.

For products with approved applications, currently, reports for all adverse experiences other than those submitted as 15-day Alert reports or follow up reports to 15-day Alert reports (i.e., reports of adverse experiences that are both serious and expected or no serious) are required to be submitted as a batch as part of the postmarketing periodic safety report for the reporting interval during which the applicant received the report. Although the ICSRs may be generated at any time from the beginning of the reporting interval through the date that the periodic report is submitted to FDA, they are currently retained by the applicant during this time period and submitted to FDA in a single batch, along with the other (descriptive) portions of the periodic report. The final rule includes language in §§ 314.80(c)(2)(ii)(B) and 600.80(c)(2)(ii)(B) to give applicants the option of submitting these ICSRs at any time up until the due date of the periodic report, rather than waiting to submit them in a single batch with the descriptive portion. All reports of adverse experiences that are both serious and expected or nonserious that the applicant received during the reporting interval must still be submitted to the Agency by the time the descriptive portion is due for that period, but the final rule permits them to be filed anytime up until the due date of the periodic report, rather than in a single batch with the descriptive portion of the periodic report. FDA has adopted this change, as proposed, because FDA understands that many applicants prefer this added flexibility of submitting the ICSRs on an ongoing basis.

To protect patient privacy, names of individual patients are not to be included in the patient identification portion of the ICSRs for drug and nonvaccine biological products. FDA instead requires that a unique code be used for patient identification. As proposed, the final rule removes from the provisions entitled “patient privacy” the language specifying an eight character limit on the code. Although FDA also proposed that the name of the reporter not be included when the reporter is also the patient, FDA is not finalizing that proposal. FDA has determined that it is important for FDA to have the name of the reporter, even when the patient is the reporter, because it will allow FDA to contact the reporter, if necessary, to obtain follow up information. Names of patients, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not releasable to the public under FDA’s public information regulations.

These same requirements addressing patient privacy have been included in § 329.100(d), applicable to reports required by section 760 of the FD&C Act. As proposed, FDA has revised §§ 310.305(c)(1)(i), 314.80(c)(1)(i), and 600.80(c)(1)(i) to state that 15-day Alert reports must be submitted as soon as possible, but no later than 15 calendar days from initial receipt of the information. FDA does not intend this change to have any substantive effect. It is being made solely to simplify the regulatory language and improve its readability.

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