2019-15103. Providing Regulatory Submissions in Electronic Format-Certain Human Pharmaceutical Product Applications and Related Submissions Using the Electronic Common Technical Document Specifications (Revision 7); Draft Guidance for Industry; ...

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Notice of availability.

SUMMARY:

The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Revision 7).” FDA has identified certain submission types that FDA believes warrant an exemption (Type III drug master files (DMFs)) or a long-term waiver (certain positron emission tomography (PET) drug products and certain Type II DMFs supporting PET drugs or noncommercial submissions or applications) from the requirement to submit to the Agency in eCTD format. In addition, this guidance outlines certain circumstances where FDA may determine that a short-term waiver from electronic common technical document (eCTD) submission requirements could be granted. This guidance is a revision of the final guidance issued on January 29, 2019, and when finalized, will supersede that guidance.

DATES:

Submit either electronic or written comments on the draft guidance by September 16, 2019 to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance.

ADDRESSES:

You may submit comments on any guidance at any time as follows:

Electronic Submissions

Submit electronic comments in the following way:

• Federal eRulemaking Portal: https://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to https://www.regulations.gov will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on https://www.regulations.gov.
• If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see “Written/Paper Submissions” and “Instructions”).

Written/Paper Submissions

Submit written/paper submissions as follows:

• Mail/Hand Delivery/Courier (for written/paper submissions): Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in “Instructions.”

Instructions: All submissions received must include the Docket No. FDA-2014-N-1006 for “Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Revision 7).” Received comments will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday.

• Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states “THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.” The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on https://www.regulations.gov. Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as “confidential.” Any information marked as “confidential” will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: https://www.gpo.gov/​fdsys/​pkg/​FR-2015-09-18/​pdf/​2015-23389.pdf.

Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

You may submit comments on any guidance at any time (see 21 CFR 10.115(g)(5)).

Submit written requests for single copies of the draft guidance to the Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10001 New Hampshire Ave., Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002; or to the Office of Communication, Outreach and Development, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. Send one self-addressed adhesive label to assist that office in processing your requests. See the SUPPLEMENTARY INFORMATION section for electronic access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT:

Ebla Ali Ibrahim, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 6302, Silver Spring, MD 20993-0002, 301-796-3691; or Stephen Ripley, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of a draft guidance for industry entitled “Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Revision 7).” This guidance provides information regarding submission types that FDA believes warrant an exemption or long-term waiver from Agency eCTD requirements. In addition, this guidance outlines certain circumstances where FDA proposes granting short-term waivers from eCTD submission requirements. This revised draft guidance is intended to address current concerns raised to FDA regarding the burden of complying with eCTD submission requirements, which could have unintended public health consequences.

In the Federal Register of January 3, 2013 (78 FR 310), FDA announced the availability of a draft guidance for industry entitled “Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.” The draft guidance was announced in accordance with the Food and Drug Administration Safety and Innovation Act, which amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to require that certain submissions under the FD&C Act and Public Health Service Act be submitted in electronic format, beginning no earlier than 2 years after publication of the final version of the draft guidance. That draft guidance described how FDA planned to implement the requirements for the electronic submission of applications for certain human pharmaceutical products. In the Federal Register of July 25, 2014 (79 FR 43494), FDA announced the availability of a revised draft guidance for industry of the same title, which contained changes from the previous 2013 draft guidance on eCTD requirements. The final guidance (Revision 3) posted on May 5, 2015, provided a timetable of 24 months after issuance of the final guidance for the initial implementation of the electronic submission requirement for new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologic license applications (BLAs), and master files (May 5, 2017), and 36 months for commercial investigational new drug applications (INDs) (May 5, 2018). In April 2017, the revised guidance updated the timetable for compliance for required master file submissions in eCTD from 24 months to 36 months. In April 2018, the guidance was revised to include an extension for the timetable for Type III DMF submissions in eCTD for an additional 12 months. FDA determined that many of the concerns outlined in the guidance remain, and Revision 6 of the guidance was published to extend Type III DMF submissions in eCTD until May 5, 2020. Revision 6 of the guidance remains in effect until this draft revised version of the guidance is finalized.

Type III DMFs. Type III DMFs are submitted to the Agency to provide information regarding packaging or packaging materials in support of NDAs, ANDAs, or BLAs. These DMFs are commonly submitted by firms that are not pharmaceutical manufacturers, but instead are material suppliers and manufacturers of packaging and packaging materials. Such firms are several steps removed from the NDA, ANDA, or BLA applicant in the supply chain. As described further below, compliance with eCTD submission requirements can represent a significant burden to support use of their packaging products for pharmaceuticals when balanced against their business interest in supplying their products for this use. In many cases, pharmaceutical packaging material is a limited portion of their overall business. In addition, the need to continue to maintain a Type III DMF to support a drug marketing application may occur even when the firm's packaging material or product is no longer actively marketed. There is a possibility that this regulatory burden could result in firms ending their supply of these critical materials to the pharmaceutical industry, which could lead to drug supply interruptions and drug shortages. Finally, only a small portion of Type III DMFs submitted to the Agency require review by FDA staff in support of a marketing application; in most cases, the information needed to support approval is already present in the marketing application. The burden on the Agency of allowing non-eCTD submissions for Type III DMFs is expected to be reasonably low. FDA reviewed the concerns expressed by the suppliers and manufacturers and proposes to exempt Type III DMFs from compliance with the eCTD submission requirement (as opposed to maintaining a compliance deadline of May 5, 2020). FDA continues to recommend use of the eCTD format for Type III DMF submissions where possible, but the Agency is issuing this revision to its guidance to propose this exemption.

PET drug products. PET is a medical imaging method that produces a computerized image (scan) using a class of positron-emitting drugs, a unique type of radiopharmaceuticals. A PET drug or biologic is a radioactive agent that exhibits spontaneous disintegration of unstable nuclei by the emission of positrons and is used for providing dual photon positron emission tomographic diagnostic images (21 CFR 212.1, 21 CFR 601.31(a)). PET is used in evaluating patients with coronary artery disease and in certain neurologic disorders. PET drugs are distinct among radiopharmaceuticals because of their unique production methods, and many are characterized by their short half-lives (some as short as 20 minutes). Many PET drug production facilities are therefore close in proximity to the patients to whom the drugs are administered.

FDA's proposal to grant waivers from eCTD requirements for certain PET drugs is consistent with FDA's and Congress's history of recognizing that PET drugs can pose unique considerations. For example, in 1997, Congress passed the Food and Drug Administration Modernization Act (FDAMA) (Pub. L. 105-115), which directed FDA to regulate PET drugs (section 121(c)) by developing appropriate procedures for the approval of PET drugs in accordance with section 505 of the FD&C Act (21 U.S.C. 355) and to establish current good manufacturing practice requirements for PET drugs. Within FDAMA, Congress recognized the unique characteristics of PET drugs—in particular, the special criteria and processes required to produce these drugs—directing the Secretary of Health and Human Services to take due account of any relevant differences between not-for profit institutions that compound the drugs for their patients and commercial manufacturers of the drugs. See section 121(c)(1)(B) of FDAMA.

Statements like this indicate that one of Congress' goals in enacting section 121 of FDAMA was to promote the availability of FDA-approved PET drug products for the patients who need them. Previously, FDA found that, because of the unique circumstances surrounding the regulation of PET drug products, assessment of an application fee on certain PET drugs would present a significant barrier to innovation, and FDA granted a waiver of application fees for certain PET drug products.^[1] Similarly, FDA believes that the requirement to submit applications in eCTD format could result in a significant burden on certain PET drug producers and may lead to reduced availability of these innovative and lifesaving diagnostic drugs. This guidance proposes that sponsors and applicants of PET drug products may request a waiver from complying with eCTD submission requirements if they meet certain factors set forth in the revised eCTD guidance. Although FDA proposes waiving eCTD requirements for these submissions, FDA continues to recommend use of the eCTD format for PET drug products if feasible. The Agency is issuing this revision to its guidance to propose this waiver.

Certain Type II DMFs. Type II DMFs are submitted to the Agency to make quality information available for Agency evaluation of the quality of active pharmaceutical ingredients and drug products used in investigational studies. Many such studies are conducted by academic, non-commercial sponsors where there is no commercial objective to support these applications. In some cases, the Type II DMF submission may be submitted by the academic sponsor or by a second party. For these academic IND sponsors, compliance with eCTD submission requirements can represent a significant burden and may present an obstacle to the conduct of research. After consideration of this regulatory burden and the potential negative impact on research and innovation, FDA proposes to waive the requirement to comply with eCTD submission requirements for certain Type II DMF submissions from an academic institution, government (State or Federal), or a non-profit research organization that are solely supporting a noncommercial application.

Short-Term Waivers. This guidance also describes the circumstances in which FDA proposes granting a temporary waiver from complying with eCTD submission requirements and the procedures for submitting requests for waivers.

This draft guidance is being issued consistent with FDA's good guidance practices regulation (21 CFR 10.115). The draft guidance, when finalized, will represent the current thinking of FDA on “Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Revision 7).”

FDA guidances ordinarily contain standard language explaining that guidances should be viewed only as recommendations unless specific regulatory or statutory requirements are cited. FDA is not including this standard language in this guidance because this guidance contains binding provisions. In section 745A(a) of the FD&C Act (21 U.S.C. 379k-1), Congress granted explicit authorization to FDA to specify in guidance the format for the electronic submissions required under that section and required that FDA “shall” issue such guidance. Accordingly, this guidance explains such requirements under section 745A(a) of the FD&C Act, indicated by the use of the words must or required, and therefore is not subject to the usual restrictions in FDA's good guidance practice regulations, such as the requirement that guidances not establish legally enforceable responsibilities. See e.g., 21 CFR 10.115(d).

II. Paperwork Reduction Act of 1995

This guidance refers to previously approved collections of information that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The collections of information in 21 CFR parts 312, 314, and 601 have been approved under OMB control numbers 0910-0014, 0910-0001, 0910-0338, and 0910-0308.

III. Electronic Access

Persons with access to the internet may obtain the draft guidance at https://www.fda.gov/​Drugs/​GuidanceComplianceRegulatoryInformation/​Guidances/​default.htm, https://www.fda.gov/​BiologicsBloodVaccines/​GuidanceComplianceRegulatoryInformation/​Guidances/​default.htm, or https://www.regulations.gov.

Dated: July 10, 2019.

Lowell J. Schiller,

Principal Associate Commissioner for Policy.

Footnotes

1.  https://www.federalregister.gov/​documents/​2000/​03/​10/​00-5865/​positron-emission-tomography-drug-products-safety-and-effectiveness-of-certain-pet-drugs-for.