2016-22689. Food and Drug Administration's Application of Statutory Factors in Determining When a Risk Evaluation and Mitigation Strategy Is Necessary; Draft Guidance for Industry; Availability

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The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “FDA's Application of Statutory Factors in Determining When a REMS Is Necessary.” This draft guidance is intended to clarify how FDA applies the factors set forth in the Federal Food, Drug, and Cosmetic Act (the FD&C Act) in determining whether a risk evaluation and mitigation strategy (REMS) is necessary to ensure that the benefits of a drug outweigh its risks. This guidance is one of several being developed to fulfill performance goals that FDA agreed to satisfy in the context of the fifth reauthorization of the prescription drug user fee program (the Prescription Drug User Fee Act V).

DATES:

Although you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance, submit either electronic or written comments on the draft guidance by November 21, 2016.

ADDRESSES:

You may submit comments as follows:

Electronic Submissions

Submit electronic comments in the following way:

• Federal eRulemaking Portal: http://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to http://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 http://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): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments submitted to the Division of Dockets Management, 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-2016-D-2730 for the “FDA's Application of Statutory Factors in Determining When a REMS Is Necessary; Draft Guidance for Industry.” Received comments will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at http://www.regulations.gov or at the Division of Dockets Management 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 http://www.regulations.gov. Submit both copies to the Division of Dockets Management. 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: http://www.fda.gov/​regulatoryinformation/​dockets/​default.htm.

Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to http://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 Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

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 the office in processing your requests. See the SUPPLEMENTARY INFORMATION section for electronic access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT:

Aaron Sherman, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 6366, Silver Spring, MD 20993, 240-402-0493, [e-mail]; 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 “FDA's Application of Statutory Factors in Determining When a REMS Is Necessary.” The Food and Drug Administration Amendments Act of 2007 (FDAAA) (Pub. L. 110-85) created section 505-1 of the FD&C Act (21 U.S.C. 355-1),^[1] which authorizes FDA to require a REMS for certain drugs if FDA determines that a REMS is necessary to ensure that the benefits of the drug outweigh its risks (see section 505-1(a) of the FD&C Act). A REMS is a required risk management strategy that can include one or more elements to ensure that the benefits of a drug outweigh its risks (see section 505-1(e) of the FD&C Act). A REMS may consist of a Medication Guide, a patient package insert, and/or a communication plan (section 505-1(e)(2) to (e)(3) of the FD&C Act). FDA may also require certain elements to assure safe use (ETASU) as part of a REMS for a drug (see section 505-1(f) of the FD&C Act). (The ETASU can include, for example, requirements that health care providers who prescribe the drug have particular training or experience, that patients using the drug be monitored, or that the drug be dispensed to patients with evidence or other documentation of safe use conditions (Id.). The ETASU may also include an implementation system through which the sponsor is able to monitor, evaluate, and improve implementation of the ETASU (see section 505-1(f)(4) of the FD&C Act).) Finally, REMS generally must have a timetable for submission of assessments of the strategy (see section 505-1(d) of the FD&C Act). FDA can require a REMS before initial approval of a new drug application or, should FDA become aware of “new safety information” (as defined in section 505-1(b)(3) of the FD&C Act) about a drug and determine that a REMS is necessary to ensure that the benefits of the drug outweigh its risks, after the drug has been approved (see section 505-1(a)(2) of the FD&C Act).

FDA's determination as to whether a REMS is necessary for a particular drug is a complex, drug-specific inquiry, reflecting an analysis of multiple, interrelated factors. In conducting this analysis, FDA considers whether (based on premarketing or postmarketing risk assessments) there is a particular risk associated with the use of the drug that, on balance, outweighs its benefits and whether additional interventions beyond FDA-approved labeling are necessary to ensure that the drug's benefits outweigh its risks.

If FDA determines that additional interventions are necessary to ensure that the benefits of a drug outweigh its risks, FDA considers what the goals of a proposed REMS to address these risks would be and what specific elements could help meet those goals. If a REMS can be designed that FDA expects will meet the relevant goals and not unduly impede patient access to the drug, then FDA will generally approve the drug with a REMS (or, if the drug is already being marketed, require that a REMS be imposed for the drug). If FDA believes that the drug's risks would exceed its benefits even if FDA were to require a REMS for the drug, FDA will not approve the drug or may consider seeking withdrawal of the drug if it is already being marketed.

FDAAA requires FDA to consider the following six factors ^[2] in making a decision about whether to require a REMS:

• The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug
• The expected benefit of the drug with respect to the disease or condition
• The seriousness of the disease or condition that is to be treated with the drug
• Whether the drug is a new molecular entity
• The expected or actual duration of treatment with the drug
• The estimated size of the population likely to use the drug

These six factors influence FDA's decisions with respect to both whether a REMS is required for a particular drug and what type of REMS might be necessary (i.e., what specific elements/tools should be included as part of the REMS). FDA makes decisions about requiring a REMS as part of a benefit-risk determination for a drug after an evaluation that includes integrated consideration of each of the statutory factors. No single factor, by itself, is determinative as to whether a REMS is necessary to ensure that the benefits of a drug outweigh its risks. This guidance describes how FDA considers each of these factors in conducting its REMS analysis.

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 how the Agency applies statutory factors in determining when a REMS is necessary. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.

II. Electronic Access

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

Dated: September 15, 2016.

Leslie Kux,

Associate Commissioner for Policy.

Footnotes

1.  Section 505-1 of the FD&C Act applies to applications for prescription drugs submitted or approved under subsections 505(b) (i.e., new drug applications) or (j) (i.e., abbreviated new drug applications) of the FD&C Act and to applications submitted or approved under section 351 (i.e., biologics license applications) of the Public Health Service Act (42 U.S.C. 262). In this document, unless otherwise specified, the term “drug” refers to drug and biological products (or biologics).

2.  Section 505-1(a)(1) of the FD&C Act requires the Agency to consider these factors in determining whether a REMS is necessary for a new drug. FDA also generally considers these factors in determining whether (based on new safety information), a REMS is necessary for a drug that is the subject of an approved application.