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agency stated ‘‘that it is at least was also approved through the UDI. The The Department wishes to engage theoretically possible.’’ 18 interpretation of the definition of ‘‘new with the public on the contours of the That was not always the case. For drug’’ espoused in the 2011 Guidance exceptions to the definition of ‘‘new many years, FDA acknowledged that at essentially foreclosed the possibility drug.’’ In this regard, HHS is reviewing least some drugs are not ‘‘new drugs’’ that these two century-old drugs were whether certain drugs, including the subject to FDA approval prior to pre-1938 grandfathered drugs exempt drug subject to Congressional scrutiny marketing. In a 1980 version of the from the approval process. The 2017 in 2016, might qualify as exempt from Orange Book, FDA stated that ‘‘[t]he law study discussed above found that the the FDA approval requirement. To aid also permits drugs to be legally average wholesale unit price of that effort, HHS asks for input from marketed without such fully approved epinephrine and colchicine increased patients, health care providers, industry, applications under certain by 58.3% and 3,323.5%, respectively,25 and other stakeholders to provide circumstances,’’ including ‘‘drugs costs absorbed by American patients information responsive to any of the marketed prior to 1938 that are not and taxpayers. topics below: subject to the pre-market clearance The regulatory history of the 1. Lists of drugs marketed prior to procedures of the law’’ and ‘‘drug prescription drug Daraprim raises June 25, 1938 that are currently products marketed between 1938 and similar issues. FDA originally approved available on the market. 1962 that were approved for safety but Daraprim (pyrimethamine) for safety in 2. The extent to which drugs not effectiveness.’’ 19 In the same 1953, and later deemed the drug marketed prior to June 25, 1938, or publication, the agency went on to effective through the Drug Efficacy drugs that might qualify as GRASE, have identify specific products, noting Study Implementation, or DESI review regulatory approvals in countries ‘‘commonly used large volume process.26 The drug is listed on the outside the United States. intravenous products are not included World Health Organization’s List of 3. Whether there would be adverse on the List [of FDA-approved drugs] Essential Medications, ‘‘a list of clinical or economic consequences to (e.g., dextrose 5% with water, dextrose minimum medicine needs for a basic deeming as GRASE those drugs 10% with water, sodium chloride 0.9% health-care system, listing the most previously approved by the FDA for injection),’’ since ‘‘all of these drug efficacious, safe and cost-effective which patent and regulatory exclusivity products came on the market in glass medicines for priority conditions.’’ 27 In have expired. containers before 1938 and have not 2015, the company Turing 4. Any published literature reviews or been required to obtain an approved Pharmaceuticals ‘‘raised the price [of clinical studies related to any drugs new drug application as a condition of the drug] to $750 a tablet from $13.50, potentially exempt from the new drug 20 marketing.’’ In the 2000 edition of the bringing the annual cost of treatment for approval requirement. Orange Book, FDA cited to the some patients to hundreds of thousands Dated: November 20, 2020. barbiturate ‘‘Phenobarbital Tablets’’ as of dollars.’’ 28 Turing came by this Alex M. Azar II, an example of ‘‘pre-1938 drugs.’’ 21 The windfall, at least in part, because of Secretary, Department of Health and Human 2011 Guidance, issued absent notice- FDA’s interpretation of the definition of Services. and-comment rulemaking and without ‘‘new drug’’ in the FD&C Act as [FR Doc. 2020–26133 Filed 11–24–20; 8:45 am] prior public comment, contains no articulated in the 2006 and 2011 acknowledgement of these prior BILLING CODE 4150–26–P 22 Guidances, a view that foreclosed the positions. possibility that Daraprim, a drug more This evolution in the agency’s than sixty years old, could ever qualify DEPARTMENT OF HEALTH AND thinking has had consequences. Under as GRASE. That position effectively HUMAN SERVICES the UDI, FDA required the manufacturer prevented other manufacturers of of an epinephrine brand which Food and Drug Administration originally came onto the market in 1901 generic versions of this product from to submit an NDA.23 The drug entering the market without an [Docket No. FDA–2010–D–0529] colchicine, a product FDA approved abbreviated new drug Qualification Process for Drug acknowledged ‘‘was available in oral application, allowing Turing to enjoy a Development Tools; Guidance for dosage form during the 19th century,’’ 24 single-source position in the marketplace while potential competitors Industry; Availability went through the regulatory process. In 18 Id. at 12 (emphasis in original). AGENCY: Food and Drug Administration, 19 February 2016, Congress held a hearing FDA, Approved Prescription Drug Products HHS. with Therapeutic Equivalence Evaluations (herein on this widely-publicized issue. ACTION: the Orange Book), at I–3 (1st ed. 1980). Ultimately, FDA approved a generic Notice of availability. 20 Id. at I–13. competitor for this single-source drug in SUMMARY: 21 Id. at I–13. FDA, Orange Book, at v (2000); see The Food and Drug also FDA, Orange Book, at iv (29th ed. 2009) February 2020. Administration’s (FDA or Agency) (containing same reference to ‘‘pre-1938 drugs’’ and Center for Drug Evaluation and Research phenobarbital tablets). FDA included a reference to 25 Gupta, supra note 7, at 1072; see also Aaron S. (CDER) and Center for Biologics ‘‘pre-1938 drugs’’ like phenobarbital tablets in the Kesselheim and Daniel H. Solomon, Incentives for Orange Book as late as 2016, FDA, Orange Book, at Drug Development—The Curious Case of Evaluation and Research (CBER) are iv (36th ed. 2016), but removed the reference in its Colchicine, N. Engl. J. Med. 362;22 at 2046 (noting announcing the availability of a final 2017 edition and subsequent versions. the dramatic rise in the price of Colchicine after guidance for industry and FDA staff 22 Cf. F.C.C. v. Fox Television Stations, Inc., 556 implementation of the UDI, but that ‘‘there is no entitled ‘‘Qualification Process for Drug U.S. 502, 515 (2009) (‘‘To be sure, the requirement evidence of any meaningful improvement to the that an agency provide reasoned explanation for its public health’’ from the regulatory changes). Development Tools.’’ Under the 21st action would ordinarily demand that it display 26 36 FR 14662, 14662–63 (Aug. 7, 1971). Century Cures Act (Cures Act), enacted awareness that it is changing position.’’) 27 World Health Organization, 20th WHO Model on December 13, 2016, a new section 23 FDA, Ctr. For Drug Evaluation and Research, List of Essential Medications, at 24 (Mar. 2017). was added to the Federal Food, Drug, Application Number: 204200Origs1s000, 28 Andrew Pollack, Drug Goes From $13.50 a and Cosmetic Act (FD&C Act), which 204200Orig2s000, Summary Review, at 3, https:// Tablet to $750, Overnight, N.Y. Times, Sept. 20, www.accessdata.fda.gov/drugsatfda_docs/nda/ 2015, https://www.nytimes.com/2015/09/21/ defined a three-stage qualification 2012/204200Orig1Orig2s000SumR.pdf. business/a-huge-overnight-increase-in-a-drugs- process for drug development tools 24 75 FR 60768 (Oct. 1, 2010). price-raises-protests.html. (DDTs). This guidance meets the Cures

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Act’s requirement to issue guidance on and, except for those submitted as Send one self-addressed adhesive label this qualification process. It elaborates ‘‘Confidential Submissions,’’ publicly to assist that office in processing your on the new qualification process and viewable at https://www.regulations.gov requests. See the SUPPLEMENTARY transparency requirements and or at the Dockets Management Staff INFORMATION section for electronic discusses the taxonomy for biomarkers between 9 a.m. and 4 p.m., Monday access to the guidance document. and other DDTs. This guidance finalizes through Friday, 240–402–7500. FOR FURTHER INFORMATION CONTACT: • the draft guidance of the same title Confidential Submissions—To Chris Leptak, Center for Drug Evaluation issued on December 16, 2019. submit a comment with confidential and Research, Food and Drug DATES: The announcement of the information that you do not wish to be Administration, 10903 New Hampshire guidance is published in the Federal made publicly available, submit your Ave., Bldg. 22, Rm. 6461, Silver Spring, Register on November 25, 2020. comments only as a written/paper MD 20993–0002, 301–796–0017; or submission. You should submit two Stephen Ripley, Center for Biologics ADDRESSES: You may submit either copies total. One copy will include the electronic or written comments on Evaluation and Research, 10903 New information you claim to be confidential Hampshire Ave., Bldg. 71, Rm. 7301, Agency guidances at any time as with a heading or cover note that states follows: Silver Spring, MD 20993–0002; 240– ‘‘THIS DOCUMENT CONTAINS 402–7911. Electronic Submissions CONFIDENTIAL INFORMATION.’’ The Agency will review this copy, including SUPPLEMENTARY INFORMATION: Submit electronic comments in the the claimed confidential information, in I. Background following way: its consideration of comments. The • CDER and CBER are announcing the Federal eRulemaking Portal: second copy, which will have the availability of a final guidance for https://www.regulations.gov. Follow the claimed confidential information industry and FDA staff entitled instructions for submitting comments. redacted/blacked out, will be available ‘‘Qualification Process for Drug Comments submitted electronically, for public viewing and posted on including attachments, to https:// https://www.regulations.gov. Submit Development Tools.’’ Signed into law www.regulations.gov will be posted to both copies to the Dockets Management on December 13, 2016, the Cures Act the docket unchanged. Because your Staff. If you do not wish your name and codified, in new section 507 of the comment will be made public, you are contact information to be made publicly FD&C Act (21 U.S.C. 357), a new solely responsible for ensuring that your available, you can provide this statutory process for DDT qualification comment does not include any information on the cover sheet and not and added transparency provisions for confidential information that you or a in the body of your comments and you information related to qualification third party may not wish to be posted, must identify this information as submissions through which there is such as medical information, your or ‘‘confidential.’’ Any information marked enhanced ability to share knowledge. In anyone else’s Social Security number, or as ‘‘confidential’’ will not be disclosed addition, Congress directed the confidential business information, such except in accordance with 21 CFR 10.20 establishment of a taxonomy for the as a manufacturing process. Please note and other applicable disclosure law. For classification of biomarkers (and related that if you include your name, contact more information about FDA’s posting scientific concepts) for use in drug information, or other information that of comments to public dockets, see 80 (including biological product) identifies you in the body of your FR 56469, September 18, 2015, or access development. CDER and CBER comments, that information will be the information at: https:// convened a public meeting on December posted on https://www.regulations.gov. www.govinfo.gov/content/pkg/FR-2015- 11, 2018, to solicit public input about • If you want to submit a comment 09-18/pdf/2015-23389.pdf. implementing the new qualification with confidential information that you Docket: For access to the docket to process under section 507 of the FD&C do not wish to be made available to the read background documents or the Act and about identifying the public, submit the comment as a electronic and written/paper comments Biomarkers, EndpointS, and other Tools written/paper submission and in the received, go to https:// (BEST) glossary as the taxonomy for manner detailed (see ‘‘Written/Paper www.regulations.gov and insert the classifying types of DDTs, including Submissions’’ and ‘‘Instructions’’). docket number, found in brackets in the biomarkers. CDER and CBER are issuing this final guidance to meet the Cures Written/Paper Submissions heading of this document, into the ‘‘Search’’ box and follow the prompts Act requirement that the Agency issue Submit written/paper submissions as and/or go to the Dockets Management final guidance on the section 507 follows: Staff, 5630 Fishers Lane, Rm. 1061, qualification process. • Mail/Hand Delivery/Courier (for Rockville, MD 20852, 240–402–7500. DDTs are methods, materials, or written/paper submissions): Dockets You may submit comments on any measures that can aid drug development Management Staff (HFA–305), Food and guidance at any time (see 21 CFR and regulatory review. Qualification Drug Administration, 5630 Fishers 10.115(g)(5)). means that a DDT and its proposed Lane, Rm. 1061, Rockville, MD 20852. Submit written requests for single context of use can be relied upon to • For written/paper comments copies of this guidance to the Division have a specific interpretation and submitted to the Dockets Management of Drug Information, Center for Drug application in drug development and Staff, FDA will post your comment, as Evaluation and Research, Food and regulatory review. Qualified DDTs can well as any attachments, except for Drug Administration, 10001 New accelerate the integration of innovation, information submitted, marked and Hampshire Ave., Hillandale Building, clinical knowledge, and scientific identified, as confidential, if submitted 4th Floor, Silver Spring, MD 20993– advances, thereby expediting drug as detailed in ‘‘Instructions.’’ 0002; or the Office of Communication, development and aiding the regulatory Instructions: All submissions received Outreach, and Development, Center for review of applications. must include the Docket No. FDA– Biologics Evaluation and Research, Although the DDT qualification 2010–D–0529 for ‘‘Qualification Process Food and Drug Administration, 10903 process is voluntary, requestors who for Drug Development Tools.’’ Received New Hampshire Ave., Bldg. 71, Rm. seek qualification under section 507 of comments will be placed in the docket 3128, Silver Spring, MD 20993–0002. the FD&C Act must follow the three-

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stage process described in the Cures information are subject to review by midreview cycle meetings with FDA. Act. This consists of the following OMB under the PRA. The collections of This guidance will assist applicants in stages: The Letter of Intent, the information pertaining to submissions generating and submitting a meeting Qualification Plan, and the Full of investigational new drug applications request and the associated meeting Qualification Package. These stages are have been approved under OMB control package to FDA for complex products to discussed in detail in section III of the number 0910–0014; the collections of be submitted under the Federal Food, final guidance. information pertaining to submissions Drug, and Cosmetic Act (FD&C Act) and The Cures Act includes transparency of new drug applications and as contemplated in the commitments provisions that require the Agency to abbreviated new drug applications have made by FDA in connection with the make information with respect to been approved under OMB control reauthorization of the Generic Drug User qualification submissions publicly number 0910–0001; and the collections Fee Amendments for Fiscal Years (FYs) available. A description of information of information pertaining to 2018–2022 (GDUFA II). This guidance that is made public on the Agency’s submissions of biologics license finalizes the draft guidance of the same website is provided in section II of the applications in 21 CFR part 601 have title issued on October 3, 2017. final guidance. been approved under OMB control DATES: The announcement of the CDER and CBER have considered number 0910–0338. guidance is published in the Federal public comments made during the III. Electronic Access Register on November 25, 2020. December 11, 2018, public meeting and ADDRESSES: You may submit either submitted to the docket in developing Persons with access to the internet electronic or written comments on the draft guidance of the same title may obtain the guidance at either Agency guidances at any time as published on December 16, 2019 (84 FR https://www.fda.gov/drugs/guidance- follows: 68460). The Agency received various compliance-regulatory-information/ comments to the docket in response to guidances-drugs, https://www.fda.gov/ Electronic Submissions the publication of the draft guidance vaccines-blood-biologics/guidance- Submit electronic comments in the and has considered those comments in compliance-regulatory-information- following way: developing this final guidance. Changes biologics, or https:// • Federal eRulemaking Portal: made in the final guidance in response www.regulations.gov. https://www.regulations.gov. Follow the to comments include requests for Dated: November 19, 2020. instructions for submitting comments. additional clarity on the qualification Lauren K. Roth, Comments submitted electronically, process, support for the proposed time Acting Principal Associate Commissioner for including attachments, to https:// frames, and requests to reference Policy. www.regulations.gov will be posted to specific programs’ content element [FR Doc. 2020–26051 Filed 11–24–20; 8:45 am] the docket unchanged. Because your outlines in the guidance. This final comment will be made public, you are BILLING CODE 4164–01–P guidance meets the Cures Act’s solely responsible for ensuring that your requirement to finalize guidance on the comment does not include any section 507 qualification process and DEPARTMENT OF HEALTH AND confidential information that you or a affirms the BEST glossary as the HUMAN SERVICES third party may not wish to be posted, taxonomy for classifying types of DDTs. such as medical information, your or This guidance does not address Food and Drug Administration anyone else’s Social Security number, or evidentiary standards for purposes of confidential business information, such [Docket No. FDA–2017–D–5739] DDT qualification. It also does not as a manufacturing process. Please note address the qualification of medical Formal Meetings Between the Food that if you include your name, contact device development tools or other and Drug Administration and information, or other information that programs under the Center for Devices Abbreviated New Drug Application identifies you in the body of your and Radiological Health oversight, Applicants of Complex Products Under comments, that information will be which are not addressed in section 507 posted on https://www.regulations.gov. Generic Drug User Fee Amendments; • of the FD&C Act. Guidance for Industry; Availability If you want to submit a comment This guidance is being issued with confidential information that you consistent with FDA’s good guidance AGENCY: Food and Drug Administration, do not wish to be made available to the practices regulation (21 CFR 10.115). HHS. public, submit the comment as a The guidance represents the current ACTION: Notice of availability. written/paper submission and in the thinking of FDA on the ‘‘Qualification manner detailed (see ‘‘Written/Paper Process for Drug Development Tools.’’ It SUMMARY: The Food and Drug Submissions’’ and ‘‘Instructions’’). does not establish any rights for any Administration (FDA or Agency) is person and is not binding on FDA or the announcing the availability of a final Written/Paper Submissions public. You can use an alternative guidance for industry entitled ‘‘Formal Submit written/paper submissions as approach if it satisfies the requirements Meetings Between FDA and ANDA follows: of the applicable statutes and Applicants of Complex Products Under • Mail/Hand Delivery/Courier (for regulations. GDUFA.’’ This guidance describes an written/paper submissions): Dockets enhanced pathway for discussions Management Staff (HFA–305), Food and II. Paperwork Reduction Act of 1995 between FDA and a prospective Drug Administration, 5630 Fishers While this guidance contains no applicant preparing to submit (or an Lane, Rm. 1061, Rockville, MD 20852. collection of information, it does refer to applicant that has submitted) to FDA an • For written/paper comments previously approved FDA collections of abbreviated new drug application submitted to the Dockets Management information. Therefore, clearance by the (ANDA) for a complex product. Staff, FDA will post your comment, as Office of Management and Budget Specifically, this guidance provides well as any attachments, except for (OMB) under the Paperwork Reduction information on requesting and information submitted, marked and Act of 1995 (44 U.S.C. 3501–3521). The conducting product development identified, as confidential, if submitted previously approved collections of meetings, presubmission meetings, and as detailed in ‘‘Instructions.’’

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