Federal Register / Vol. 85, No. 228 / Wednesday, November 25, 2020 / Notices 75331 

human consumption are not considered 

prohibited cattle materials, and their use 

does not render human food or 

cosmetics adulterated. Sections 189.5(e) 

and 700.27(e) provide that a country 

seeking to be designated must send a 

written request to the Director of the 

Center for Food Safety and Applied 

Nutrition. The information the country 

is required to submit includes 

information about a country’s BSE case 

history, risk factors, measures to prevent 

the introduction and transmission of 

BSE, and any other information relevant 

to determining whether SRMs, the small 

intestine of cattle not otherwise 

excluded from being a prohibited cattle 

material, material from nonambulatory 

disabled cattle, or MS beef from the 

country seeking designation should be 

considered prohibited cattle materials. 

We use the information to determine 

whether to grant a request for 

designation and to impose conditions if 

a request is granted. 

Sections 189.5 and 700.27 further 

state that countries designated under 

§§ 189.5(e) and 700.27(e) will be subject 

to future review by FDA to determine 

whether their designations remain 

appropriate. As part of this process, we 

may ask designated countries to confirm 

that their BSE situation and the 

information submitted by them, in 

support of their original application, has 

remained unchanged. We may revoke a 

country’s designation if we determine 

that it is no longer appropriate. 

Therefore, designated countries may 

respond to periodic FDA requests by 

submitting information to confirm their 

designations remain appropriate. We 

use the information to ensure their 

designations remain appropriate. 

Description of Respondents: 

Respondents to this information 

collection include manufacturers, 

processors, and importers of FDAregulated human food, including dietary 

supplements, and cosmetics 

manufactured from, processed with, or 

otherwise containing material derived 

from cattle, as well as, with regard to 

§§ 189.5(e) and 700.27(e), foreign 

governments seeking designation under 

those regulations. 

In the Federal Register of August 14, 

2020 (85 FR 49657), we published a 60- 

day notice requesting public comment 

on the proposed collection of 

information. Although some comments 

were received, only one pertained to the 

information collection. The comment 

suggested requiring greater than a 2-year 

retention period for records; however, 

we believe that additional retention 

requirements may impose undue burden 

on respondents to the information 

collection without providing greater 

utility to the Agency. 

We estimate the burden of this 

collection of information as follows: 

TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1

21 CFR section; activity Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average burden per 

response Total hours 

189.5(c)(6) and 700.27(c)(6); affirmation of compliance.54,825 1 54,825 0.033 (2 minutes) ...... 1,809 

189.5(e) and 700.27(e); request for designation ..... 1 1 1 80 .............................. 80 

189.5(e) and 700.27(e); response to request for review by FDA.1 1 1 26 .............................. 26 

Total .................................................................. ........................ ........................ ........................ .................................... 1,915 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

TABLE 2—ESTIMATED ANNUAL RECORDKEEPING BURDEN1

Type of respondent Number of 

recordkeepers 

Number of 

records per 

recordkeeper 

Total annual 

records 

Average burden per 

recordkeeper Total hours 

Domestic facilities .................................................... 697 52 36,244 0.25 (15 minutes) ...... 9,061 

Foreign facilities ....................................................... 916 52 47,632 0.25 (15 minutes) ...... 11,908 

Total .................................................................. ........................ ........................ ........................ .................................... 20,969 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

Based on a review of the information 

collection since our last request for 

OMB approval, we have made no 

adjustments to our burden estimate. 

Dated: November 18, 2020. 

Lauren K. Roth, 

Acting Principal Associate Commissioner for 

Policy. 

[FR Doc. 2020–26059 Filed 11–24–20; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

Termination of the Food and Drug 

Administration’s Unapproved Drugs 

Initiative; Request for Information 

Regarding Drugs Potentially Generally 

Recognized as Safe and Effective 

AGENCY: Food and Drug Administration 

(FDA), Department of Health and 

Human Services (HHS). 

ACTION: Notice; request for information. 

SUMMARY: The Department of Health and 

Human Services is issuing this Notice to 

withdraw FDA’s Marketed Unapproved 

Drugs—Compliance Policy Guide, Sec. 

440.100, Marketed New Drugs Without 

Approved NDAs or ANDAs, and to 

request information from the public 

regarding drugs that may be 

grandfathered or generally recognized as 

safe and effective. 

DATES: Part I of this Notice shall be 

effective thirty days from the date of 

publication in the Federal Register. To 

be considered, responses and comments 

related to Part II of this Notice must be 

received electronically at the email 


jbell on DSKJLSW7X2PROD with NOTICES
75332 Federal Register / Vol. 85, No. 228 / Wednesday, November 25, 2020 / Notices 

1There is a third, related exemption which 

relieves manufacturers from the obligation of 

showing their drugs are effective prior to marketing. 

In section 107(c)(4) of the Drug Amendments of 

1962, Public Law 87–81, 76 Stat. 780, 789 (Oct. 10, 

1962), Congress exempted from the efficacy 

requirement ‘‘product[s] that, on the day before the 

1962 amendments became effective, (A) [were] used 

or sold commercially in the United States, (B) 

[were] generally recognized by the experts as safe; 

and (C) [were] not ‘covered’ by an ‘effective’ 

application.’’ USV Pharmaceutical Corp. v. 

Weinberger, 412 U.S. 655, 653 (1973). In 

Weinberger, the Supreme Court held that so-called 

‘‘me-too drugs,’’ i.e., drugs that were copies of NDA 

drugs, were effectively ‘‘covered’’ by an effective 

application and thus subject to the efficacy 

requirement just like drugs covered by NDAs. Id. at 

664–65. Practically, Weinberger left as the lone 

remaining candidates for this exemption from the 

efficacy requirement drugs (a) on the market prior 

to 1962, (b) generally recognized as safe, and (c) not 

themselves subject to a 1938–1962 ‘‘effective’’ NDA. 

2FDA, Marketed Unapproved Drugs— 

Compliance Policy Guide Sec. 440.100, Marketed 

New Drugs Without Approved NDAs or ANDAs 

(June 2006) (hereinafter the 2006 Guidance); FDA, 

Marketed Unapproved Drugs—Compliance Policy 

Guide Sec. 440.100, Marketed New Drugs Without 

Approved NDAs or ANDAs (Sept. 19, 2011) 

(hereinafter the 2011 Guidance). 

3 2011 Guidance at 8. 

4 Id. 

5Harris Meyer, The High Price of FDA Approval, 

Kaiser Health News, Dec. 29, 2009, https://khn.org/ 

news/fda-approval/. 

address listed below. The Department 

will consider information submitted by 

the public in response to Part II of this 

Notice on a rolling basis, and until 

further notice. 

ADDRESSES: Responses to Part II must be 

submitted electronically, and should be 

addressed to Import@hhs.gov. In the 

subject line of the email message, 

submissions should include ‘‘GRASE 

RFI Response.’’ 

FOR FURTHER INFORMATION CONTACT: Nick 

Uehlecke, 200 Independence Ave. SW, 

Washington, DC 20201; or by email at 

Import@hhs.gov; or by telephone at 1– 

877–696–6775. 

SUPPLEMENTARY INFORMATION: The 

Trump Administration, through the 

Department of Health and Human 

Services (HHS), is continuing its efforts 

to reduce the price of prescription 

drugs. This Notice addresses two related 

but distinct issues: (1) The Food and 

Drug Administration’s (FDA) 

Unapproved Drugs Initiative (UDI) and 

(2) the construction of the statutory 

exemptions from the definition of ‘‘new 

drugs’’ subject to FDA approval under 

the federal Food, Drug, and Cosmetic 

Act (FD&C Act), namely so-called pre1938 grandfathered drugs and drugs that 

are ‘‘generally recognized as safe and 

effective’’ or ‘‘GRASE.’’ 

I. Unapproved Drugs Initiative 

In 1938, Congress created the modern 

scheme for federal regulation of drugs. 

Before 1938, there was no requirement 

under federal law for a manufacturer to 

obtain FDA approval before marketing a 

drug. Today, as a general rule, under the 

FD&C Act, a ‘‘new drug’’ must be 

approved by the FDA for safety and 

efficacy pursuant to an approved New 

Drug Application (NDA) or Abbreviated 

New Drug Application (ANDA) before 

the drug is introduced into interstate 

commerce. See FD&C Act 201(p), 21 

U.S.C. 321(p) (defining ‘‘new drug’’ 

under the Act); FD&C Act 505(a), 21 

U.S.C. 355(a) (‘‘No person shall 

introduce or deliver for introduction 

into interstate commerce any new drug, 

unless an approval of an application 

. . . is effective with respect to such 

drug.’’). A ‘‘person’’ that introduces a 

‘‘new drug’’ into interstate commerce is 

subject to, among other sanctions, 

injunctions and/or having the subject 

product seized in an ex parte 

proceeding under admiralty rules. See 

FD&C Act 302, 21 U.S.C. 332 (injunction 

authority); FD&C Act 304, 21 U.S.C. 334 

(seizure authority). 

Not all drugs are ‘‘new drugs’’ which 

require FDA approval. There are two 

primary carve-outs from the FD&C Act’s 

definition of ‘‘new drug.’’ 1 First, when 

Congress enacted the modern FD&C Act 

in 1938, it exempted from the definition 

of ‘‘new drug’’ all drugs ‘‘subject to the 

Food and Drugs Act of June 30, 1906, as 

amended, and if at such time its labeling 

contained the same representations 

concerning the conditions of its use.’’ 

FD&C Act 201(p)(1), 21 U.S.C. 321(p)(1). 

Second, drugs that are generally 

recognized as safe and effective which 

have also ‘‘been used to a material 

extent or for a material time’’ are not 

‘‘new drugs.’’ FD&C Act 201(p)(1) and 

(2), 21 U.S.C. 321(p)(1) and (2). Drugs 

that meet either of these exceptions may 

be legally marketed without FDA preapproval for safety and efficacy, subject 

to the agency’s other regulatory 

authorities. 

Through a guidance document issued 

in 2006 and later revised in 2011, and 

without conducting notice-andcomment rulemaking, FDA launched a 

program called the Unapproved Drugs 

Initiative (UDI).2 The UDI sprang from 

a laudable objective, namely to reduce 

the number of unapproved drugs on the 

market. To achieve this end, FDA 

provided in its 2011 UDI Guidance that 

‘‘the first company to obtain an approval 

[of a previously unapproved drug] will 

have a period of de facto market 

exclusivity before other products obtain 

approval.’’ 3 The agency ‘‘hope[d] that 

this period of market exclusivity will 

provide an incentive to firms to be the 

first to obtain approval to market a 

previously unapproved drug.’’ 4

Ultimately, manufacturers of older 

drugs previously thought to be exempt 

from the FDA approval requirement 

obtained market exclusivity for those 

products after FDA took unapproved 

versions off the market. An unintended 

consequence of the ‘‘period of de facto 

market exclusivity’’ provided by the 

UDI allowed manufacturers an 

opportunity to raise prices in an 

environment largely insulated from 

market competition. 

Based on its ongoing review of FDA 

regulatory programs, the Department 

has decided to withdraw the 2006 and 

2011 Guidance, effective thirty days 

after the date of publication of this 

Notice in the Federal Register. All 

compliance manuals, website 

statements, and other informal 

issuances with respect to the 2006 and 

2011 Guidance are also hereby 

withdrawn. The withdrawal of the 2006 

and 2011 Guidance Documents 

complies with FDA’s current Good 

Guidance Practices regulation, which 

allows for ‘‘periodic[ ] review of [of] 

existing guidance documents to 

determine whether they need to be 

changed or withdrawn.’’ 21 CFR 

10.115(k)(1). Nothing in this Notice 

otherwise limits FDA’s authority to take 

action against manufacturers of 

unapproved drugs that meet the 

statutory definition of a ‘‘new drug’’ 

(such as, for example, an unapproved 

drug that claims to mitigate, treat, or 

cure COVID–19) or violate the FD&C Act 

in other ways. Further, nothing in this 

Notice limits FDA’s grant of regulatory 

exclusivities authorized by statute, such 

as a new chemical entity exclusivity, 

orphan drug exclusivity, or pediatric 

exclusivity. This Notice does not apply 

to drugs subject to (1) Investigational 

New Drug applications (IND) that are in 

effect as of the effective date of this 

Notice, (2) any subsequent NDA based 

on new clinical trial investigations 

(other than bioavailability studies) 

derived under such IND, and (3) 

existing approved NDAs. 

The Department is withdrawing the 

2006 and 2011 Guidances for several 

evidence-based reasons. After the UDI 

began, reports emerged that Americans 

were paying significantly more for 

prescription drugs approved by FDA 

through the UDI than they had paid 

previously. One report noted that a drug 

approved through the UDI ‘‘sells for 

about $4.50 a tablet—nearly 50 times 

the price of the unapproved version.’’ 5

Another report asserted that ‘‘[t]hanks at 

least partially to the FDA program, the 

price of vasopressin . . . has risen 10- 

fold’’ and the cost of ‘‘a vial of 


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Federal Register / Vol. 85, No. 228 / Wednesday, November 25, 2020 / Notices 75333 

6Michael Hiltzik, The little-known FDA program 

that’s driving drug prices higher, L.A. Times (Sept. 

23, 2015), https://www.latimes.com/business/ 

hiltzik/la-fi-mh-the-little-known-fda-program20150923-column.html. 

7Ravi Gupta et al., The FDA Unapproved Drugs 

Initiative: An Observational Study of the 

Consequences for Drug Prices and Shortages in the 

United States, 23 J. of Man. Care & Specialty Pharm. 

1066 (Oct. 2017). 

8 Id. at 1071. 

9See id. at 1072. 

10 Id. at 1068. 

11 Id. at 1073. 

12 Id. 

13 Id.; see also Aaron S. Kesselheim and Daniel 

H. Solomon, Incentives for Drug Development—The 

Curious Case of Colchicine, N. Engl. J. Med. 362;22 

at 2046 (noting the dramatic rise in the price of 

Colchicine after implementation of the UDI, but that 

‘‘there is no evidence of any meaningful 

improvement to the public health’’ from the 

regulatory changes). 

13 36 FR 14662, 14662–63 (Aug. 7, 1971). 

14See, e.g., 5 U.S.C. 553. The Department also has 

concerns regarding whether the issuance of the 

2011 Guidance complied with FDA’s good guidance 

practices regulation, 21 CFR 10.115, in effect at the 

time. FDA issued the 2011 Guidance ‘‘without 

public comment because the Agency has 

determined that prior public participation is not 

feasible or appropriate.’’ 76 FR 58398 (Sept. 21, 

2011). 

15 2011 Guidance at 7. 16 Id. at 2. 17 Id. at 3. 

neostigimine . . . has gone from less 

than $5 to $90.’’ 6

In 2017, scholars from the Yale 

School of Medicine and the University 

of Utah published a peer-reviewed 

study corroborating the previous 

reports.7 The study reviewed 34 drugs 

subject to the UDI between 2006 and 

2015. The scholars found the average 

wholesale unit price of 26 of the 34 

drugs for which pricing data was 

available increased by a median of 37% 

(interquartile range of 23%–204%).8

The average wholesale unit price of 11 

of the drugs surveyed in the study 

increased by more than 128%.9

The study also linked the UDI to drug 

shortages, which the authors defined as 

‘‘a supply issue that affects how a 

pharmacy prepares or dispenses a drug 

product that influences patient care 

when prescribers must use an 

alternative agent.’’ 10 In this regard, the 

scholars found that 24 of the 34 drugs 

experienced shortages after FDA took 

enforcement action after an entity 

obtained FDA approval of a previously 

unapproved drug. The median shortage 

was 217 days.11

Finally, the authors considered 

whether the UDI generated new clinical 

data evidence for older drugs. The 

authors found that, of the nineteen 

drugs that obtained FDA approval 

during the study period, only two were 

supported by ‘‘new clinical trial 

evidence.’’ 12 The other seventeen drugs 

‘‘were supported by literature reviews 

and bioequivalence to older drug 

products.’’ 13

Therefore, the Department has 

concluded that while the UDI began 

with laudable goals, it has had 

numerous negative, unintended 

consequences on Americans’ access to 

prescription drugs and generated very 

limited benefits. 

Moreover, the fact that the program 

was initiated through guidance, as 

opposed to notice-and-comment 

rulemaking, further supports the 

Department’s decision to withdraw the 

2006 and 2011 Guidances, because the 

Department has serious legal concerns 

about whether the UDI was 

implemented through legally 

permissible procedures.14 The 

Department recognizes that some 

persons might contend that they have 

reliance interests in the 2011 Guidance 

remaining in effect. In Dep’t of 

Homeland Sec. v. Regents of the Univ. 

of California, 140 S. Ct. 1891 (2020), the 

Supreme Court struck down the 

Department of Homeland Security’s 

rescission of the Deferred Action for 

Childhood Arrivals (DACA) 

immigration program, in part based on 

the reliance interests of persons eligible 

to obtain the benefits of the program. 

Notably, in that case, immigration 

authorities ‘‘solicited applications from 

eligible aliens, instituted a standardized 

review process, and sent formal notices 

indicating whether the alien would 

receive the two-year forbearance.’’ Id. 

As the Court explained, DACA ‘‘created 

a program for conferring affirmative 

immigration relief.’’ Id. 

The UDI is distinguishable from the 

DACA program. Unlike DACA, the 2011 

Guidance described how the FDA 

intended to exercise its enforcement 

discretion, but stopped short of 

committing FDA to any particular 

action. FDA stated that it was ‘‘more 

likely to take enforcement action’’ 

against unapproved competitors of 

newly approved drugs under the UDI, 

but that the agency ‘‘intend[s] to take 

into account the circumstances once the 

product is approved in determining how 

to exercise our enforcement discretion 

with regard to the unapproved 

products.’’ 15 Moreover, the 2011 

Guidance stated that it ‘‘does not create 

or confer any rights for or on any person 

and does not operate to bind FDA or the 

public.’’ 16 Any reliance interests are 

thus illusory. Furthermore, Congress 

vested FDA with the sole authority to 

enforce the FD&C Act. FD&C Act 310, 21 

U.S.C. 337. Under Heckler v. Chaney, 

470 U.S. 821 (1985), FDA’s decision 

about the extent to which it shall 

enforce the FD&C Act is unreviewable 

under the Administrative Procedure 

Act. 

Even if there were cognizable reliance 

interests in the UDI, the Department has 

ample evidence-based justification for 

rescinding the 2006 and 2011 

Guidances. After more than fourteen 

years of experience with the program, 

evidence has emerged that the UDI has 

caused significant prescription drug 

price increases and drug shortages while 

providing limited new clinical data on 

older drugs. The Department believes 

these costs imposed on American 

patients and taxpayers outweigh any 

reliance interests that may exist in the 

program. The Department has also 

considered the public health effects of 

withdrawing the 2006 and 2011 

Guidances. As the 2011 Guidance 

acknowledges, there are ‘‘several 

thousand’’ products on the market that 

lack FDA approval.17 To the extent this 

program has limited patient access to 

important, safe medications due to price 

increases or drug shortages, the 

withdrawal of the 2006 and 2011 

Guidances will have a positive impact 

on public health. Moreover, eliminating 

this program allows FDA’s resources to 

be directed toward monitoring 

unapproved ‘‘new drugs’’ that fall 

squarely within the traditional scope of 

the definition of that term in the FD&C 

Act. At the same time, the Notice allows 

FDA to use its limited review resources 

on innovative potential therapies, as 

opposed to older drugs with 

longstanding use. 

Besides, any reliance interests (if they 

existed) would be minimal. This Notice 

does not apply to drugs subject to (1) 

INDs in effect as of the effective date of 

this Notice, (2) any subsequent NDA 

based on new clinical investigations 

(other than bioavailability studies) 

derived under such IND, and (3) 

existing approved NDAs. 

II. Pre-1938 Grandfathered and GRASE 

Drugs; Request for Information 

As noted above, when Congress 

enacted the FD&C Act in 1938 and later 

amended the Act in 1962, it exempted 

certain drugs from the FDA approval 

requirement. Section 201(p) of the FD&C 

Act, 21 U.S.C. 321(p), excludes from the 

definition of ‘‘new drug’’ certain drugs 

marketed prior to June 25, 1938 and 

drugs generally recognized as safe and 

effective, or GRASE. In the 2011 

Guidance, FDA stated that ‘‘it is not 

likely that any currently marketed 

prescription drug is grandfathered or is 

otherwise not a new drug,’’ though the 


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75334 Federal Register / Vol. 85, No. 228 / Wednesday, November 25, 2020 / Notices 

18 Id. at 12 (emphasis in original). 

19FDA, Approved Prescription Drug Products 

with Therapeutic Equivalence Evaluations (herein 

the Orange Book), at I–3 (1st ed. 1980). 

20 Id. at I–13. 

21 Id. at I–13. FDA, Orange Book, at v (2000); see 

also FDA, Orange Book, at iv (29th ed. 2009) 

(containing same reference to ‘‘pre-1938 drugs’’ and 

phenobarbital tablets). FDA included a reference to 

‘‘pre-1938 drugs’’ like phenobarbital tablets in the 

Orange Book as late as 2016, FDA, Orange Book, at 

iv (36th ed. 2016), but removed the reference in its 

2017 edition and subsequent versions. 

22Cf. F.C.C. v. Fox Television Stations, Inc., 556 

U.S. 502, 515 (2009) (‘‘To be sure, the requirement 

that an agency provide reasoned explanation for its 

action would ordinarily demand that it display 

awareness that it is changing position.’’) 

23FDA, Ctr. For Drug Evaluation and Research, 

Application Number: 204200Origs1s000, 

204200Orig2s000, Summary Review, at 3, https://

www.accessdata.fda.gov/drugsatfda_docs/nda/ 

2012/204200Orig1Orig2s000SumR.pdf. 

24 75 FR 60768 (Oct. 1, 2010). 

25 Gupta, supra note 7, at 1072; see also Aaron S. 

Kesselheim and Daniel H. Solomon, Incentives for 

Drug Development—The Curious Case of 

Colchicine, N. Engl. J. Med. 362;22 at 2046 (noting 

the dramatic rise in the price of Colchicine after 

implementation of the UDI, but that ‘‘there is no 

evidence of any meaningful improvement to the 

public health’’ from the regulatory changes). 

26 36 FR 14662, 14662–63 (Aug. 7, 1971). 

27World Health Organization, 20th WHO Model 

List of Essential Medications, at 24 (Mar. 2017). 

28Andrew Pollack, Drug Goes From $13.50 a 

Tablet to $750, Overnight, N.Y. Times, Sept. 20, 

2015, https://www.nytimes.com/2015/09/21/ 

business/a-huge-overnight-increase-in-a-drugsprice-raises-protests.html. 

agency stated ‘‘that it is at least 

theoretically possible.’’ 18

That was not always the case. For 

many years, FDA acknowledged that at 

least some drugs are not ‘‘new drugs’’ 

subject to FDA approval prior to 

marketing. In a 1980 version of the 

Orange Book, FDA stated that ‘‘[t]he law 

also permits drugs to be legally 

marketed without such fully approved 

applications under certain 

circumstances,’’ including ‘‘drugs 

marketed prior to 1938 that are not 

subject to the pre-market clearance 

procedures of the law’’ and ‘‘drug 

products marketed between 1938 and 

1962 that were approved for safety but 

not effectiveness.’’ 19 In the same 

publication, the agency went on to 

identify specific products, noting 

‘‘commonly used large volume 

intravenous products are not included 

on the List [of FDA-approved drugs] 

(e.g., dextrose 5% with water, dextrose 

10% with water, sodium chloride 0.9% 

injection),’’ since ‘‘all of these drug 

products came on the market in glass 

containers before 1938 and have not 

been required to obtain an approved 

new drug application as a condition of 

marketing.’’ 20 In the 2000 edition of the 

Orange Book, FDA cited to the 

barbiturate ‘‘Phenobarbital Tablets’’ as 

an example of ‘‘pre-1938 drugs.’’ 21 The 

2011 Guidance, issued absent noticeand-comment rulemaking and without 

prior public comment, contains no 

acknowledgement of these prior 

positions.22

This evolution in the agency’s 

thinking has had consequences. Under 

the UDI, FDA required the manufacturer 

of an epinephrine brand which 

originally came onto the market in 1901 

to submit an NDA.23 The drug 

colchicine, a product FDA 

acknowledged ‘‘was available in oral 

dosage form during the 19th century,’’ 24

was also approved through the UDI. The 

interpretation of the definition of ‘‘new 

drug’’ espoused in the 2011 Guidance 

essentially foreclosed the possibility 

that these two century-old drugs were 

pre-1938 grandfathered drugs exempt 

from the approval process. The 2017 

study discussed above found that the 

average wholesale unit price of 

epinephrine and colchicine increased 

by 58.3% and 3,323.5%, respectively,25

costs absorbed by American patients 

and taxpayers. 

The regulatory history of the 

prescription drug Daraprim raises 

similar issues. FDA originally approved 

Daraprim (pyrimethamine) for safety in 

1953, and later deemed the drug 

effective through the Drug Efficacy 

Study Implementation, or DESI review 

process.26 The drug is listed on the 

World Health Organization’s List of 

Essential Medications, ‘‘a list of 

minimum medicine needs for a basic 

health-care system, listing the most 

efficacious, safe and cost-effective 

medicines for priority conditions.’’ 27 In 

2015, the company Turing 

Pharmaceuticals ‘‘raised the price [of 

the drug] to $750 a tablet from $13.50, 

bringing the annual cost of treatment for 

some patients to hundreds of thousands 

of dollars.’’ 28 Turing came by this 

windfall, at least in part, because of 

FDA’s interpretation of the definition of 

‘‘new drug’’ in the FD&C Act as 

articulated in the 2006 and 2011 

Guidances, a view that foreclosed the 

possibility that Daraprim, a drug more 

than sixty years old, could ever qualify 

as GRASE. That position effectively 

prevented other manufacturers of 

generic versions of this product from 

entering the market without an 

approved abbreviated new drug 

application, allowing Turing to enjoy a 

single-source position in the 

marketplace while potential competitors 

went through the regulatory process. In 

February 2016, Congress held a hearing 

on this widely-publicized issue. 

Ultimately, FDA approved a generic 

competitor for this single-source drug in 

February 2020. 

The Department wishes to engage 

with the public on the contours of the 

exceptions to the definition of ‘‘new 

drug.’’ In this regard, HHS is reviewing 

whether certain drugs, including the 

drug subject to Congressional scrutiny 

in 2016, might qualify as exempt from 

the FDA approval requirement. To aid 

that effort, HHS asks for input from 

patients, health care providers, industry, 

and other stakeholders to provide 

information responsive to any of the 

topics below: 

1. Lists of drugs marketed prior to 

June 25, 1938 that are currently 

available on the market. 

2. The extent to which drugs 

marketed prior to June 25, 1938, or 

drugs that might qualify as GRASE, have 

regulatory approvals in countries 

outside the United States. 

3. Whether there would be adverse 

clinical or economic consequences to 

deeming as GRASE those drugs 

previously approved by the FDA for 

which patent and regulatory exclusivity 

have expired. 

4. Any published literature reviews or 

clinical studies related to any drugs 

potentially exempt from the new drug 

approval requirement. 

Dated: November 20, 2020. 

Alex M. Azar II, 

Secretary, Department of Health and Human 

Services. 

[FR Doc. 2020–26133 Filed 11–24–20; 8:45 am] 

BILLING CODE 4150–26–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2010–D–0529] 

Qualification Process for Drug 

Development Tools; Guidance for 

Industry; Availability 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice of availability. 

SUMMARY: The Food and Drug 

Administration’s (FDA or Agency) 

Center for Drug Evaluation and Research 

(CDER) and Center for Biologics 

Evaluation and Research (CBER) are 

announcing the availability of a final 

guidance for industry and FDA staff 

entitled ‘‘Qualification Process for Drug 

Development Tools.’’ Under the 21st 

Century Cures Act (Cures Act), enacted 

on December 13, 2016, a new section 

was added to the Federal Food, Drug, 

and Cosmetic Act (FD&C Act), which 

defined a three-stage qualification 

process for drug development tools 

(DDTs). This guidance meets the Cures 


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