Federal Register / Vol. 86, No. 154 / Friday, August 13, 2021 / Notices 44731 

proposed collection of information, 

including each proposed extension or 

reinstatement of an existing collection 

of information, before submitting the 

collection to OMB for approval. To 

comply with this requirement, CMS is 

publishing this notice that summarizes 

the following proposed collection(s) of 

information for public comment: 

1. Type of Information Collection 

Request: Revision of a currently 

approved collection; Title of 

Information Collection: Request for 

Certification as Supplier of Portable XRay Services under the Medicare/ 

Medicaid Program; Use: CMS–1880 is 

initially completed by suppliers of 

portable X-ray services, expressing an 

interest in and requesting participation 

in the Medicare program. The CMS– 

1880 form initiates the process of 

obtaining a decision as to whether the 

conditions of coverage are met by the 

portable X-ray supplier seeking 

Medicare participation. It also promotes 

data reduction or introduction to, and 

retrieval from, the Certification and 

Survey Provider Enhanced Reporting 

(CASPER) by the CMS Regional Offices 

(ROs). The CMS–1880 form is also 

completed by current Medicare 

participating portable x-ray supplier 

during each recertification survey. Form 

Numbers: CMS–1880 (OMB control 

number: 0938–0027); Frequency: 

Occasionally; Affected Public: State, 

Local, or Tribal Governments; Number 

of Respondents: 104; Total Annual 

Responses: 104; Total Annual Hours: 

26. (For policy questions regarding this 

collection contact Caroline Gallaher at 

410–786–8705.) 

2. Type of Information Collection 

Request: Extension of a currently 

approved collection; Title of 

Information Collection: Request for 

Certification in the Medicare/Medicaid 

Program for Provides of Outpatient 

Physical Therapy and/or SpeechLanguage Pathology; Use: The form is 

used as an application to be completed 

by providers of outpatient physical 

therapy and/or speech-language 

pathology services requesting 

participation in the Medicare and 

Medicaid programs. This form initiates 

the process of obtaining a decision as to 

whether the conditions of participation 

are met as a provider of outpatient 

physical therapy and/or speechlanguage pathology services. The form is 

used by the State Agencies (SAs) to 

enter the new prospective provider into 

the national surveyor database. The 

form is also used for recertification of 

the provider. Surveyors are no longer 

required to use form CMS–1856. 

Surveyors are now able to access survey 

resources electronically from the 

national surveyor database, as a result, 

the need for surveyors to carry printed 

copies of the survey information data is 

no longer efficient. Form Number: 

CMS–1856 (OMB control number: 

0938–0065); Frequency: Annually, 

occasionally; Affected Public: Private 

sector—Business or other for-profit and 

Not-for-profit institutions; Number of 

Respondents: 195; Total Annual 

Responses: 195; Total Annual Hours: 

49. (For policy questions regarding this 

collection contact Caecilia Blondiaux at 

410–786–2190.) 

Dated: August 10, 2021. 

William N. Parham, III, 

Director, Paperwork Reduction Staff, Office 

of Strategic Operations and Regulatory 

Affairs. 

[FR Doc. 2021–17374 Filed 8–12–21; 8:45 am] 

BILLING CODE 4120–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2020–N–1245] 

Drug Products Approved in 

Abbreviated New Drug Applications 

Before the Enactment of the HatchWaxman Amendments; Establishment 

of a Public Docket; Request for 

Comments 

AGENCY: Food and Drug Administration, 

Health and Human Services (HHS). 

ACTION: Notice; establishment of a 

public docket; request for comments. 

SUMMARY: The Food and Drug 

Administration (FDA or Agency) is 

announcing the establishment of a 

public docket to solicit comments on 

several issues related to FDA’s postapproval regulation of certain drug 

products approved in abbreviated 

applications before the Drug Price 

Competition and Patent Term 

Restoration Act of 1984 (Hatch-Waxman 

Amendments) amended the Federal 

Food, Drug, and Cosmetic Act (FD&C 

Act) to establish the current abbreviated 

new drug application (ANDA) process. 

Because these pre-Hatch-Waxman 

abbreviated new drug applications 

(referred to in this notice as ‘‘PANDAs’’) 

were submitted and approved under the 

provisions of the FD&C Act that apply 

to 505(b) new drug applications, they 

can serve as a reference listed drug 

(RLD) for ANDAs and can also be a 

listed drug relied on by 505(b)(2) 

applications. PANDAs have historically 

been overseen by FDA’s Office of 

Generic Drugs, and FDA is aware that 

there may be some confusion about the 

applicability of certain statutory and 

regulatory provisions to PANDAs. FDA 

is seeking input from holders of 

PANDAs and other interested persons 

regarding whether there are regulatory 

or policy rationales for treating PANDAs 

differently from other 505(b) 

applications in certain respects. 

DATES: Submit either electronic or 

written comments by December 13, 

2021. 

ADDRESSES: FDA is establishing a docket 

for public comments on this document. 

The docket number is FDA–2020–N– 

1245. The docket will close on 

December 13, 2021. Submit either 

electronic or written comments by that 

date. Please note that late, untimely 

filed comments will not be considered. 

Electronic comments must be submitted 

on or before December 13, 2021. The 

https://www.regulations.gov electronic 

filing system will accept comments 

until 11:59 p.m. Eastern Time at the end 

of December 13, 2021. Comments 

received by mail/hand delivery/courier 

(for written/paper submissions) will be 

considered timely if they are 

postmarked or the delivery service 

acceptance receipt is on or before that 

date. 

You may submit comments 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: 


jbell on DSKJLSW7X2PROD with NOTICES
44732 Federal Register / Vol. 86, No. 154 / Friday, August 13, 2021 / Notices 

1 If a drug product was found to be less than 

effective for one or more labeled indications in 

FDA’s initial DESI review, the Agency provided an 

opportunity to submit additional data and 

eventually an opportunity for a hearing on those 

indications found to be less than effective. FDA 

considered the basis of any hearing request and 

either granted or denied the hearing request and 

published its final determination in the Federal 

Register. If FDA’s final determination classified a 

drug product as effective for an indication, those 

marketing that drug product and drugs identical, 

related or similar to it were required to obtain 

approved applications for continued marketing for 

that indication. If FDA’s final determination 

classified the drug product as lacking substantial 

evidence of effectiveness for an indication, the 

product and those identical, related or similar to it 

could no longer be legally marketed for that 

indication. 

2See the Washington briefing on FDA’s drug 

efficacy review, FDA Papers, at pp. 10–12 (March 

1968) and Address of Commissioner James L. 

Goddard, M.D., at the Alpha Omega Alpha Lecture 

at Yale New Haven Medical Center on New Drug 

Research and Development (April 17, 1968). 

3The content of section 505(b) of the FD&C Act 

regarding the required contents of an application 

remained largely unchanged following the 

enactment of the Hatch-Waxman Amendments, 

except for changes related to new patent submission 

requirements and, for applications submitted 

• 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– 

2020–N–1245 for ‘‘Drug Products 

Approved in Abbreviated New Drug 

Applications Before the Enactment of 

the Hatch-Waxman Amendments; 

Establishment of a Public Docket; 

Request for Comments.’’ Received 

comments, those filed in a timely 

manner (see ADDRESSES), 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, 240–402–7500. 

• 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.govinfo.gov/content/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, 240–402–7500. 

FOR FURTHER INFORMATION CONTACT: 

Melissa Mannion, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 75, Room 1611, 

Silver Spring, MD 20993, 301–796– 

2747, Melissa.Mannion@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

A. Abbreviated New Drug Applications 

Before the Hatch-Waxman Amendments 

After the enactment of the FD&C Act 

(Pub. L. 75–717) in 1938, new drug 

products were required to be approved 

on the basis of safety before they could 

be marketed. Between 1938 and 1962, if 

a drug product obtained approval, FDA 

considered drug products that were 

identical, related, or similar to the 

approved product to be covered by that 

approval; such identical, related, or 

similar products were marketed without 

independent approval. An identical, 

related, or similar drug includes another 

brand, potency, dosage form, salt, or 

ester of the same drug moiety related in 

chemical structure or known 

pharmacological properties (see 21 CFR 

310.6(b)(1)). In 1962, the KefauverHarris Drug Amendments (Pub. L. 87– 

781) amended the FD&C Act to require 

that new drug products also be shown 

to be effective in order to obtain 

approval of a new drug application 

(NDA). After the enactment of the 

Kefauver-Harris Drug Amendments, 

FDA initiated the Drug Efficacy Study 

Implementation (DESI) to evaluate the 

effectiveness of drug products that had 

been approved between 1938 and 1962 

solely on the basis of safety. DESI also 

covered the identical, related, or similar 

products that had entered the market 

without approval. If drug products were 

determined to be effective for one or 

more indications,1 manufacturers that 

were already marketing under an NDA 

were required to submit a supplement to 

update the application and revise the 

product labeling as necessary. 

Manufacturers of drug products that 

were identical, related, or similar were 

required to submit applications for their 

drug products. 

FDA introduced the concept of an 

‘‘abbreviated new drug application’’ in 

1968 2 as a vehicle for approval of 

certain drugs affected by the DESI 

review, and in 1970, FDA published a 

final rule establishing a regulatory 

pathway for submission of abbreviated 

applications for these drugs (see 35 FR 

6574 (April 24, 1970); see also 34 FR 

2673 (February 27, 1969)). This 

abbreviated approval mechanism was 

created to offer manufacturers of certain 

drugs a streamlined and more 

administratively efficient path to seek 

FDA approval as part of the DESI review 

(47 FR 46622 at 46631 to 46632 (October 

19, 1982)). 

When a drug product subject to the 

DESI review was determined to be 

effective for one or more indications, 

FDA would issue a Federal Register 

notice (DESI notice) for that drug 

product describing the DESI review 

findings and stating whether 

abbreviated new drug applications that 

met specified criteria could be 

submitted to FDA (see generally 35 FR 

11273 (July 14, 1970); 35 FR 6574) for 

products that had not been marketed 

under an NDA. Such a finding allowed 

manufacturers to submit an abbreviated 

new drug application (i.e., a PANDA) in 

lieu of an NDA. 

For approval of PANDAs, FDA relied 

on the evidence of effectiveness that had 

been provided, reviewed, and accepted 

during the DESI process. FDA evaluated 

the safety of these drug products on the 

basis of information included in NDAs 

submitted prior to 1962, as well as the 

subsequent marketing experience with 

the drugs (see 54 FR 28872 at 28873 

(July 10, 1989)). PANDAs were 

submitted under section 505(b) of the 

FD&C Act and approved under section 

505(c) of the FD&C Act.3


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pursuant to section 505(b)(2) of the FD&C Act, 

patent certification requirements. 

4Prior to the enactment of the Food and Drug 

Administration Modernization Act of 1997, 

applications for antibiotic drugs were generally 

approved for safety and effectiveness under section 

507 of the FD&C Act rather than under section 505 

of the FD&C Act. For purposes of section 507, the 

term ‘‘antibiotic drug’’ was defined as any drug 

intended for use by man containing any quantity of 

any chemical substance which is produced by a 

microorganism and which has the capacity to 

inhibit or destroy microorganisms in dilute solution 

(including the chemically synthesized equivalent of 

any such substance). See 21 U.S.C. 357 (1964 ed.; 

1994 ed.). Although there was a mechanism for 

approving abbreviated applications for antibiotics 

under section 507 that pre-dated the HatchWaxman Amendments, in this notice the term 

PANDAs refers only to those applications submitted 

under section 505(b) of the FD&C Act, and not to 

applications for antibiotic drug products submitted 

under section 507 of the FD&C Act. FDA intends 

to address these antibiotic products separately. 

5 In the context of PANDAs, the term ‘duplicate’ 

applied to a drug product that was the same as an 

already approved drug product in dosage form, 

route of administration, kind and amount of active 

ingredient, indication(s), and any other conditions 

of use. See 54 FR 28872 at 28872 (July 10, 1989). 

6 In the context of the Hatch-Waxman 

Amendments, the term duplicate generally refers to 

a ‘‘drug product that has the same active 

ingredient(s), dosage form, strength, route of 

administration, and conditions of use as a listed 

drug . . .’’ 54 FR 28872 at 28877. 

Because the history of FDA review of 

applications for antibiotic drug products 

is more complex and historically many 

were subject to section 507 of the FD&C 

Act (21 U.S.C. 357 (1994 ed.); repealed 

upon the enactment of the Food and 

Drug Administration Modernization Act 

of 1997 (Pub. L. 105–115)), the scope of 

this notice is limited to drug products 

approved in PANDAs under section 505 

of the FD&C Act prior to the HatchWaxman Amendments; this notice does 

not cover applications for antibiotic 

drug products that were originally 

submitted under section 507 of the 

FD&C Act.4

Because PANDAs could be for 

products that were ‘‘similar or related’’ 

to, and not just ‘‘duplicates’’ 5 of, drug 

products approved in NDAs before 

October 10, 1962, and listed in DESI 

notices (pre-1962 NDA drug products), 

FDA’s ‘‘Approved Drug Products With 

Therapeutic Equivalence Evaluations’’ 

(Orange Book) lists both unique 

products approved in PANDAs (i.e., no 

NDA was ever approved for the 

identical drug product), and products 

approved in PANDAs that may be 

duplicates of pre-1962 NDA drug 

products. In the Orange Book, a product 

approved in a PANDA typically is 

identified as an ‘‘ANDA.’’ (The 

application type for a product is 

identified in the Orange Book by either 

an ‘‘N’’ (for an NDA) or an ‘‘A’’ (for an 

ANDA) before the application number.) 

Although the regulations establishing 

the pathway for PANDAs were similar 

in some respects to the ANDA pathway 

created by the Hatch-Waxman 

Amendments and described in section 

505(j) of the FD&C Act, the requirements 

under the old regulatory pathway 

(which evolved over the decade-plus in 

which it was operational before the 

Hatch-Waxman Amendments) also 

differed in many respects from current 

ANDA requirements. For example, 

although the conditions of use and 

labeling for PANDA products had to be 

in accord with the relevant DESI notice 

(which frequently covered a class of 

drugs that included multiple products 

and multiple active ingredients) (see, 

e.g., 36 FR 11227 (June 10, 1971); 35 FR 

18215 (November 28, 1970); and 35 FR 

12356 (August 1, 1970)), PANDA 

products were not required to have the 

same labeling as a particular pre-1962 

NDA drug product listed in the DESI 

notice. In addition, although PANDAs 

were required to include adequate data 

to assure biological availability of the 

drug if the relevant DESI notice for that 

drug specified that such data should be 

submitted for the formulation intended 

for marketing, PANDAs generally did 

not have to include data to demonstrate 

bioequivalence to a particular pre-1962 

NDA drug product (see, e.g., 21 CFR 

130.4(f)(3) (1971 ed.) and 21 CFR 

314.2(f)(3) (1984 ed.)). In addition, drug 

products with a different formulation, 

active ingredient, route of 

administration, dosage form, or strength 

than the pre-1962 NDA drug products 

listed in the DESI notice could be 

submitted in PANDAs. Prior to the 

Hatch-Waxman Amendments, there 

were also no requirements related to 

patent listing or patent certification or 

exclusivity for PANDAs or other 

applications approved under section 

505(c) of the FD&C Act. 

B. Hatch-Waxman Amendments 

In 1984, the Hatch-Waxman 

Amendments added section 505(b)(2) 

and section 505(j) to the FD&C Act. 

These sections provide an abbreviated 

approval pathway for submission of two 

types of applications: Section 505(b)(2) 

new drug applications (505(b)(2) 

applications) and section 505(j) 

abbreviated new drug applications (for 

purposes of this notice, referred to 

hereinafter as ‘‘505(j) ANDAs’’). A 

505(b)(2) application is an NDA 

submitted under section 505(b)(1) and 

approved under section 505(c) of the 

FD&C Act that contains full reports of 

investigations of safety and 

effectiveness, where at least some of the 

information required for approval comes 

from studies not conducted by or for the 

applicant and for which the applicant 

has not obtained a right of reference or 

use (e.g., the Agency’s finding of safety 

and/or effectiveness for a listed drug). A 

505(j) ANDA is an application that 

requests FDA approval to market a 

duplicate of a listed drug.6 Regulations 

implementing the Hatch-Waxman 

Amendments define a listed drug as a 

new drug product that has been 

approved under section 505(c) of the 

FD&C Act for safety and effectiveness or 

under section 505(j) of the FD&C Act, 

which has not been withdrawn or 

suspended under section 505(e)(1) 

through (5) or section 505(j)(6) of the 

FD&C Act, and which has not been 

withdrawn from sale for what FDA has 

determined are reasons of safety or 

effectiveness. Listed drug status is 

evidenced by the drug product’s 

identification in the current edition of 

FDA’s ‘‘Approved Drug Products With 

Therapeutic Equivalence Evaluations’’ 

(the list) as an approved drug. A drug 

product is deemed to be a listed drug on 

the date of approval for the NDA or 

ANDA for that drug product. (See 

§ 314.3(b) (21 CFR 314.3(b)), as 

amended at 81 FR 69580 at 69638 

(October 6, 2016); see also section 

505(j)(2)(A), (j)(7) of the FD&C Act). 

FDA regulations require an applicant 

to refer in its 505(j) ANDA to the 

specific listed drug on which the 

applicant relies in seeking approval of 

the 505(j) ANDA (§ 314.94(a)(3) (21 CFR 

314.94(a)(3)); see also section 505(j)(2) 

of the FD&C Act). The listed drug that 

a generic applicant seeks to duplicate is 

commonly referred to as the reference 

listed drug (RLD) (see definition in 

§ 314.3(b)). A 505(j) ANDA applicant 

must show, among other things, that the 

proposed generic drug is bioequivalent 

to the RLD, and that it has the same 

active ingredient(s), conditions of use, 

route of administration, dosage form, 

strength, and (with limited exceptions) 

labeling as the RLD (section 505(j)(2)(A), 

(j)(2)(C), and (j)(4) of the FD&C Act; see 

also § 314.94(a)). We note that certain 

differences between an RLD and a 

proposed generic drug product may be 

permitted in an ANDA if these 

differences are the subject of an 

approved suitability petition (see 

section 505(j)(2)(C) of the FD&C Act and 

21 CFR 314.93). An applicant may 

submit a suitability petition to FDA 

requesting permission to submit an 

ANDA for a generic drug product that 

differs from an RLD in its route of 

administration, dosage form, or strength 

or that has one different active 

ingredient in a fixed-combination drug 

product (ibid.). 

Because a 505(j) ANDA applicant is 

relying on FDA’s finding that the RLD 


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44734 Federal Register / Vol. 86, No. 154 / Friday, August 13, 2021 / Notices 

7For the most recent version of a guidance, check 

the FDA guidance web page at https://www.fda.gov/ 

regulatory-information/search-fda-guidancedocuments. 

is safe and effective, FDA’s general 

practice is to designate as RLDs drug 

products that have been approved under 

section 505(c) for safety and 

effectiveness. Similarly, FDA 

regulations require a 505(b)(2) applicant 

to identify in its application each listed 

drug for which FDA has made a finding 

of safety and effectiveness on which the 

applicant relies in seeking approval of 

its proposed drug product (21 CFR 

314.54(a)(1)(iii)). 

Listed drugs appear in the Orange 

Book, and beginning in 1992, the 

Orange Book also began identifying 

which listed drugs were designated as 

RLDs to aid 505(j) ANDA applicants. 

The listed drugs that were designated as 

RLDs were labeled with a ‘‘+’’ sign in 

the paper version of the Orange Book, 

and with the word ‘‘Yes’’ in the column 

titled RLD in the electronic version of 

the Orange Book. Before 2017, the ‘‘+’’ 

sign and the word ‘‘Yes’’ in the column 

labeled RLD were used to denote at 

times an RLD and at other times a 

reference standard, which is the drug 

product selected by FDA that an 

applicant seeking approval of a 505(j) 

ANDA must use in conducting an in 

vivo bioequivalence study required for 

approval of the ANDA (§ 314.3(b)). 

The reference standard selected by 

FDA is ordinarily the RLD. However, at 

times the reference standard is a drug 

product other than the RLD. For 

example, if the NDA RLD is no longer 

marketed, FDA generally will select as 

the reference standard a previously 

approved 505(j) ANDA that refers to that 

RLD. Where the RLD was no longer 

marketed and FDA selected a new 

reference standard, FDA’s practice prior 

to 2017 was to identify the reference 

standard with the ‘‘+’’ sign in the paper 

version of the Orange Book and ‘‘Yes’’ 

in the RLD column of the electronic 

version of the Orange Book; FDA also 

would move the previously identified 

RLD to the discontinued section of the 

Orange Book without a ‘‘+’’ sign in the 

paper version or RLD designation in the 

electronic version of the Orange Book. 

Because the ‘‘+’’ sign or RLD 

designation in some cases identified 

drug products that were RLDs as well as 

reference standards, and in other cases 

identified reference standards that were 

not also the RLD, there may have been 

some confusion among 505(j) ANDA 

applicants about which product to cite 

as the RLD when the reference standard 

and RLD were not the same drug 

product. Inconsistent use of 

terminology, as well as certain longstanding FDA practices, may have 

added to this confusion. 

C. FDA’s Current Identification of RLDs 

and Reference Standards in the Orange 

Book 

In 2017, FDA began to separately 

identify in the Orange Book which 

listed drugs, including some in the 

‘‘Discontinued Drug Product List’’ 

(discontinued section), are designated as 

RLDs, and which listed drugs in the 

Active Section (i.e., in the sections 

entitled ‘‘Prescription Drug Product 

List’’ and ‘‘Over-the-Counter Drug 

Product List’’) are selected as reference 

standards. In the electronic version of 

the Orange Book, there is one column 

that identifies RLDs and a separate 

column that identifies reference 

standards. In the printed version of the 

Orange Book, the RLDs and reference 

standards are identified by distinct 

symbols. 

These changes to the Orange Book 

were intended to provide clarity to 

505(j) ANDA applicants as to which 

listed drugs are the RLDs (versus the 

reference standards) for a drug product. 

For some drug products, however, these 

changes revealed that no product is 

identified as being approved under an 

NDA (in either the active or 

discontinued sections of the Orange 

Book) that could serve as an RLD for a 

505(j) ANDA. The lack of an RLD is 

confusing because the Orange Book 

reflects that there are approved ANDAs 

for the drug product, including ANDAs 

identified as reference standards. One 

reason for this lack of an RLD is that 

some of the products listed in the 

Orange Book and identified as being 

approved in an ‘‘ANDA’’ are actually 

drugs that were approved for safety and 

effectiveness under section 505(c) of the 

FD&C Act in PANDAs that appeared to 

have been identified as RLDs before the 

2017 update to the Orange Book. As 

noted previously, products approved in 

PANDAs could be unique products that 

differed from products approved under 

pre-1962 NDAs in various ways, 

including in their active ingredient, 

route of administration, dosage form, or 

strength. In addition, even when certain 

listed drugs approved in a PANDA 

appear to be pharmaceutical equivalents 

(as defined in § 314.3(b)) of products 

approved under an NDA, these products 

can differ from the products approved 

under the NDA in other respects, 

including in the approved conditions of 

use reflected in the labeling or in their 

formulation, and may not have been 

determined to be bioequivalent to the 

products approved under an NDA. 

Further, even if the drug product 

approved in a PANDA was a duplicate 

of a drug product that was at one time 

also approved and marketed under an 

NDA, if the product approved under the 

NDA was no longer marketed when the 

Orange Book was first published in 

October 1980, it was not listed in the 

Orange Book. 

D. Designation of Additional Drugs as 

RLDs 

In light of the changes to the Orange 

Book in 2017, FDA examined the types 

of products for which there were no 

RLDs designated and determined that 

many were approved in PANDAs. After 

consideration of the history of PANDAs, 

FDA determined that it was appropriate 

and consistent with FDA’s general 

practice regarding the designation of 

RLDs to designate PANDA products as 

RLDs because these products were 

approved for safety and effectiveness 

under section 505(c) of the FD&C Act. 

In addition, as noted in section I.C, 

many of these products appeared to 

have been identified as RLDs before the 

2017 update to the Orange Book. 

Designation of the PANDA products as 

RLDs provides clarity both to 

prospective 505(j) ANDA applicants 

seeking to make generic versions of 

these products, and to applicants of 

505(b)(2) applications that there is a 

finding of safety and effectiveness for 

these products that may be relied upon 

for approval. In addition, it is aligned 

with FDA’s efforts to help advance 

competition and increase patient access 

to more affordable medicines. 

FDA has begun adding RLD 

designations for PANDAs to the Orange 

Book and will continue making these 

designations as expeditiously as 

resources permit. If a prospective 505(j) 

ANDA applicant is seeking to duplicate 

a product approved in a PANDA that 

has not yet been designated as an RLD 

by FDA, the prospective applicant may 

submit controlled correspondence to 

FDA identifying the drug it intends to 

duplicate and asking FDA to designate 

that drug as an RLD (see FDA’s guidance 

for industry, ‘‘Controlled 

Correspondence Related to Generic Drug 

Development,’’ announced in 85 FR 

81928 (December 17, 2020)).7

To aid stakeholders in identifying 

PANDAs, FDA has posted a list of the 

products currently included in the 

Orange Book and identified as an 

‘‘ANDA’’ in the Orange Book that were 

approved in a PANDA for safety and 

effectiveness under section 505(c) prior 

to the enactment of the Hatch-Waxman 

Amendments. This list includes only 

PANDAs described in this notice, i.e., 


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Federal Register / Vol. 86, No. 154 / Friday, August 13, 2021 / Notices 44735 

8For products approved prior to January 1, 1982, 

the electronic version of the Orange Book indicates 

the product was ‘‘Approved Prior to Jan. 1, 1982’’ 

under Product Details in the Approval Date field, 

and the printed version of the Orange Book has a 

blank Approval Date field. For products approved 

on or after January 1, 1982, the electronic and 

printed versions of the Orange Book provide the 

specific date of approval in the Approval Date field. 

9The Hatch-Waxman Amendments were signed 

into law on September 24, 1984. PANDAs that were 

submitted before September 24, 1984, were 

processed by FDA in accordance with the 

procedures that existed before the passage of the 

Hatch-Waxman Amendments. See November 16, 

1984, letter to interested persons from Harry M. 

Meyer, Jr., M.D., Director, FDA’s Center for Drugs 

and Biologics. The list of PANDAs posted on FDA’s 

Orange Book web page (https://www.fda.gov/drugs/ 

drug-approvals-and-databases/approved-drugproducts-therapeutic-equivalence-evaluationsorange-book) includes all the abbreviated 

applications approved on or before September 24, 

1984. FDA is aware that certain applications 

submitted before this date but approved after this 

date and identified as ANDAs in the Orange Book 

were approved under section 505(c) of the FD&C 

Act; FDA will update this list as appropriate to 

include such applications. If a prospective 505(j) 

ANDA applicant is seeking to duplicate a product 

approved after September 24, 1984, and the 

applicant believes the application for the product 

was submitted before that date and approved under 

section 505(c) of the FD&C Act, the prospective 

applicant may submit controlled correspondence to 

FDA identifying the drug they intend to duplicate 

and asking FDA to designate that drug as an RLD. 

The controlled correspondence should include any 

information known to the prospective applicant 

that supports the belief that the identified drug was 

approved in a PANDA. When FDA receives such 

designation requests, it will evaluate whether the 

product was approved under section 505(c) of the 

FD&C Act in determining whether to grant the 

request. 

10See Title III of the Food and Drug 

Administration Safety and Innovation Act (Pub. L. 

112–144) and Title III of the FDA Reauthorization 

Act of 2017 (Pub. L. 115–52). 

those abbreviated applications 

submitted under section 505(b) of the 

FD&C Act and does not include 

applications for antibiotic drug products 

approved under section 507 of the FD&C 

Act before the enactment of the Food 

and Drug Administration Modernization 

Act of 1997 (FDAMA). This list is 

available under ‘‘Additional Resources’’ 

on FDA’s ‘‘Approved Drug Products 

with Therapeutic Equivalence 

Evaluations (Orange Book)’’ web page 

(available at https://www.fda.gov/drugs/ 

drug-approvals-and-databases/ 

approved-drug-products-therapeuticequivalence-evaluations-orange-book). 

In addition, the Orange Book provides 

information about the approval date of 

listed drugs,8 allowing interested 

persons to refer to this information to 

determine which products identified as 

being approved in an ANDA in the 

Orange Book were approved before the 

enactment of the Hatch-Waxman 

Amendments.9

II. Additional Issues for Consideration 

and Request for Comments 

The Agency is seeking input from 

holders of PANDAs and other interested 

stakeholders on several issues related to 

FDA’s post-approval regulation of drug 

products approved in PANDAs. As 

explained in section I of this notice, 

PANDAs were submitted under section 

505(b) and approved under section 

505(c) of the FD&C Act, which are the 

same provisions under which NDAs are 

submitted and approved. However, 

PANDA products have historically been 

overseen by FDA’s Office of Generic 

Drugs and are included in the definition 

of abbreviated new drug application for 

user fee purposes under the Generic 

Drug User Fee Amendments (GDUFA),10

which specify that this term includes an 

abbreviated new drug application 

submitted pursuant to regulations in 

effect prior to the implementation of the 

Drug Price Competition and Patent 

Term Restoration Act of 1984 (see 21 

U.S.C. 379j–41). PANDAs are not 

included in the FD&C Act statutory 

definition of the term abbreviated drug 

application, which is limited to 

applications submitted under section 

505(j) of the FD&C Act (see 21 U.S.C. 

321(aa)). 

FDA recognizes that PANDAs may 

have been treated similarly to 505(j) 

ANDAs in some respects over the 

decades after the enactment of the 

Hatch-Waxman Amendments, and that 

there may be confusion among holders 

of PANDAs about the applicability of 

certain statutory and regulatory 

provisions to their products and in 

particular, whether their products are 

subject to the requirements that apply to 

other 505(b) applications or to those that 

apply to 505(j) applications (to the 

extent there are differences between the 

two), including with respect to 

requirements regarding labeling 

updates, patent listing, eligibility for 

exclusivity, and certain drug safetyrelated requirements or procedures. 

For example, with respect to labeling 

updates, FDA is aware that some 

PANDA holders have followed 

procedures applicable to 505(b) 

applications when proposing labeling 

updates for their products (e.g., 

submitting labeling supplements and 

making labeling changes independent of 

the pre-1962 NDA product or products 

that were listed in the DESI notice). 

However, FDA is also aware that some 

PANDA holders have followed 

procedures applicable to 505(j) ANDA 

holders when proposing labeling 

updates for their products (e.g., 

submitting labeling supplements to 

conform to labeling changes approved 

for a pre-1962 NDA product listed in a 

relevant DESI notice). 

With respect to patent listing, to 

FDA’s knowledge, PANDA holders have 

neither sought to list patent information 

in the Orange Book for their products 

after the enactment of the HatchWaxman Amendments, nor have they 

submitted patent listing information 

when submitting supplements to their 

approved applications during the years 

after the enactment of the HatchWaxman Amendments. Similarly, 

PANDA holders have generally not 

submitted supplements containing 

reports of new clinical investigations or 

sought exclusivity under provisions 

applicable to 505(b) applications (see, 

e.g., section 505(c)(3)(E)(iv) and 

505(j)(5)(F)(iv) of the FD&C Act) 

following enactment of the HatchWaxman Amendments. 

FDA is also aware that there may be 

confusion among PANDA holders about 

the applicability of certain safety-related 

requirements to their applications. For 

example, section 505(o) of the FD&C 

Act, which relates to postmarket studies 

and clinical trials and labeling, and 

section 505–1 of the FD&C Act, which 

relates to risk evaluation and mitigation 

strategies, reflect some differences in the 

safety-related requirements or 

procedures that apply to 505(b) 

application holders versus 505(j) ANDA 

holders, and PANDA holders may 

consider the requirements that apply to 

505(j) ANDA holders to also apply to 

their applications. 

Although, as noted in section I of this 

notice, PANDAs are section 505(b) 

applications, FDA understands, as 

outlined above, that the holders of some 

PANDAs may have been following 

various requirements applicable to 

505(j) ANDAs over the years after the 

enactment of the Hatch-Waxman 

Amendments, and that for them to 

instead follow requirements applicable 

to 505(b) applications could be a change 

in practice. FDA also understands that 

PANDAs are a unique category of 505(b) 

applications and that there could be 

valid reasons to treat PANDAs 

differently from other 505(b) 

applications in certain circumstances, to 

the extent permitted by the applicable 

statutory provisions. 

FDA is seeking input from PANDA 

holders and other interested 

stakeholders on whether there are 

regulatory or policy reasons for treating 

PANDAs differently from other 505(b) 

applications, consistent with the 

statutory requirements for applications 

submitted under section 505(b) and 

approved under section 505(c) of the 

FD&C Act. To facilitate this input, FDA 

has developed the following list of 

questions. These questions are not 

meant to be exhaustive, and FDA is also 


jbell on DSKJLSW7X2PROD with NOTICES
44736 Federal Register / Vol. 86, No. 154 / Friday, August 13, 2021 / Notices 

interested in any other pertinent 

information stakeholders would like to 

share on this topic. In all cases, FDA 

encourages stakeholders to provide the 

specific rationale and basis for their 

comments, including any available 

supporting data and information. 

Questions 

1. Given the legal requirements in 

place for applications submitted under 

section 505(b) and approved under 

section 505(c) of the FD&C Act, are there 

regulatory or policy rationales for 

treating PANDAs differently from other 

505(b) applications in certain respects, 

in particular with respect to the 

following: 

1.1. Labeling requirements, including 

requirements related to updating 

product labeling to reflect certain types 

of newly acquired safety-related 

information by submitting a ‘‘changes 

being effected’’ (CBE–0) supplement to 

FDA? 

1.2. Patent listing requirements? 

1.3. Eligibility for exclusivity? 

1.4. Certain safety-related 

requirements, such as the postmarket 

studies and clinical trials or safetylabeling change requirements in section 

505(o) of the FD&C Act or the risk 

evaluation and mitigation strategies 

requirements in section 505–1 of the 

FD&C Act? 

In responding to the questions above, 

please provide a specific rationale for 

treating these applications differently. 

2. To the extent that PANDA holders 

are expected to make changes to their 

current practices, what factors should 

FDA consider in determining a 

reasonable amount of time for PANDA 

holders to make such changes to their 

practices? 

3. Are there additional steps FDA 

should take to highlight for PANDA 

holders that their ‘‘abbreviated new 

drug application’’ is a PANDA, i.e., that 

it is a 505(b) application? 

4. Are there additional steps FDA 

should take beyond posting the list on 

the Orange Book website to aid other 

interested persons in identifying 

PANDAs? 

5. Are modifications needed to the list 

of PANDAs posted on the Orange Book 

website for accuracy? For example, are 

some PANDAs missing from the list? 

6. Are there other issues FDA should 

consider in assessing the regulatory 

framework for PANDAs under the FD&C 

Act? Please provide specific examples 

and explain FDA’s authority to address 

these issues. 

Dated: August 10, 2021. 

Lauren K. Roth, 

Acting Principal Associate Commissioner for 

Policy. 

[FR Doc. 2021–17378 Filed 8–12–21; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

National Institute of Dental & 

Craniofacial Research; Notice of 

Meeting 

Pursuant to section 10(d) of the 

Federal Advisory Committee Act, as 

amended, notice is hereby given of a 

meeting of the National Advisory Dental 

and Craniofacial Research Council. 

The meeting will be held as a virtual 

meeting and is open to the public. 

Individuals who plan to view the virtual 

meeting and need special assistance or 

other reasonable accommodations to 

view the meeting, should notify the 

Contact Person listed below in advance 

of the meeting. The open session will be 

videocast and can be accessed from the 

NIH Videocasting and Podcasting 

website (http://videocast.nih.gov/). 

The meeting will be closed to the 

public in accordance with the 

provisions set forth in sections 

552b(c)(4) and 552b(c)(6), Title 5 U.S.C., 

as amended. The grant applications 

and/or contract proposals and the 

discussions could disclose confidential 

trade secrets or commercial property 

such as patentable material, and 

personal information concerning 

individuals associated with the grant 

applications and/or contract proposals, 

the disclosure of which would 

constitute a clearly unwarranted 

invasion of personal privacy. 

Name of Committee: National Advisory 

Dental and Craniofacial Research Council. 

Date: September 9, 2021. 

Open: 10:00 a.m. to 2:30 p.m. 

Agenda: Report of the Director, NICDR and 

concept clearances. 

Place: National Institutes of Health, 

National Institute of Dental and Craniofacial 

Research, 6701 Democracy Blvd., Bethesda, 

MD 20892 (Virtual Meeting). 

Closed: 2:45 p.m. to 4:00 p.m. 

Agenda: To review and evaluate grant 

applications and/or proposals. 

Place: National Institutes of Health, 

National Institute of Dental and Craniofacial 

Research, 6701 Democracy Blvd., Bethesda, 

MD 20892 (Virtual Meeting). 

Contact Person: Alicia J. Dombroski, Ph.D., 

Director, Division of Extramural Activities, 

National Institute of Dental and Craniofacial 

Research, National Institutes of Health, 

Bethesda, MD 20892, 301–594–4805, 

adombroski@nidcr.nih.gov. 

Any interested person may file written 

comments with the committee by forwarding 

the statement to the Contact Person listed on 

this notice. The statement should include the 

name, address, telephone number and when 

applicable, the business or professional 

affiliation of the interested person. 

Information is also available on the 

Institute’s/Center’s home page: http://

www.nidcr.nih.gov/about, where an agenda 

and any additional information for the 

meeting will be posted when available. 

(Catalogue of Federal Domestic Assistance 

Program No. 93.121, Oral Diseases and 

Disorders Research, National Institutes of 

Health, HHS) 

Dated: August 9, 2021. 

Melanie J. Pantoja, 

Program Analyst, Office of Federal Advisory 

Committee Policy. 

[FR Doc. 2021–17302 Filed 8–12–21; 8:45 am] 

BILLING CODE 4140–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

National Institute of Mental Health; 

Notice of Meeting 

Pursuant to section 10(d) of the 

Federal Advisory Committee Act, as 

amended, notice is hereby given of a 

meeting of the National Advisory 

Mental Health Council. 

The meeting will be held as a virtual 

meeting and is open to the public. 

Individuals who plan to view the virtual 

meeting and need special assistance or 

other reasonable accommodations to 

view the meeting, should notify the 

Contact Person listed below in advance 

of the meeting. The open session will be 

videocast and can be accessed from the 

NIH Videocasting and Podcasting 

website (http://videocast.nih.gov/). 

The meeting will be closed to the 

public in accordance with the 

provisions set forth in sections 

552b(c)(4) and 552b(c)(6), Title 5 U.S.C., 

as amended. The grant applications 

and/or contract proposals and the 

discussions could disclose confidential 

trade secrets or commercial property 

such as patentable material, and 

personal information concerning 

individuals associated with the grant 

applications and/or contract proposals, 

the disclosure of which would 

constitute a clearly unwarranted 

invasion of personal privacy. 

Name of Committee: National Advisory 

Mental Health Council. 

Date: September 14–15, 2021. 

Open: September 14, 2021, 12:00 p.m. to 

4:30 p.m. 

Agenda: Presentation of the NIMH 

Director’s Report and discussion of NIMH 

program. 


jbell on DSKJLSW7X2PROD with NOTICES