How are rules codified in the CFR ?

The Rulemaking Process from Start to Finish

Food and Drugs

21
PARTS 500 TO 599 Revised as of April 1, 1998

Rulemaking Process

The following discussion and examples track a rule from the grant of authority in law to the proposed rule, the final rule, and codification in the CFR

Public Law

Federal Register NPRM

Federal Register RULE

Code of Federal Regulations

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What Triggers Rulemaking ?

Legislation, Congressional hearings/reports Executive orders and OMB Circulars Court Orders Agencies act on own initiative to carry out mission See the Unified Agenda for regulatory plans Petitions for Rulemaking and informal requests from affected parties Federal Advisory Committee Recommendations Emergency situations, technological developments Political Factors

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Authorization in Public Law

Rulemaking usually begins with Congressional action. The next example shows a grant of rulemaking authority:
! Under the Animal Drug Availability Act of 1996 (ADAA) (Public Law 104- 250), enacted October 9, 1996 ! The ADAA amended the Food, Drug and Cosmetic Act.
Signals Congressional intent for Food and Drug Administration (FDA) to administer the regulations on behalf of the Secretary of Health and Human Services (HHS).

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PUBLIC LAW 104-250 OCTOBER 9, 1996

110 STAT. 3151

Statutes at Large citation

Public Law Number

Public Law 104-250 th 104 Congress An Act

To amend the Federal Food, Drug, and Cosmetic Act to provide for improvements in the process of approving and using animal drugs, and for other purposes. Oct. 9, 1996 [H.R. 2508]

Be it enacted by the Senate and House of Representatives of the United States of America in Congress assembled,
SECTION 1. SHORT TITLE; REFERENCE.

Date of enactment

Animal Drug Availability Act of 1996. 21 USC 301 note.

Note the identifying information in headings and side notes

(a) SHORT TITLE.This Act may be cited as the Animal Drug Availability Act of 1996. (b) REFERENCE.Whenever in this Act an amendment or repeal is expressed in terms of an amendment to, or repeal of, a section or other provision, the reference shall be considered to be made to a section or other provision of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321 et seq.).
SEC. 2. EVIDENCE OF EFFECTIVENESS.

Popular name of law

(a) ORIGINAL APPLICATIONS.Paragraph (3) of section 512(d) (21 U.S.C. 360b(d)) is amended to read as follows: (3) As used in this section, the term substantial evidence means evidence consisting of one or more adequate and well controlled investigations, such as (A) a study in a target species; (B) a study in laboratory animals; (C) any field investigation that may be required under this section and that meets the requirements of subsection (b)(3) if a presubmission conference is requested by the applicant; (D) a bioequivalence study; or (E) an in vitro study; by experts qualified by scientific training and experience to evaluate

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Rulemaking Instructions in the Law

FDA must issue regulations to implement the law.

! Law sets a schedule for issuing proposed and final rules ! Instruction to publish regulations will not always make explicit reference to FR, but the agency must publish in Federal Register and follow APA notice and comment rulemaking process.

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United States Code citation in the side note

110 STAT. 3154

PUBLIC LAW 104-250 OCTOBER 9, 1996

Regulations. (e) IMPLEMENTATION. Effective date. (1) IN G ENERAL.Not later than 6 months after the date of 21 USC 360b note. enactment of this Act, the Secretary of Health and Human

Directive to HHS to issue regulations Timeline for action

Services shall issue proposed regulations implementing the amendments made by this Act as described in paragraph (2)(A) of this subsection, and not later than 18 months after the date of enactment of this Act, the Secretary shall issue final regulations implementing such amendments. Not later than 12 months after the date of enactment of this Act, the Secretary shall issue proposed regulations implementing the other amendments made by this Act as described in paragraphs (2)(B) and (2)(C) of this subsection, and not later than 24 months after the date of enactment of this Act, the Secretary shall issue final regulations implementing such amendments. (2) CONTENTS.In issuing regulations implementing the amendments made by this Act, and in taking an action to review an application for approval of a new animal drug under section 512 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b), or a request for an investigational exemption for a new animal drug under subsection (j) of such section, that is pending or has been submitted prior to the effective date of the regulations, the Secretary shall (A) further define the term adequate and well controlled, as used in subsection (d)(3) of section 512 of such Act, to require that field investigations be designed and conducted in a scientifically sound manner, taking into account practical conditions in the field and differences between field conditions and laboratory conditions; (B) further define the term substantial evidence, as defined in subsection (d)(3) of such section, in a manner that encourages the submission of applications and supplemental applications; and (C) take into account the proposals contained in the citizen petition (FDA Docket No. 91P0434/CP) jointly submitted by the American Veterinary Medical Association and the Animal Health Institute, dated October 21, 1991. Until the regulations required by subparagraph (A) are

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Proposed Rulemaking
The APA requires agencies to give the public the opportunity to comment by submitting:
! Written data ! Views or arguments

The time needed to issue an NPRM varies

! The animal drug law set a 6 month time limit

In the next example:

! FDA published the proposed rule on May 8, 1997, about 7 months after the law was enacted, slightly past the deadline

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Federal Register/Vol. 62, No. 89/ Thursday, May 8, 1997/Proposed Rules 25153

NPRM published May 8, 1997

DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 514
[Docket No. 97N-0141]

Adequate and Well-Controlled Studies for Investigational Use and Approval of New Animal Drugs AGENCY: Food and Drug Administration, HHS. ACTION: Notice of proposed rulemaking. ---------------------------------------------------------------SUMMARY: The Food and Drug Administration (FDA), as directed by the Animal Drug Availability Act of 1996 (ADAA), is publishing a proposed regulation to further define the term adequate and well-controlled to require that field investigations be designed and conducted in a scientifically sound manner. Elsewhere in this issue of the Federal Register, FDA is reopening docket number 96N-0411 to receive comments regarding a concept, good study practices, that is related to the definition of adequate and well-controlled studies. DATES: Written comments by July 22, 1997. ADDRESSES: Submit written comments to the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. FOR FURTHER INFORMATION CONTACT: Herman M. Schoenemann, Center for Veterinary Medicine (HFV-126), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1638. SUPPLEMENTARY INFORMATION: I. Background Congress enacted the ADAA (Pub. L. 104-250) on October 9, 1996. Section 2(e) of the ADAA directs FDA to issue, within 6 months of its enactment, proposed regulations to further define the term adequate and well-controlled to require that field

The public has 75 days to comment

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Federal Register / Vol. 62, No. 89 / May 8, 1997/ Proposed Rules 25157

3. New Sec. 514.117 is added to subpart B to read as follows:

Proposed Amendment to the CFR

514.117 Adequate and wellcontrolled studies. (a) Purpose. The primary purpose of conducting adequate and well-controlled studies of a new animal drug is to distinguish the effect of the new animal drug from other influences, such as spontaneous change in the course of the disease, normal animal production performance, or biased observation. One or more adequate and wellcontrolled studies are required to establish, by substantial evidence, that a new animal drug is effective. The characteristics described in paragraph (b) of this section have been developed over a period of years and are generally recognized as the essentials of an adequate and well-controlled study. Wellcontrolled, as used in the phrase adequate and well-controlled, emphasizes an important aspect of adequacy. FDA considers these characteristics in determining whether a study is adequate and well-controlled for purposes of section 512 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b).. . .

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Final Rulemaking
It is not unusual for more than a year to pass between proposed and final rules.
! In the next example, FDA published the final rule on March 5, 1998, in time to meet the 18 month statutory deadline

The preamble of a final rule typically contains:

! Statement of the requirements in the law ! Cite to proposed rule and other rulemaking history ! Discussion and analysis of public comments received ! Justification for agencys final decisions

Rulemaking Process Final rule published in FR on March 5, 1998

Fe der al Regis ter / Vol . 6 3 , N o. 4 3 / T hurs da y, March 5 1 9 9 8 / Rules an d Regul ati ons 1 0 7 65

D EP A RTM EN T OF H E ALT H A ND HUM A N S E RV IC ES Food a nd Drug Adm ini stra tion 21 CF R P a rt 51 4

[Docket No . 97N-0141]

Ade qua te a nd W e ll-Controlle d S tudie s f or Inve stiga tiona l U se a nd Appro va l of Ne w Anim al Drug s AG E NC Y: Foo d an d D rug A d m inis tratio n, HHS . ACTIO N: Final rule. ----- --------- --------- --------- --------- --------- ---------------- --------- --------- --------- --------- SUMM A R Y: Th e Fo od an d Dru g A dminis tratio n (F DA ), as d irected b y th e A n ima l Dru g A v ailab ility A ct o f 19 9 6 (A DA A ), is amen d ing its regu latio n s g ov ernin g n ew animal d rug ap p licatio n s to fu rth er d efin e th e term ad equ ate an d well-co n tro lled s tud ies . The pu rp os e o f this fin al ru le is to furth er defin e ad eq u ate and well con tro lled to req u ire th at field inv es tig atio ns b e des ig ned an d con d ucted in a s cien tifica lly s o u n d man ner, tak in g in to acco u nt p ractical co nd ition s in the fie ld an d d iffe ren ces b etween field co nd ition s an d lab o ratory co n d itio ns . DA T ES : Th e reg u latio ns are effectiv e o n A pril 6, 1 998. FOR FUR T H ER IN FO R MA T ION C ON T AC T : Herman M . Sch o en eman n , Cen ter fo r Vete rin ary M ed ic in e (HF V-1 2 6), Foo d an d Dru g A dmin is tratio n , 7 50 0 Stan d is h Pl., Ro ckv ille, M D 2 0 85 5, 3 0 1-59 4-1 638. S UPP L E M EN T AR Y IN FOR MA T IO N: I. B ack g rou n d Co n g res s en acted th e A DA A (Pu b . L. 1 04-250) o n Octo ber 9, 199 6. Section 2(e) o f th e A DA A directs FDA to is s u e, within 18 mo n th s o f its en actment, fina l reg u lat io ns to furth er d efin e th e term ad eq u ate an d well co n tro lled to requ ire th at f ield in ves tig atio ns be des ig ned and co n du cted in a s cientifically s ou n d man n er, tak ing into accou nt p ractical co nd ition s in the fie ld an d d ifferen ces b etween fie ld co n d itio n s an d lab o rato ry co n ditio ns . In an ad v an ce no tice of p ro p os ed rule makin g th at p u b lis hed in th e Fed eral Reg is ter of Nov emb e r 21 , 19 96 (6 1 F R 5 9 20 9) , FDA s o lic ited co mments fro m in teres ted p arties o n ho w to fu rth er d efin e ad eq u ate an d well co n trolled as it 1 relates to fie ld s tu d ies . Do cket No . 9 6N -04 1 1 was created fo r co mmen ts res p ond in g to this n otice. In the Fed eral Reg is ter o f M ay 8, 1 9 97 (6 2 F R 2 5 15 3) , F DA pro p o s ed to amen d its regu latio n s in p art 5 14 (2 1 CF R p art 5 14) to fu rth er d efin e th e ter m ad eq u ate an d well-co n trolled s tud ies . FDA p ro vid ed 7 5 d ay s fo r pu b lic co mment o n the p ro pos ed ru le. Do c ket No. 9 7N -014 1 was created fo r co mments reg ard in g th is p ro pos ed ru le. A s

Rule is effective 18 months from enactment of public law

References to public law and proposed rule

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Federal Register / Vol. 63, No. 43 / Thursday, March 5, 1998 / .. 10768

A. Section 514.117(a)
1. AHI recommended that FDA clarify in proposed Sec. 514.117(a) that reports of adequate and well-controlled studies refer to reports of adequate and well-controlled effectiveness studies. Based on the following discussion, FDA does not find it necessary to make such a clarification. Under section 512(d)(1)(E) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b(d)(1)(E)), FDA must refuse to approve a new animal drug application if there is a lack of substantial evidence that the drug will have the effect it is purported or represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling. By definition, substantial evidence consists of one or more adequate and well-controlled studies on the basis of which experts qualified by scientific training and experience to evaluate the effectiveness of the drug could fairly and reasonably conclude that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in its proposed labeling (section 512(d)(3) of the act). Thus, it is clear and well established that adequate and well-controlled studies are studies intended to determine whether or not a drug is effective. Because it is adequate and well-controlled studies and not just reports of adequate and well-controlled studies that provide a basis for determining whether a new animal drug is effective, and in some instances support a claim of target animal safety, FDA is deleting Reports of in the second to last sentence in proposed Sec. 514.117(a). In that same sentence, FDA is also clarifying that adequate and well-controlled studies may be relied upon to support target animal safety but are not necessary to support claims of target animal safety. Studies intended to demonstrate safety need not be adequate and well-controlled studies (see section 512(d)(1) of the act, which states that in order to secure approval of a new animal drug, a sponsor must conduct adequate tests by all methods reasonably applicable to show whether or not such drug is safe). In proposed Sec. 514.117(a), FDA intended only to note that adequate and well-controlled studies intended to demonstrate whether a new animal drug is effective may be designed in a manner that also permits sponsors to simultaneously collect target animal safety data. If a sponsor needs to demonstrate through a field study that a new animal drug is safe for use in the target animal, the sponsor may do so by adequate tests by methods that are reasonably applicable or as part of an adequate and well-controlled study that is designed to determine the effectiveness of the new animal drug. Accordingly the second to last sentence in Sec. 514.117(a) will now provide that adequate and well-controlled studies, in addition to providing a basis for determining whether a new animal drug is effective, may also be relied upon to support target animal safety.

Point-by-point analysis and response to public comments

Discussion of variations between proposed rule and final rule

Rulemaking Process

Federal Register / Vol. 63, No. 43 / Thursday, March 5, 1998 . 10770 Lists of Subjects in 21 CFR Part 514 Administrative practice and procedure, Animal drugs, Confidential business information, Reporting and recordkeeping requirements. Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs, 21 CFR part 514 is amended as follows: PART 514--NEW ANIMAL DRUG APPLICATIONS 1. The authority citation for 21 CFR part 514 continues to read as follows: Authority: 21 U.S.C. 351, 352, 360b, 371, 379e, 381. 2. Section 514.111 is amended by revising paragraph (a)(5) to read as follows: 514.111 Refusal to approve an application. (a) * * * (5) Evaluated on the basis of information submitted as part of the application and any other information before the Food and Drug Administration with respect to such drug, there is lack of substantial evidence consisting of one or more adequate and well-controlled studies by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and reasonably be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. ***** 3. New Sec. 514.117 is added to subpart B to read as follows:

Amendatory instructions

514.117 Adequate and well-controlled studies.

(a) Purpose. The primary purpose of conducting adequate and well-controlled studies of a new animal drug is to distinguish the effect of the new animal drug from other influences, such as spontaneous change in the course of the disease, normal animal production performance, or biased observation. One or more adequate and well-controlled studies are required to establish, by substantial evidence, that a new animal drug is effective. The characteristics described in paragraph (b) of this section have been developed over a period of years and are generally recognized as the essentials of an adequate and well-controlled study. /\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\

Text of new section 514.117 in part 514 of title 21

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CFR Codification

In the next example: FDA published the new animal drugs rule on March 5, 1998 The rule was integrated into the April 1, 1998 revision of title 21 -- Food and Drugs

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Food and Drugs

21
PARTS 500 TO 599 Revised as of April 1, 1998

Title 21, like most CFR titles, has multiple volumes. The new rule was codified in the volume containing parts 500-599 of title 21.

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Part Level Table of Contents, Authority Citations, and Source Notes

The next example shows: A new entry in the table of contents at the part level to reflect the newly added section of regulatory text The authority citation below the table of contents:
! Refers readers to the agencys statutory, Presidential or internal authority to issue regulations in this part

The source note below the authority cite:

! Indicates when the part was last published in full, citing the volume, page and date

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Table of Contents, Authority Cite, Source Note

Title 21--Food and Drugs C H A PT E R I--FO O D AN D D RU G AD M INIST R ATIO N , D E PA R T M EN T O F H E ALT H AN D H U M AN S ER V ICE S--(C ontin ued) PA R T 514--N E W A N IM A L D R U G A PPLIC A TIO N S

Su bp art A G en eral Provisions *** Su bp art B A dm inistrative A ction s on A pplications Section 514.117 added to Table of Contents 514.100 514.105 514.106 514.110 514.111 514.112 Evaluation and com m ent on applications. Approval of applications. Approval of supplem ental applications. R easons for refusing to file applications. R efusal to approve an application. R eturn of applications for anim al feeds bearing or containing new anim al drugs. 514.115 W ithdraw al of approval of applications. 514.116 N otice of w ithdraw al of approval of application. 514.117 Adequate and w ell-controlled studies. 514.120 R evocation of order refusing to approve an application or suspending or w ithdraw ing approval of an application. 514.121 Service of notices and orders. Su bp art C H earing Procedures *** Su bp arts D -E [R eserved] Su bp art F Ju d icial R eview 514.235 Judicial review.

Authority Citation and Source Note

A UTHO RITY : 21 U .S.C . 351, 352, 360b, 371, 379e, 381 S O URCE : 40 FR 13825, M ar. 27, 1975, unless otherw ise noted.

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CFR Text, Section Level Source Notes, and Authority Citations

In the next example: The text of new section 514.117 has been inserted into CFR Title 21, Chapter I, Part 514, Subpart B according to instructions in final rule A source note follows the text of the section to indicate the recent amendment that added this section No separate authority citation for this section
! The section level authority for this section is the same as the part level authority

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TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION, DE AND HUMAN SERVICES--(Continued) PART 514--NEW ANIMAL DRUG APPLICATIONS--Table Subpart B--Administrative Actions on Applications

continue >

CFR Text & Section Source Note

Text of 514.117 added to CFR

514.116 Notice of withdrawal of approval of

application. When an approval of an application submitted pursuant to section 512 of the act is withdrawn by the Commissioner, he will give appropriate public notice of such action by publication in the FEDERAL REGISTER.

514.117 Adequate and well-controlled studies.

(a) Purpose. The primary purpose of conducting adequate and well-controlled studies of a new animal drug is to distinguish the effect of the new animal drug from other influences, such as spontaneous change in the course of the disease, normal animal production performance, or biased observation. One or more adequate and well-controlled studies are required to establish, by substantial evidence, that a new animal drug is effective. The characteristics described in paragraph (b) of this section have been developed over a period of years and are generally recognized as the essentials of an adequate and well-controlled study. Well controlled, as used in the phrase adequate and well controlled, emphasizes an important aspect of adequacy. The Food and Drug Administration (FDA) considers these characteristics in determining whether a study is adequate and well controlled for purposes of section 512 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b). Adequate and wellcontrolled studies, in addition to providing a basis for determining whether a new animal drug is effective, may also be relied upon to support target animal safety. /\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\/\

Updated Source Note cites to the final rule

[63 FR 10770, Mar.5, 1998]