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U.S. Department of Health and Human Services

CFR - Code of Federal Regulations Title 21

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Help | More About 21CFR
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2013]
[CITE: 21CFR516]





TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER E--ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS
 
PART 516NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES
 

Subpart C--Index of Legally Marketed Unapproved New Animal Drugs for Minor Species

Sec. 516.111 Scope of this subpart.

This subpart implements section 572 of the act and provides standards and procedures to establish an index of legally marketed unapproved new animal drugs. This subpart applies only to minor species and not to minor use in major species. This index is only available for new animal drugs intended for use in a minor species for which there is a reasonable certainty that the animal or edible products from the animal will not be consumed by humans or food-producing animals and for new animal drugs intended for use only in a hatchery, tank, pond, or other similar contained man-made structure in an early, nonfood life stage of a food-producing minor species, where safety for humans is demonstrated in accordance with the standard of section 512(d) of the act (including, for an antimicrobial new animal drug, with respect to antimicrobial resistance). The index shall not include a new animal drug that is contained in, or a product of, a transgenic animal. Among its topics, this subpart sets forth the standards and procedures for:

(a) Investigational exemptions for indexing purposes;

(b) Submissions to FDA of requests for determination of eligibility of a new animal drug for indexing;

(c) Establishment and operation of expert panels;

(d) Submissions to FDA of requests for addition of a new animal drug to the index;

(e) Modifications to index listings;

(f) Publication of the index; and

(g) Records and reports.

Sec. 516.115 Definitions.

(a) The following definitions of terms apply only in the context of subpart C of this part:

Director OMUMS means the Director of the Office of Minor Use and Minor Species Animal Drug Development of the FDA Center for Veterinary Medicine.

Holder means the requestor of an index listing after the request is granted and the new animal drug is added to the index.

Index means FDA's list of legally marketed unapproved new animal drugs for minor species.

Intended use has the same meaning as that given in 516.13 of this chapter.

Qualified expert panel means a panel that is composed of experts qualified by scientific training and experience to evaluate the target animal safety and effectiveness of a new animal drug under consideration for indexing.

Requestor means the person making a request for determination of eligibility for indexing or a request for addition to the index.

Transgenic animal means an animal whose genome contains a nucleotide sequence that has been intentionally modified in vitro, and the progeny of such an animal, provided that the term `transgenic animal' does not include an animal of which the nucleotide sequence of the genome has been modified solely by selective breeding.

(b) The definitions of the following terms are given in 514.3 of this chapter:

Adverse drug experience.

Product defect/manufacturing defect.

Serious adverse drug experience.

Unexpected adverse drug experience.

(c) The definitions of the following terms are given in 516.3 of this chapter:

Same dosage form.

Same drug.

Same intended use.

Sec. 516.117 Submission of correspondence under this subpart.

Unless directed otherwise by FDA, all correspondence relating to any aspect of the new animal drug indexing process described in this subpart must be addressed to the Director, OMUMS. The initial correspondence for a particular index listing should include the name and address of the authorized contact person. Notifications of changes in such person or changes of address of such person should be provided in a timely manner.

Sec. 516.119 Permanent-resident U.S. agent for foreign requestors and holders.

Every foreign requestor and holder shall name a permanent resident of the United States as their agent upon whom service of all processes, notices, orders, decisions, requirements, and other communications may be made on behalf of the requestor or holder. Notifications of changes in such agents or changes of address of agents should preferably be provided in advance, but not later than 60 days after the effective date of such changes. The permanent resident U.S. agent may be an individual, firm, or domestic corporation and may represent any number of requestors or holders. The name and address of the permanent-resident U.S. agent shall be submitted to the Director, OMUMS, and included in the index file.

Sec. 516.121 Meetings.

(a) A requestor or potential requestor is entitled to one or more meetings to discuss the requirements for indexing a new animal drug.

(b) Requests for such meetings should be in writing, be addressed to the Director, OMUMS, specify the participants attending on behalf of the requestor or potential requestor, and contain a proposed agenda for the meeting.

(c) Within 30 days of receiving a request for a meeting, FDA will attempt to schedule the meeting at a time agreeable to both FDA and the person making the request.

Sec. 516.123 Informal conferences regarding agency administrative actions.

(a) Should FDA make an initial decision denying a request for determination of eligibility for indexing, terminating an investigational exemption, determining that a qualified expert panel does not meet the selection criteria, denying a request for addition to the index, or removing a new animal drug from the index, FDA will give written notice that specifies the grounds for the initial decision and provides an opportunity for an informal conference for review of the decision.

(b) The written notice will include information for scheduling the informal conference and state that a written request for a conference must be made within 60 days of the date FDA sends its notice.

(c) Within 45 days of receiving a request for an informal conference, FDA will schedule and hold the informal conference at a time agreeable to both FDA and the person making the request.

(d) Such an informal conference will be conducted by a presiding officer who will be the Director of the Center for Veterinary Medicine or his or her designee, excluding the Director of the Office of Minor Use and Minor Species Animal Drug Development and other persons significantly involved in the initial decision.

(e) The person requesting an informal conference must provide a written response to FDA's initial decision at least 2 weeks prior to the date of the scheduled meeting. Generally, this written response would be attached to the request for an informal conference. At the option of the person requesting an informal conference, such written response to FDA's initial decision may act in lieu of a face-to-face meeting. In this case, the informal conference will consist of a review by the presiding officer of the submitted written response.

(f) The purpose of an informal conference is to discuss scientific and factual issues. It will involve a discussion of FDA's initial decision and any written response to that decision.

(g) Internal agency review of a decision must be based on the information in the administrative file. If the person requesting an informal conference presents new information not in the file, the matter will be returned to the appropriate lower level in the agency for reevaluation based on the new information.

(h) Informal conferences under this part are not subject to the separation of functions rules in 10.55 of this chapter.

(i) The rules of evidence do not apply to informal conferences. No motions or objections relating to the admissibility of information and views will be made or considered, but any party to the conference may comment upon or rebut all such data, information and views.

(j) [Reserved]

(k) The presiding officer will prepare a written report regarding the subject of the informal conference that states and describes the basis for his or her findings. Whenever time permits, the parties to the informal conference will have 30 days to review and comment on the report.

(l) The administrative record of the informal conference will consist of:

(1) The notice providing an opportunity for an informal conference and the written response to the notice.

(2) All written information and views submitted to the presiding officer at the conference or, at the discretion of the presiding officer, thereafter.

(3) The presiding officer's written report.

(4) All correspondence and memoranda of any and all meetings between the participants and the presiding officer.

(m) The administrative record of the informal conference is closed to the submission of information at the close of the conference, unless the presiding officer specifically permits additional time for further submission.

(n) The administrative record of the informal conference specified herein constitutes the exclusive record for decision.

Sec. 516.125 Investigational use of minor species new animal drugs to support indexing.

(a) The investigational use of a new animal drug or animal feed bearing or containing a new animal drug intended solely for investigational use in minor species shall meet the requirements of part 511 of this chapter if the investigational use is for the purpose of:

(1) Demonstrating human food safety under section 572(a)(1)(B) of the act;

(2) Demonstrating safety with respect to individuals exposed to the new animal drug through its manufacture and use under section 572(c)(1)(F) of the act;

(3) Conducting an environmental assessment under section 572(c)(1)(E) of the act; or

(4) Obtaining approval of a new animal drug application or abbreviated new animal drug application under section 512(b) of the act.

(b) Correspondence and information associated with investigations described in paragraph (a) of this section shall not be sent to the Director, OMUMS, but shall be submitted to FDA in accordance with the provisions of part 511 of this chapter.

(c) The investigational use of a new animal drug or animal feed bearing or containing a new animal drug intended solely for investigational use in minor species, other than for an investigational use described in paragraph (a) of this section, shall meet the requirements of this section. For such investigations, all provisions of part 511 of this chapter apply with the following modifications:

(1) Under 511.1(a)(1) of this chapter, the label statement is as follows:

"Caution . Contains a new animal drug for investigational use only in laboratory animals or for tests in vitro in support of index listing. Not for use in humans."

(2) Under 511.1(b)(1) of this chapter, the label statement is as follows:

"Caution . Contains a new animal drug for use only in investigational animals in clinical trials in support of index listing. Not for use in humans. Edible products of investigational animals are not to be used for food for humans or other animals unless authorization has been granted by the U.S. Food and Drug Administration or by the U.S. Department of Agriculture."

(3) Under 511.1(b)(4) of this chapter, the notice is titled "Notice of Claimed Investigational Exemption for a New Animal Drug for Index Listing" and is submitted in duplicate to the Director, OMUMS.

(4) Under 511.1(c)(3) of this chapter, if an investigator is determined to be ineligible to receive new animal drugs, each "Notice of Claimed Investigational Exemption for a New Animal Drug for Index Listing" and each request for indexing shall be examined with respect to the reliability of information submitted by the investigator.

(5) Under 511.1(c)(4) and (d)(2) of this chapter, with respect to termination of exemptions, the sponsor of an investigation shall not be granted an opportunity for a regulatory hearing before FDA pursuant to part 16 of this chapter. Instead, the sponsor shall have an opportunity for an informal conference as described in 516.123.

(6) Under 511.1(c)(5) of this chapter, if the Commissioner of Food and Drugs determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the data remaining are such that a request for addition to the index would have been denied, FDA will remove the new animal drug from the index in accordance with 516.167.

(d) The investigational use of a new animal drug or animal feed bearing or containing a new animal drug subject to paragraph (c) of this section shall not be subject to the good laboratory practice requirements in part 58 of this chapter.

(e) Correspondence and information associated with investigations described in paragraph (c) of this section shall be sent to the Director, OMUMS, in accordance with the provisions of this section.

Sec. 516.129 Content and format of a request for determination of eligibility for indexing.

(a) Each request for determination of eligibility:

(1) May involve only one drug (or one combination of drugs) in one dosage form;

(2) May not involve a new animal drug that is contained in or a product of a transgenic animal;

(3) May not involve the same drug in the same dosage form for the same intended use as a drug that is already approved or conditionally approved; and

(4) Must be submitted separately.

(b) A request for determination of eligibility for indexing may involve multiple intended uses and/or multiple minor species. However, if a request for determination of eligibility for indexing that contains multiple intended uses and/or multiple minor species cannot be granted in any part, the entire request will be denied.

(c) A requestor must submit two copies of a dated request signed by the authorized contact person for determination of eligibility for indexing that contains the following:

(1) Identification of the minor species or groups of minor species for which the new animal drug is intended;

(2) Information regarding drug components and composition;

(3) A statement of the intended use(s) of the new animal drug in the identified minor species or groups of minor species;

(4) A statement of the proposed conditions of use associated with the stated intended use(s) of the new animal drug, including the proposed dosage, route of administration, contraindications, warnings, and any other significant limitations associated with the intended use(s) of the new animal drug;

(5) A brief discussion of the need for the new animal drug for the intended use(s);

(6) An estimate of the anticipated annual distribution of the new animal drug, in terms of the total quantity of active ingredient, after indexing;

(7) Information to establish that the new animal drug is intended for use:

(i) In a minor species for which there is a reasonable certainty that the animal or edible products from the animal will not be consumed by humans or food-producing animals; or

(ii) In a hatchery, tank, pond, or other similar contained man-made structure in (which includes on) an early, non-food life stage of a food-producing minor species, and information to demonstrate food safety in accordance with the standards of section 512(d) of the act and 514.111 of this chapter (including, for an antimicrobial new animal drug, with respect to antimicrobial resistance);

(8) A description of the methods used in, and the facilities and controls used for, the manufacture, processing and packing of the new animal drug sufficient to demonstrate that the requestor has established appropriate specifications for the manufacture and control of the new animal drug and that the requestor has an understanding of current good manufacturing practices;

(9) Either a claim for categorical exclusion under 25.30 or 25.33 of this chapter or an environmental assessment under 25.40 of this chapter;

(10) Information sufficient to support the conclusion that the new animal drug is safe under section 512(d) of the act with respect to individuals exposed to the new animal drug through its manufacture and use; and

(11) The name and address of the contact person or permanent-resident U.S. agent.

Sec. 516.131 Refuse to file a request for determination of eligibility for indexing.

(a) If a request for determination of eligibility for indexing contains all of the information required by 516.129, FDA shall file it, and the filing date shall be the date FDA receives the request.

(b) If a request for a determination of eligibility lacks any of the information required by 516.129, FDA will not file it, but will inform the requestor in writing within 30 days of receiving the request as to what information is lacking.

Sec. 516.133 Denying a request for determination of eligibility for indexing.

(a) FDA will deny a request for determination of eligibility for indexing if it determines upon the basis of the request evaluated together with any other information before it with respect to the new animal drug that:

(1) The same drug in the same dosage form for the same intended use is already approved or conditionally approved;

(2) There is insufficient information to demonstrate that the new animal drug is intended for use:

(i) In a minor species for which there is a reasonable certainty that the animal or edible products from the animal will not be consumed by humans or food-producing animals, or

(ii) In a hatchery, tank, pond, or other similar contained man-made structure in (which includes on) an early, non-food life stage of a food-producing minor species, and there is insufficient evidence to demonstrate safety for humans in accordance with the standard of section 512(d) of the act and 514.111 of this chapter (including, for an antimicrobial new animal drug, with respect to antimicrobial resistance);

(3) The new animal drug is contained in or is a product of a transgenic animal;

(4) There is insufficient information to demonstrate that the requestor has established appropriate specifications for the manufacture and control of the new animal drug and that the requestor has an understanding of current good manufacturing practices;

(5) The requester fails to submit an adequate environmental assessment under 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under 25.30 or 25.33 of this chapter;

(6) There is insufficient information to determine that the new animal drug is safe with respect to individuals exposed to the new animal drug through its manufacture or use; or

(7) The request for determination of eligibility for indexing fails to contain any other information required under the provisions of 516.129.

(b) FDA may deny a request for determination of eligibility for indexing if it contains any untrue statement of a material fact or omits material information.

(c) When a request for determination of eligibility for indexing is denied, FDA will notify the requestor in accordance with 516.137.

Sec. 516.135 Granting a request for determination of eligibility for indexing.

(a) FDA will grant the request for determination of eligibility for indexing if none of the reasons described in 516.133 for denying such a request applies.

(b) When a request for determination of eligibility for indexing is granted, FDA will notify the requestor in accordance with 516.137.

Sec. 516.137 Notification of decision regarding eligibility for indexing.

(a) Within 90 days after the filing of a request for a determination of eligibility for indexing based on 516.129(c)(7)(i), or 180 days for a request based on 516.129(c)(7)(ii), FDA shall grant or deny the request, and notify the requestor of FDA's decision in writing.

(b) If FDA denies the request, FDA shall provide due notice and an opportunity for an informal conference as described in 516.123 regarding its decision. A decision of FDA to deny a request for determination of eligibility for indexing following an informal conference shall constitute final agency action subject to judicial review.

Sec. 516.141 Qualified expert panels.

(a)Establishment of a qualified expert panel . Establishing a qualified expert panel is the first step in the process of requesting the addition of a new animal drug to the index. A qualified expert panel may not be established until FDA has determined that the new animal drug is eligible for indexing. The requestor must choose members for the qualified expert panel in accordance with selection criteria listed in paragraph (b) of this section and submit information about these proposed members to FDA. FDA must determine whether the proposed qualified expert panel meets the selection criteria prior to the panel beginning its work. Qualified expert panels operate external to FDA and are not subject to the Federal Advisory Committee Act, as amended, 5 U.S.C. App.

(b)Criteria for the selection of a qualified expert panel . (1) A qualified expert panel member must be an expert qualified by training and experience to evaluate a significant aspect of target animal safety or effectiveness of the new animal drug under consideration.

(2) A qualified expert panel member must certify that he or she has a working knowledge of section 572 of the act (the indexing provisions of the statute) and this subpart, and that he or she has also read and understood a clear written statement provided by the requestor stating his or her duties and responsibilities with respect to reviewing the new animal drug proposed for addition to the index.

(3) A qualified expert panel member may not be an FDA employee.

(4) A qualified expert panel must have at least three members.

(5) A qualified expert panel must have members with a range of expertise such that the panel, as a whole, is qualified by training and experience to evaluate the target animal safety and effectiveness of the new animal drug under consideration.

(6) Unless FDA makes a determination to allow participation notwithstanding an otherwise disqualifying financial interest, a qualified expert panel member must not have a conflict of interest or the appearance of a conflict of interest, as described in paragraph (g) of this section.

(c)Requestor responsibilities . (1) The requestor must:

(i) Choose members for the qualified expert panel in accordance with selection criteria listed in paragraph (b) of this section.

(ii) Provide each potential expert panel member a copy of section 572 of the act (the indexing provisions of the statute) and this subpart and obtain certification that he or she has a working knowledge of the information.

(iii) Provide each potential expert panel member a written statement describing the purpose and scope of his or her participation on the qualified expert panel and obtain certification that he or she has read and understood the information. The written statement should describe the duties and responsibilities of qualified expert panels and their members established by paragraphs (e) and (f) of this section, including the need to prepare a written report under 516.143.

(iv) Obtain information from each potential expert panel member demonstrating that he or she is qualified by training and experience to evaluate the target animal safety and effectiveness of the new animal drug under consideration. This information can be obtained from a comprehensive curriculum vitae or similar document.

(v) Notify each potential expert panel member that he or she must submit information relating to potential conflict of interest directly to FDA in a timely manner, as required in paragraph (e)(6) of this section.

(2) The requestor must submit, in writing, the names and addresses of the proposed qualified expert panel members and sufficient information about each proposed member for FDA to determine whether the panel meets the selection criteria listed in paragraphs (b)(1) through (b)(5) of this section.

(3) After FDA has determined that the qualified expert panel meets the selection criteria, the requestor must provide to the panel all information known by the requestor that is relevant to a determination of the target animal safety and the effectiveness of the new animal drug at issue. In addition, the requestor must notify FDA of the name of the qualified expert panel leader.

(4) The requestor must immediately notify FDA if it believes a qualified expert panel member no longer meets the selection criteria listed in paragraph (b) of this section or is otherwise not in compliance with the requirements of this section.

(5) If a qualified expert panel member cannot complete the review for which he or she was selected, the requestor must either choose a replacement or justify the continued work of the panel in the absence of the lost panelist. In either case, the requestor must submit sufficient information for FDA to determine whether the proposed revised qualified expert panel meets the selection criteria listed in paragraphs (b)(1) through (b)(5) of this section.

(6) The requestor must keep copies of all information provided to, or received from, qualified expert panel members, including the written report, for 2 years after the completion of the report, or the product is added to the index, whichever occurs later, and make them available to a duly authorized employee of the agency at all reasonable times.

(d)FDA responsibilities . (1) FDA will determine whether the requestor's proposed qualified expert panel meets the selection criteria listed in paragraph (b) of this section. FDA will expeditiously inform the requestor, in writing, of its determination. If FDA determines that the qualified expert panel does not meet the selection criteria, FDA will provide due notice and an opportunity for an informal conference as described in 516.123. A determination by FDA that a proposed qualified expert panel does not meet the selection criteria following an informal conference shall constitute final agency action subject to judicial review.

(2) If FDA determines that a qualified expert panel no longer meets the selection criteria listed in paragraph (b) of this section or that the panel or its members are not in compliance with the requirements of this section, the agency will expeditiously inform the requestor, in writing, of this determination and provide due notice and an opportunity for an informal conference as described in 516.123. A determination by FDA, following an informal conference, that a qualified expert panel no longer meets the selection criteria listed in paragraph (b) of this section or that the panel or its members are not in compliance with the requirements of this section shall constitute final agency action subject to judicial review.

(e)Responsibilities of a qualified expert panel member . A qualified expert panel member must do the following:

(1) Continue to meet all selection criteria described in paragraph (b) of this section.

(2) Act in accordance with generally accepted professional and ethical business practices.

(3) Review all information relevant to a determination of the target animal safety and effectiveness of the new animal drug provided by the requestor. The panel should also consider all relevant information otherwise known by the panel members, including anecdotal information.

(4) Participate in the preparation of the written report of the findings of the qualified expert panel, described in 516.143.

(5) Sign, or otherwise approve in writing, the written report. Such signature or other written approval will serve as certification that the written report meets the requirements of the written report in 516.143.

(6) Provide the information relating to potential conflict of interest described in paragraph (g) of this section to FDA for its consideration. Such information should be submitted directly to the Director, OMUMS, when notified by the requestor.

(7) Immediately notify the requestor and FDA of any change in conflict of interest status.

(8) Certify at the time of submission of the written report that there has been no change in conflict of interest status, or identify and document to FDA any such change.

(f)Additional responsibilities of a qualified expert panel leader . (1) The qualified expert panel leader must ensure that the activities of the panel are performed efficiently and in accordance with generally accepted professional and ethical business practices.

(2) The qualified expert panel leader serves as the principal point of contact between representatives of the agency and the panel.

(3) The qualified expert panel leader is responsible for submitting the written report and all notes or minutes relating to panel deliberations to the requestor.

(4) The qualified expert panel leader must maintain a copy of the written report and all notes or minutes relating to panel deliberations that are submitted to the requestor for 2 years after the report is submitted. Such records must be made available to a duly authorized employee of the agency for inspection at all reasonable times.

(g)Prevention of conflicts of interest . (1) For the purposes of this subpart, FDA will consider a conflict of interest to be any financial or other interest that could impair a person's objectivity in serving on the qualified expert panel or could create an unfair competitive advantage for a person or organization.

(2) Factors relevant to whether there is a conflict of interest or the appearance of a conflict of interest include whether the qualified expert panel member, their spouse, their minor children, their general partners, or any organizations in which they serve as an officer, director, trustee, general partner or employee:

(i) Is currently receiving or seeking funding from the requestor through a contract or research grant (either directly or indirectly through another entity, such as a university).

(ii) Has any employment, contractual, or other financial arrangement with the requestor other than receiving a reasonable fee for serving as a member of the qualified expert panel.

(iii) Has any ownership or financial interest in any drug, drug manufacturer, or drug distributor which will benefit from either a favorable or unfavorable evaluation or opinion.

(iv) Has any ownership or financial interest in the new animal drug being reviewed by the qualified expert panel.

(v) Has participated in the design, manufacture, or distribution of any drug that will benefit from either a favorable or unfavorable opinion of the qualified expert panel.

(vi) Has provided within 1 year any consultative services regarding the new animal drug being reviewed by the qualified expert panel.

(vii) Has entered into an agreement in which fees charged or accepted are contingent upon the panel member making a favorable evaluation or opinion.

(viii) Receives payment for services related to preparing information the requestor presents to the qualified expert panel, other than for services related to the written report described in 516.143.

(3) To permit FDA to make a decision regarding potential conflict of interest, a potential qualified expert panel member must submit to the Director, OMUMS, the following information relating to themselves, their spouse, their minor children, their general partners, or any organizations in which they serve as an officer, director, trustee, general partner or employee, regarding the following issues to the extent that they are, in any way, relevant to the subject of the review of the qualified expert panel:

(i) Investments (for example, stocks, bonds, retirement plans, trusts, partnerships, sector funds, etc.), including for each the following: Name of the firm, type of investment, owner (self, spouse, etc.), number of shares / current value.

(ii) Employment (full or part time, current or under negotiation), including for each the following: Name of the firm, relationship (self, spouse, etc.), position in firm, date employment or negotiation began.

(iii) Consultant/advisor (current or under negotiation), including for each the following: Name of the firm, topic/issue, amount received, date initiated.

(iv) Contracts, grants, Cooperation Research and Development Agreement (CRADAs) (current or under negotiation), including for each the following: Type of agreement, product under study and indications, amount of remuneration (institution/self), time period, sponsor (government, firm, institution, individual), role of the person (site investigator, principal investigator, co-investigator, partner, no involvement, other), awardee.

(v) Patents/royalties/trademarks, including for each the following: Description, name of firm involved, income received.

(vi) Expert witness (last 12 months or under negotiation), including for each the following: For or against, name of firm, issue, amount received.

(vii) Speaking/writing (last 12 months or under negotiation), including for each the following: Firm, topic/issue, amount received (honorarium/travel), date.

(viii) Whether the potential qualified expert panel member, their spouse, their minor children, their general partners or any organizations in which they serve as an officer, director, trustee, general partner or employee, have had, at any time in the past, involvement of the kind noted in paragraph (g)(3)(i) through (g)(3)(vii) of this section with respect to the animal drug that is the subject of the qualified expert panel review.

(ix) Whether there are any other involvements (other kinds of relationships) that would give the appearance of a conflict of interest which have not been described in paragraph (g)(3)(i) through (g)(3)(viii) of this section.

(x) In all cases, a response of "no," "none," or "not applicable" is satisfactory when there is no relevant information to submit.

(xi) A certification statement signed by the potential qualified expert panel member to the effect that all information submitted is true and complete to the best of their knowledge, that they have read and understood their obligations as an expert panel member, and that they will notify FDA and the requestor of any change in their conflict of interest status.

(4) The fact that a qualified expert panel member receives a reasonable fee for services as a member of the qualified expert panel, provided that the fee is no more than commensurate with the value of the time that the member devotes to the review process, does not constitute a conflict of interest or the appearance of a conflict of interest.

Sec. 516.143 Written report.

The written report required in 516.145(b)(3) shall:

(a) Be written in English by a qualified expert panel meeting the requirements of 516.141;

(b) Describe the panel's evaluation of all available target animal safety and effectiveness information relevant to the proposed use of the new animal drug, including anecdotal information;

(c) For all information considered, including anecdotal information, include either a citation to published literature or a summary of the information;

(d) State the panel's opinion regarding whether the benefits of using the new animal drug for the proposed use in a minor species outweigh its risks to the target animal, taking into account the harm being caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question;

(e) Be signed, or otherwise approved in writing, by all panel members, in accordance with 516.141; and

(f) If the panel unanimously concludes that the benefits of using the new animal drug for the proposed use in a minor species outweigh its risks to the target animal, taking into account the harm being caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question, the written report shall:

(1) Provide draft labeling that includes all conditions of use and limitations of use of the new animal drug deemed necessary by the panel to assure that the benefits of use of the new animal drug outweigh the risks, or provide narrative information from which such labeling can be written by the requestor; and

(2) Include a recommendation regarding whether the new animal drug should be limited to use under the professional supervision of a licensed veterinarian.

Sec. 516.145 Content and format of a request for addition to the index.

(a) A requestor may request addition of a new animal drug to the index only after the new animal drug has been granted eligibility for indexing.

(b) A requestor shall submit two copies of a dated request signed by the authorized contact for addition of a new animal drug to the index that contains the following:

(1) A copy of FDA's determination of eligibility issued under 516.137;

(2) A copy of FDA's written determination that the proposed qualified expert panel meets the selection criteria provided for in 516.141(b);

(3) A written report that meets the requirements of 516.143;

(4) A proposed index entry that contains the information described in 516.157;

(5) Proposed labeling, including representative labeling proposed to be used for Type B and Type C medicated feeds if the drug is intended for use in the manufacture of medicated feeds;

(6) Anticipated annual distribution of the new animal drug, in terms of the total quantity of active ingredient, after indexing;

(7) A written commitment to manufacture the new animal drug and animal feeds bearing or containing such new animal drug according to current good manufacturing practices;

(8) A written commitment to label, distribute, and promote the new animal drug only in accordance with the index entry;

(9) The name and address of the contact person or permanent-resident U.S. agent; and

(10) A draft Freedom of Information summary which includes the following information:

(i) A general information section that contains the name and address of the requestor and a description of the drug, route of administration, indications, and recommended dosage.

(ii) A list of the names and affiliations of the members of the qualified expert panel, not including their addresses or other contact information.

(iii) A summary of the findings of the qualified expert panel concerning the target animal safety and effectiveness of the drug.

(iv) Citations of all publicly-available literature considered by the qualified expert panel.

(v) For an early life stage of a food-producing minor species animal, a human food safety summary.

(c) Upon specific request by FDA, the requestor shall submit the information described in 516.141 that it submitted to the qualified expert panel. Any such information not in English should be accompanied by an English translation.

Sec. 516.147 Refuse to file a request for addition to the index.

(a) If a request for addition to the index contains all of the information required by 516.145(b), FDA shall file it, and the filing date shall be the date FDA receives the request.

(b) If a request for addition to the index lacks any of the information required by 516.145, FDA will not file it, but will inform the requestor in writing within 30 days of receiving the request as to what information is lacking.

Sec. 516.149 Denying a request for addition to the index.

(a) FDA will deny a request for addition to the index if it finds the following:

(1) The same drug in the same dosage form for the same intended use is already approved or conditionally approved;

(2) On the basis of new information, the new animal drug no longer meets the conditions for eligibility for indexing;

(3) The request for indexing fails to contain information required under the provisions of 516.145;

(4) The qualified expert panel fails to meet any of the selection criteria listed in 516.141(b);

(5) The written report of the qualified expert panel and other information available to FDA is insufficient to permit FDA to determine that the benefits of using the new animal drug for the proposed use in a minor species outweigh its risks to the target animal, taking into account the harm caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question;

(6) On the basis of the report of the qualified expert panel and other information available to FDA, the benefits of using the new animal drug for the proposed use in a minor species do not outweigh its risks to the target animal, taking into account the harm caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question; or

(7) The request contains any untrue statement of a material fact or omits material information.

(b) When a request for addition to the index is denied, FDA will notify the requestor in accordance with 516.153.

Sec. 516.151 Granting a request for addition to the index.

(a) FDA will grant the request for addition of a new animal drug to the index if none of the reasons described in 516.149 for denying such a request applies.

(b) When a request for addition of a new animal drug to the index is granted, FDA will notify the requestor in accordance with 516.153.

Sec. 516.153 Notification of decision regarding index listing.

(a) Within 180 days after the filing of a request for addition of a new animal drug to the index, FDA shall grant or deny the request and notify the requestor of FDA's decision in writing.

(b) If FDA denies the request for addition of a new animal drug to the index, FDA shall provide due notice and an opportunity for an informal conference as described in 516.123. A decision of FDA to deny a request to index a new animal drug following an informal conference shall constitute final agency action subject to judicial review.

Sec. 516.155 Labeling of indexed drugs.

(a) The labeling of an indexed drug that is found to be eligible for indexing under 516.129(c)(7)(i) shall state, prominently and conspicuously:"NOT APPROVED BY FDA.--Legally marketed as an FDA indexed product. Extra-label use is prohibited." "This product is not to be used in animals intended for use as food for humans or other animals."

(b) The labeling of an indexed drug that was found to be eligible for indexing for use in an early, non-food life stage of a food-producing minor species animal, under 516.129(c)(7)(ii), shall state, prominently and conspicuously:"NOT APPROVED BY FDA.--Legally marketed as an FDA indexed product. Extra-label use is prohibited."

(c) The labeling of an indexed drug shall contain such other information as may be prescribed in the index listing.

Sec. 516.157 Publication of the index and content of an index listing.

(a) FDA will make the list of indexed drugs available through the FDA Web site. A printed copy can be obtained by writing to the FDA Division of Freedom of Information or by visiting FDA's Division of Freedom of Information Public Reading Room.

(b) The list will contain the following information for each indexed drug:

(1) The name and address of the person who holds the index listing;

(2) The name of the drug and the intended use and conditions of use for which it is indexed;

(3) Product labeling; and

(4) Conditions and any limitations that FDA deems necessary regarding use of the drug.

[72 FR 69121, Dec. 6, 2007, 76 FR 31470, June 1, 2011]

Sec. 516.161 Modifications to indexed drugs.

(a) After a drug is listed in the index, certain modifications to the index listing may be requested. Any modification of an index listing may not cause an indexed drug to be a different drug (or different combination of drugs) or a different dosage form. If such modification is requested, FDA will notify the holder that a new index listing is required for the new drug or dosage form.

(b) Modifications to the indexed drug will fall under one of three categories and must be submitted as follows:

(1)Urgent changes . (i) The following modifications to an indexed drug or its labeling should be made as soon as possible, and a request to modify the indexed drug should be concurrently submitted:

(A) The addition to package labeling, promotional labeling, or prescription drug advertising of additional warning, contraindication, side effect, or cautionary information.

(B) The deletion from package labeling, promotional labeling, and drug advertising of false, misleading, or unsupported indications for use or claims for effectiveness.

(C) Changes in manufacturing methods or controls required to correct product or manufacturing defects that may result in serious adverse drug events.

(ii) The modifications described in paragraph (b)(1)(i) of this section must be submitted to the Director, OMUMS, in the form of a request for modification of an indexed drug, and must contain sufficient information to permit FDA to determine the need for the modification and whether the modification appropriately addresses the need.

(iii) FDA will take no action against an indexed drug or index holder solely because modifications of the kinds described in paragraph (b)(1)(i) of this section are placed into effect by the holder prior to receipt of a written notice granting the request if all the following conditions are met:

(A) A request to modify the indexed drug providing a full explanation of the basis for the modifications has been submitted, plainly marked on the mailing cover and on the request as follows: "Special indexing request-- modifications being effected;"

(B) The holder specifically informs FDA of the date on which such modifications are to be effected and submits two printed copies of any revised labeling to be placed in use, and

(C) All promotional labeling and all drug advertising are promptly revised consistent with modifications made in the labeling on or within the indexed drug package.

(2)Significant changes . (i) The following modifications to an indexed drug or its labeling may be made only after a request has been submitted to and subsequently granted by FDA:

(A) Addition of an intended use.

(B) Addition of a species.

(C) Addition or alteration of an active ingredient.

(D) Alteration of the concentration of an active ingredient.

(E) Alteration of dose or dosage regimen.

(F) Alteration of prescription or over-the-counter status.

(ii) Each modification described in paragraph (b)(2)(i) of this section must go through the same review process as an original index listing and is subject to the same standards for review.

(iii) Each submission of a request for a modification described in paragraph (b)(2)(i) of this section should contain only one type of modification unless one modification is actually necessitated by another, such as a modification of dose necessitated by a modification of the concentration of an active ingredient. Submissions relating to addition of an intended use for an existing species or addition of a species should be submitted separately, but each such submission may include multiple additional intended uses and/or multiple additional species.

(3)Minor changes . All modifications other than those described in paragraphs (b)(1) and (b)(2) of this section including, but not limited to, formulation, labeling, and manufacturing methods and controls (at the same level of detail that these were described in the request for determination of eligibility for indexing) must be submitted as part of the annual indexed drug experience report or as otherwise required by 516.165.

(c) When changes affect the index listing, it will be updated accordingly.

Sec. 516.163 Change in ownership of an index file.

(a) A holder may transfer ownership of a drug's index file to another person.

(1) The former owner shall submit in writing to FDA a statement that all rights in the index file have been transferred, giving the name and address of the new owner and the date of the transfer. The former owner shall also certify that a complete copy of the following, to the extent that they exist at the time of the transfer of ownership, has been provided to the new owner:

(i) The request for determination of eligibility;

(ii) The request for addition to the index;

(iii) Any modifications to the index listing;

(iv) Any records and reports under 516.165; and

(v) All correspondence with FDA relevant to the indexed drug and its index listing.

(2) The new owner shall submit the following information in writing to FDA:

(i) The date that the change in ownership is effective;

(ii) A statement that the new owner has a complete copy of all documents listed in paragraph (a)(1) of this section to the extent that they exist at the time of the transfer of ownership;

(iii) A statement that the new owner understands and accepts the responsibilities of a holder of an indexed drug;

(iv) The name and address of a new primary contact person or permanent-resident U.S. agent; and

(v) A list of labeling changes associated with the change of ownership (e.g., a new trade name) as draft labeling, with complete final printed labeling to be submitted in the indexed drug annual report in accordance with 516.161 and 516.165.

(b) Upon receiving the necessary information to support a change of ownership of a drug's index file, FDA will update its publicly-available listing in accordance with 516.157.

Sec. 516.165 Records and reports.

(a)Scope and purpose . (1) The recordkeeping and reporting requirements of this section apply to all holders of indexed drugs, including indexed drugs intended for use in medicated feeds.

(2) A holder is not required to report information under this section if the holder has reported the same information under 514.80 of this chapter.

(3) The records and reports referred to in this section are in addition to those required by the current good manufacturing practice regulations in parts 211, 225, and 226 of this chapter.

(4) FDA will review the records and reports required in this section to determine, or facilitate a determination, whether there may be grounds for removing a drug from the index under section 572(f) of the act.

(b)Recordkeeping requirements . (1) Each holder of an indexed drug must establish and maintain complete files containing full records of all information pertinent to the safety or effectiveness of the indexed drug. Such records must include information from foreign and domestic sources.

(2) The holder must, upon request from any authorized FDA officer or employee, at all reasonable times, permit such officer or employee to have access to copy and to verify all such records.

(c)Reporting requirements . (1)Three-day indexed drug field alert report . The holder must inform the appropriate FDA District Office or local FDA resident post of any product or manufacturing defects that may result in serious adverse drug events within 3 working days of first becoming aware that such a defect may exist. The holder may initially provide this information by telephone or other electronic communication means, with prompt written followup. The mailing cover must be plainly marked "3-Day Indexed Drug Field Alert Report."

(2)Fifteen-day indexed drug alert report . The holder must submit a report on each serious, unexpected adverse drug event, regardless of the source of the information. The holder must submit the report within 15 working days of first receiving the information. The mailing cover must be plainly marked "15-Day Indexed Drug Alert Report."

(3)Annual indexed drug experience report . The holder must submit this report every year on the anniversary date of the letter granting the request for addition of the new animal drug to the index, or within 60 days thereafter. The report must contain data and information for the full reporting period. Any previously submitted information contained in the report must be identified as such. The holder may ask FDA to change the date of submission and, after approval of such request, file such reports by the new filing date. The report must contain the following:

(i) The number of distributed units of each size, strength, or potency (e.g., 100,000 bottles of 100 5-milligram tablets; 50,000 10-milliliter vials of 5- percent solution) distributed during the reporting period. This information must be presented in two categories: Quantities distributed domestically and quantities exported. This information must include any distributor-labeled product.

(ii) If the labeling has changed since the last report, include a summary of those changes and the holder's and distributor's current package labeling, including any package inserts. For large-size package labeling or large shipping cartons, submit a representative copy (e.g., a photocopy of pertinent areas of large feed bags). If the labeling has not changed since the last report, include a statement of such fact.

(iii) A summary of any changes made during the reporting period in the methods used in, and facilities and controls used for, manufacture, processing, and packing. This information must be presented in the same level of detail that it was presented in the request for determination of eligibility for indexing. Do not include changes that have already been submitted under 516.161.

(iv) Nonclinical laboratory studies and clinical data not previously reported under this section.

(v) Adverse drug experiences not previously reported under this section.

(vi) Any other information pertinent to safety or effectiveness of the indexed drug not previously reported under this section.

(4)Distributor's statement . At the time of initial distribution of an indexed drug by a distributor, the holder must submit a report containing the following:

(i) The distributor's current product labeling. This must be identical to that in the index listing except for a different and suitable proprietary name (if used) and the name and address of the distributor. The name and address of the distributor must be preceded by an appropriate qualifying phrase such as "manufactured for" or "distributed by."

(ii) A signed statement by the distributor stating:

(A) The category of the distributor's operations (e.g., wholesale or retail);

(B) That the distributor will distribute the drug only under the indexed drug labeling;

(C) That the distributor will promote the indexed drug only for use under the conditions stated in the index listing; and

(D) If the indexed drug is a prescription new animal drug, that the distributor is regularly and lawfully engaged in the distribution or dispensing of prescription products.

(5)Other reporting . FDA may by order require that a holder submit information in addition to that required by this section or that the holder submit the same information but at different times or reporting periods.

Sec. 516.167 Removal from the index.

(a) After due notice to the holder of the index listing and an opportunity for an informal conference as described in 516.123, FDA shall remove a new animal drug from the index if FDA finds that:

(1) The same drug in the same dosage form for the same intended use has been approved or conditionally approved;

(2) The expert panel failed to meet the requirements in 516.141;

(3) On the basis of new information before FDA, evaluated together with the evidence available to FDA when the new animal drug was listed in the index, the benefits of using the new animal drug for the indexed use do not outweigh its risks to the target animal, taking into account the harm caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question;

(4) Any of the conditions in 516.133(a)(2), (5), or (6) are present;

(5) The manufacture of the new animal drug is not in accordance with current good manufacturing practices;

(6) The labeling, distribution, or promotion of the new animal drug is not in accordance with the index listing;

(7) The conditions and limitations of use associated with the index listing have not been followed; or

(8) Any information used to support the request for addition to the index contains any untrue statement of material fact.

(b) The agency may partially remove an indexing listing if, in the opinion of the agency, such partial removal would satisfactorily resolve a safety or effectiveness issue otherwise warranting removal of the listing under section 572(f)(1)(B) of the act.

(c) FDA may immediately suspend a new animal drug from the index if FDA determines that there is a reasonable probability that the use of the drug would present a risk to the health of humans or other animals. The agency will subsequently provide due notice and an opportunity for an informal conference as described in 516.123.

(d) A decision of FDA to remove a new animal drug from the index following an informal conference, if any, shall constitute final agency action subject to judicial review.

Sec. 516.171 Confidentiality of data and information in an index file.

(a) For purposes of this section, the index file includes all data and information submitted to or incorporated by reference into the index file, such as data and information related to investigational use exemptions under 516.125, requests for determination of eligibility for indexing, requests for addition to the index, modifications to indexed drugs, changes in ownership, reports submitted under 516.165, and master files. The availability for public disclosure of any record in the index file shall be handled in accordance with the provisions of this section.

(b) The existence of an index file will not be disclosed by FDA before an index listing has been made public by FDA, unless it has previously been publicly disclosed or acknowledged by the requestor.

(c) If the existence of an index file has not been publicly disclosed or acknowledged, no data or information in the index file are available for public disclosure.

(d) If the existence of an index file has been publicly disclosed or acknowledged before an index listing has been made public by FDA, no data or information contained in the file will be available for public disclosure before such index listing is made public, but the agency may, at its discretion, disclose a brief summary of such selected portions of the safety and effectiveness data as are appropriate for public consideration of a specific pending issue, e.g., at an open session of a Food and Drug Administration advisory committee or pursuant to an exchange of important regulatory information with a foreign government.

(e) After FDA sends a written notice to the requestor granting a request for addition to the index, the following data and information in the index file are available for public disclosure unless extraordinary circumstances are shown:

(1) All safety and effectiveness data and information previously disclosed to the public, as defined in 20.81 of this chapter.

(2) A summary or summaries of the safety and effectiveness data and information submitted with or incorporated by reference in the index file. Such summaries do not constitute the full information described under section 572(c) and (d) of the act on which the safety or effectiveness of the drug may be determined. Such summaries will be based on the draft Freedom of Information summary submitted under 516.145, which will be reviewed and, where appropriate, revised by FDA.

(3) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial information in 20.61 of this chapter.

(4) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of the following:

(i) Names and any information that would identify the person using the product.

(ii) Names and any information that would identify any third party involved with the report, such as a veterinarian.

(5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as defined in 20.81 of this chapter.

(6) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and is shown to fall within the exemption established in 20.61 of this chapter.

(7) All correspondence and written summaries of oral discussions relating to the index file, in accordance with the provisions of part 20 of this chapter.

(f) The following data and information in an index file are not available for public disclosure unless they have been previously disclosed to the public as defined in 20.81 of this chapter, or they relate to a product or ingredient that has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in 20.61 of this chapter:

(1) Manufacturing methods or processes, including quality control procedures.

(2) Production, sales, distribution, and similar data and information, except that any compilation of such data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure.

(3) Quantitative or semiquantitative formulas.

(g) Subject to the disclosure provisions of this section, the agency shall regard the contents of an index file as confidential information unless specifically notified in writing by the holder of the right to disclose, to reference, or otherwise utilize such information on behalf of another named person.

(h) For purposes of this regulation, safety and effectiveness data include all studies and tests of an animal drug on animals and all studies and tests on the animal drug for identity, stability, purity, potency, and bioavailability.

(i) Safety and effectiveness data and information that have not been previously disclosed to the public are available for public disclosure at the time any of the following events occurs unless extraordinary circumstances are shown:

(1) No work is being or will be undertaken to have the drug indexed in accordance with the request.

(2) A final determination is made that the drug cannot be indexed and all legal appeals have been exhausted.

(3) The drug has been removed from the index and all legal appeals have been exhausted.

(4) A final determination has been made that the animal drug is not a new animal drug.

Authority: 21 U.S.C. 360ccc-1, 360ccc-2, 371.
Source: 72 FR 41017, July 26, 2007, unless otherwise noted.

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