§ 601.25 - Review procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or suggested conditions of use.

Link to an amendment published at 81 FR 7446, Feb. 12, 2016.

For purposes of reviewing biological products that have been licensed prior to July 1, 1972, to determine that they are safe and effective and not misbranded, the following regulations shall apply. Prior administrative action exempting biological products from the provisions of the Federal Food, Drug, and Cosmetic Act is superseded to the extent that these regulations result in imposing requirements pursuant to provisions therein for a designated biological product or category of products.

(a) Advisory review panels. The Commissioner of Food and Drugs shall appoint advisory review panels (1) to evaluate the safety and effectiveness of biological products for which a license has been issued pursuant to section 351 of the Public Health Service Act, (2) to review the labeling of such biological products, and (3) to advise him on which of the biological products under review are safe, effective, and not misbranded. An advisory review panel shall be established for each designated category of biological product. The members of a panel shall be qualified experts, appointed by the Commissioner, and shall include persons from lists submitted by organizations representing professional, consumer, and industry interests. Such persons shall represent a wide divergence of responsible medical and scientific opinion. The Commissioner shall designate the chairman of each panel, and summary minutes of all meetings shall be made.

(b) Request for data and views. (1) The Commissioner of Food and Drugs will publish a notice in the Federal Register requesting interested persons to submit, for review and evaluation by an advisory review panel, published and unpublished data and information pertinent to a designated category of biological products.

(2) Data and information submitted pursuant to a published notice, and falling within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by the advisory review panel and the Food and Drug Administration as confidential until publication of a proposed evaluation of the biologics under review and the full report or reports of the panel. Thirty days thereafter such data and information shall be made publicly available and may be viewed at the Division of Dockets Management of the Food and Drug Administration, except to the extent that the person submitting it demonstrates that it still falls within the confidentiality provisions of one or more of those statutes.

(3) To be considered, 12 copies of the submission on any marketed biological product within the class shall be submitted, preferably bound, indexed, and on standard sized paper, approximately 81⁄2 × 11 inches. The time allotted for submissions will be 60 days, unless otherwise indicated in the specific notice requesting data and views for a particular category of biological products. When requested, abbreviated submissions should be sent. All submissions shall be in the following format, indicating “none” or “not applicable” where appropriate, unless changed in the Federal Register notice:

Biological Products Review Information

I. Label or labels and all other labeling (preferably mounted. Facsimile labeling is acceptable in lieu of actual container labeling), including labeling for export.

II. Representative advertising used during the past 5 years.

III. The complete quantitative composition of the biological product.

IV. Animal safety data.

A. Individual active components.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

B. Combinations of the individual active components.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

C. Finished biological product.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

V. Human safety data.

A. Individual active components.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

3. Documented case reports.

4. Pertinent marketing experiences that may influence a determination as to the safety of each individual active component.

5. Pertinent medical and scientific literature.

B. Combinations of the individual active components.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

3. Documented case reports.

4. Pertinent marketing experiences that may influence a determination as to the safety of combinations of the individual active components.

5. Pertinent medical and scientific literature.

C. Finished biological product.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

3. Documented case reports.

4. Pertinent marketing experiences that may influence a determination as to the safety of the finished biological product.

5. Pertinent medical and scientific literature.

VI. Efficacy data.

A. Individual active components.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

3. Documented case reports.

4. Pertinent marketing experiences that may influence a determination on the efficacy of each individual active component.

5. Pertinent medical and scientific literature.

B. Combinations of the individual active components.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

3. Documented case reports.

4. Pertinent marketing experiences that may influence a determination as to the effectiveness of combinations of the individual active components.

5. Pertinent medical and scientific literature.

C. Finished biological product.

1. Controlled studies.

2. Partially controlled or uncontrolled studies.

3. Documented case reports.

4. Pertinent marketing experiences that may influence a determination as to the effectiveness of the finished biological product.

5. Pertinent medical and scientific literature.

VII. A summary of the data and views setting forth the medical rational and purpose (or lack thereof) for the biological product and its components and the scientific basis (or lack thereof) for the conclusion that the biological product, including its components, has been proven safe and effective and is properly labeled for the intended use or uses. If there is an absence of controlled studies in the materials submitted, an explanation as to why such studies are not considered necessary or feasible shall be included.

VIII. If the submission is by a licensed manufacturer, a statement signed by the authorized official of the licensed manufacturer shall be included, stating that to the best of his or her knowledge and belief, it includes all information, favorable and unfavorable, pertinent to an evaluation of the safety, effectiveness, and labeling of the product, including information derived from investigation, commercial marketing, or published literature. If the submission is by an interested person other than a licensed manufacturer, a statement signed by the person responsible for such submission shall be included, stating that to the best of his knowledge and belief, it fairly reflects a balance of all the available information, favorable and unfavorable available to him, pertinent to an evaluation of the safety, effectiveness, and labeling of the product.

(c) Deliberations of an advisory review panel. An advisory review panel will meet as often and for as long as is appropriate to review the data submitted to it and to prepare a report containing its conclusions and recommendations to the Commissioner of Food and Drugs with respect to the safety, effectiveness, and labeling of the biological products in the designated category under review.

(1) A panel may also consult any individual or group.

(2) Any interested person may request in writing an opportunity to present oral views to the panel. Such written requests for oral presentations should include a summarization of the data to be presented to the panel. Such request may be granted or denied by the panel.

(3) Any interested person may present written data and views which shall be considered by the panel. This information shall be presented to the panel in the format set forth in paragraph (b)(3) of this section and within the time period established for the biological product category in the notice for review by a panel.

(d) Standards for safety, effectiveness, and labeling. The advisory review panel, in reviewing the submitted data and preparing the panel's conclusions and recommendations, and the Commissioner of Food and Drugs, in reviewing and implementing the conclusions and recommendations of the panel, shall apply the following standards to determine that a biological product is safe and effective and not misbranded.

(1) Safety means the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time. Proof of safety shall consist of adequate tests by methods reasonably applicable to show the biological product is safe under the prescribed conditions of use, including results of significant human experience during use.

(2) Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological or other effect of the biological product, when used under adequate directions, for use and warnings against unsafe use, will serve a clinically significant function in the diagnosis, cure, mitigation, treatment, or prevention of disease in man. Proof of effectiveness shall consist of controlled clinical investigations as defined in §314.126 of this chapter, unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the biological product or essential to the validity of the investigation, and that an alternative method of investigation is adequate to substantiate effectiveness. Alternate methods, such as serological response evaluation in clinical studies and appropriate animal and other laboratory assay evaluations may be adequate to substantiate effectiveness where a previously accepted correlation between data generated in this way and clinical effectiveness already exists. Investigations may be corroborated by partially controlled or uncontrolled studies, documented clinical studies by qualified experts, and reports of significant human experience during marketing. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered.

(3) The benefit-to-risk ratio of a biological product shall be considered in determining safety and effectiveness.

(4) A biological product may combine two or more safe and effective active components: (i) When each active component makes a contribution to the claimed effect or effects; (ii) when combining of the active ingredients does not decrease the purity, potency, safety, or effectiveness of any of the individual active components; and (iii) if the combination, when used under adequate directions for use and warnings against unsafe use, provides rational concurrent preventive therapy or treatment for a significant proportion of the target population.

(5) Labeling shall be clear and truthful in all respects and may not be false or misleading in any particular. It shall comply with section 351 of the Public Health Service Act and sections 502 and 503 of the Federal Food, Drug, and Cosmetic Act, and in particular with the applicable requirements of §§610.60 through 610.65 and subpart D of part 201 of this chapter.

(e) Advisory review panel report to the Commissioner. An advisory review panel shall submit to the Commissioner of Food and Drugs a report containing the panel's conclusions and recommendations with respect to the biological products falling within the category covered by the panel. Included within this report shall be:

(1) A statement which designates those biological products determined by the panel to be safe and effective and not misbranded. This statement may include any condition relating to active components, labeling, tests required prior to release of lots, product standards, or other conditions necessary or appropriate for their safety and effectiveness.

(2) A statement which designates those biological products determined by the panel to be unsafe or ineffective, or to be misbranded. The statement shall include the panel's reasons for each such determination.

(3) A statement which designates those biological products determined by the panel not to fall within either paragraph (e) (1) or (2) of this section on the basis of the panel's conclusion that the available data are insufficient to classify such biological products, and for which further testing is therefore required. The report shall recommend with as must specificity as possible the type of further testing required and the time period within which it might reasonably be concluded. The report shall also recommend whether the product license should or should not be revoked, thus permitting or denying continued manufacturing and marketing of the biological product pending completion of the testing. This recommendation will be based on an assessment of the present evidence of the safety and effectiveness of the product and the potential benefits and risks likely to result from the continued use of the product for a limited period of time while the questions raised concerning the product are being resolved by further study.2

2As of November 4, 1982, the provisions under paragraphs (e)(3) and (f)(3) of this section for the interim marketing of certain biological products pending completion of additional studies have been superseded by the review and reclassification procedures under §601.26 of this chapter. The superseded text is included for the convenience of the user only.

(f) Proposed order. After reviewing the conclusions and recommendations of the advisory review panel, the Commissioner of Food and Drugs shall publish in the Federal Register a proposed order containing:

(1) A statement designating the biological products in the category under review that are determined by the Commissioner of Food and Drugs to be safe and effective and not misbranded. This statement may include any condition relating to active components, labeling, tests required prior to release of lots, product standards, or other conditions necessary or appropriate for their safety and effectiveness, and may propose corresponding amendments in other regulations under this subchapter F.

(2) A statement designating the biological products in the category under review that are determined by the Commissioner of Food and Drugs to be unsafe or ineffective, or to be misbranded, together with the reasons therefor. All licenses for such products shall be proposed to be revoked.

(3) A statement designating the biological products not included in either of the above two statements on the basis of the Commissioner of Food and Drugs determination that the available data are insufficient to classify such biological products under either paragraph (f) (1) or (2) of this section. Licenses for such products may be proposed to be revoked or to remain in effect on an interim basis. Where the Commissioner determines that the potential benefits outweigh the potential risks, the proposed order shall provide that the biologics license for any biological product, falling within this paragraph, will not be revoked but will remain in effect on an interim basis while the data necessary to support its continued marketing are being obtained for evaluation by the Food and Drug Administration. The tests necessary to resolve whatever safety or effectiveness questions exist shall be described.2

2As of November 4, 1982, the provisions under paragraphs (e)(3) and (f)(3) of this section for the interim marketing of certain biological products pending completion of additional studies have been superseded by the review and reclassification procedures under §601.26 of this chapter. The superseded text is included for the convenience of the user only.

(4) The full report or reports of the panel to the Commissioner of Food and Drugs.

The summary minutes of the panel meeting or meetings shall be made available to interested persons upon request. Any interested person may within 90 days after publication of the proposed order in the Federal Register, file with the Hearing Clerk of the Food and Drug Administration written comments in quintuplicate. Comments may be accompanied by a memorandum or brief in support thereof. All comments may be reviewed at the office of the Division of Dockets Management during regular working hours, Monday through Friday.

(g) Final order. After reviewing the comments, the Commissioner of Food and Drugs shall publish in the Federal Register a final order on the matters covered in the proposed order. The final order shall become effective as specified in the order.

(h) [Reserved]

(i) Court Appeal. The final order(s) published pursuant to paragraph (g) of this section, and any notice published pursuant to paragraph (h) of this section, constitute final agency action from which appeal lies to the courts. The Food and Drug Administration will request consolidation of all appeals in a single court. Upon court appeal, the Commissioner of Food and Drugs may, at his discretion, stay the effective date for part or all of the final order or notice, pending appeal and final court adjudication.

[38 FR 32052, Nov. 20, 1973, as amended at 39 FR 11535, Mar. 29, 1974; 40 FR 13498, Mar. 27, 1975; 43 FR 44838, Sept. 29, 1978; 47 FR 44071, Oct. 5, 1982; 47 FR 50211, Nov. 5, 1982; 51 FR 15607, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997; 64 FR 56452, Oct. 20, 1999]