decided under §601.25(g) that available data are insufficient to determine whether the product license should be revoked or affirmed and which may be marketed pending the completion of further testing. All of these Category IIIA products will either be reclassified into Category I (safe, effective, and not misbranded) or Category II (unsafe, ineffective, or misbranded) in accordance with the procedures set forth below.

(a) Advisory review panels. The Commissioner will appoint advisory review panels and use existing advisory review panels to (1) evaluate the safety and effectiveness of all Category IIIA biological products; (2) review the labeling of such products; and (3) advise the Commissioner on which Category IIIA biological products are safe, effective, and not misbranded. These advisory review panels will be established in accordance with procedures set forth in §601.25(a).

(b) Deliberations of advisory review panels. The deliberations of advisory review panels will be conducted in accordance with § 601.25(d).

(c) Advisory review panel report to the Commissioner. An advisory review panel shall submit to the Commissioner a report containing the panel's conclusions and recommendations with respect to the biological products falling within the category of products reviewed by the panel. The panel report shall include:

(1) A statement designating the biological products in the category under review in accordance with either § 601.25(e)(1) or § 601.25(e)(2).

(2) A statement identifying those biological products designated under §601.25(e)(2) that the panel recommends should be designated as safe and presumptively effective and should remain on the market pending completion of further testing because there is a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent that is available in sufficient quantities to meet current medical needs. For the products or categories of products so recommended, the report shall include: (i) A description and evaluation of the available evidence concerning effectiveness and an explanation why the evidence shows that the product has any benefit; and

(ii) a description of the alternative therapeutic, prophylactic, or diagnostic agents considered and a statement of why such alternatives are not suitable. In making this recommendation the panel shall also take into account the seriousness of the condition intended to be treated, prevented, or diagnosed by the product, the risks involved in the continued use of the product, and the likelihood that, based upon existing data, the effectiveness of the product can eventually be established by further testing and new test development. The report shall also recommend with as much specificity as possible the type of further testing required and the time period within which it might reasonably be concluded.

(d) Proposed order. After reviewing the conclusions and recommendations of the advisory review panels, the Commissioner shall publish in the FEDERAL REGISTER a proposed order containing:

(1) A statement designating the biological products in the category under review in accordance with either § 601.25(e)(1) or 601.25(e)(2);

(2) A notice of availability of the full panel report or reports. The full panel report or reports shall be made publicly available at the time of publication of the proposed order.

(3) A proposal to accept or reject the findings of the advisory review panel required by §601.26(c)(2)(i) and (ii).

(4) A statement identifying those biological products that the Commissioner proposes should be designated as safe and presumptively effective under § 601.26(c)(2) and should be permitted to remain on the market pending completion of further testing because there is a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent for the product that is available in sufficient quantities to meet current medical needs. In making this proposal, the Commissioner shall take into account the seriousness of the condition to be treated, prevented, or diagnosed by the product, the risks involved in the continued use of the product, and the likelihood that, based upon existing data, the effectiveness of the product can eventually be established by further testing.

(e) Final order. After reviewing the comments on the proposed order, the Commissioner shall publish in the FEDERAL REGISTER a final order on the matters covered in the proposed order. Where the Commissioner determines that there is a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent for any biological product that is available in sufficient quantities to meet current medical needs, the final order shall provide that the product license for that biological product 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 final order shall describe the tests necessary to resolve whatever effectiveness questions exist.

(f) Additional studies and labeling. (1) Within 60 days following publication of the final order, each licensee for a biological product designated as requiring further study to justify continued marketing on an interim basis, pursuant to paragraph (e) of this section, shall submit to the Commissioner a written statement intended to show that studies adequate and appropriate to resolve the questions raised about the product have been undertaken. The Federal Government may undertake the studies. Any study involving a clinical investigation that involves human subjects shall be conducted in compliance with the requirements for informed consent under part 50 of this chapter. Such a study is also subject to the requirements for institutional review under part 56 of this chapter unless exempt under §56.104 or § 56.105. The Commissioner may extend this 60-day period if necessary, either to review and act on proposed protocols or upon indication from the licensee that the studies will commence at a specified reasonable time. If no such commitment is made, or adequate and appropriate studies are not undertaken, the product license or licenses shall be revoked.

(2) A progress report shall be filed on the studies by January 1 and July 1 until completion. If the progress report is inadequate or if the Commissioner concludes that the studies are not being pursued promptly and diligently,

or if interim results indicate the product is not a medical necessity, the product license or licenses shall be revoked.

(3) Promptly upon completion of the studies undertaken on the product, the Commissioner will review all available data and will either retain or revoke the product license or licenses involved. In making this review the Commissioner may again consult the advisory review panel which prepared the report on the product, or other advisory committees, professional organizations, or experts. The Commissioner shall take such action by notice published in the FEDERAL REGISTER.

(4) Labeling and promotional material for those biological products requiring additional studies shall bear a box statement in the following format:

Based on a review by the (insert name of appropriate advisory review panel) and other information, the Food and Drug Administration has directed that further investigation be conducted before this product is conclusively determined to be effective for labeled indication(s).

(5) A written informed consent shall be obtained from participants in any additional studies required under paragraph (f)(1) of this section, explaining the nature of the product and the investigation. The explanation shall consist of such disclosure and be made so that intelligent and informed consent be given and that a clear opportunity to refuse is presented.

(g) Court appeal. The final order(s) published pursuant to paragraph (e) 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 the Commissioner's discretion, stay the effective date for part or all of the final order or notice, pending appeal and final court adjudication. (h) [Reserved]

(i) Institutional review and informed consent. Information and data submitted under this section after July 27, 1981, shall include statements regarding each clinical investigation involving human subjects, that it was conducted in compliance with the requirements for informed consent under part

50 of this chapter. Such a study is also subject to the requirements for institutional review under part 56 of this chapter, unless exempt under § 56.104 or § 56.105.

[47 FR 44071, Oct. 5, 1982]

Subpart D-Licensing of Foreign Establishments and Products

§ 601.30 Licenses required; products for controlled investigation only. Any biological or trivalent organic arsenical manufactured in any foreign country and intended for sale, barter, or exchange shall be refused entry by collectors of customs unless manufactured in an establishment holding an unsuspended and unrevoked establishment license and license for the product. Unlicensed products that are not imported for sale, barter, or exchange and that are intended solely for purposes of controlled investigation are admissible only if the investigation is conducted in accordance with section 505 of the Federal Food, Drug, and Cosmetic Act and the requirements set forth in parts 50, 56 unless exempted under §56.104 as granted a waiver under §56.105, parts 58 and 312 of this chapter. [46 FR 8956, Jan. 27, 1981]

§ 601.31 Procedure.

Except as otherwise provided in this subchapter, licenses for foreign establishments and products shall be issued, suspended, and revoked in the same manner as licenses for domestic establishments and products. Each foreign establishment holding a license and sending, carrying, or bringing any licensed product into any State or possession for sale, barter, or exchange shall file with the Director, Center for Biologics Evaluation and Research, the name and address of each person to whom such a product is thus sent, carried, or brought. Foreign licensees shall notify each person in the United States to whom such a product is thus sent, carried, or brought, to keep such records of distribution as are required of domestic licensed establishments. Failure to give such notice to maintain

records shall constitute ground for revocation of license.

[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]

§ 601.32 Form of license.

Licenses for establishments located in foreign countries shall be in form similar to that for domestic establishments except that they shall authorize manufacture for sending, carrying, or bringing for sale, barter or exchange from the foreign country designated in the license into any State or possession of the United States and shall specify that it is issued upon the condition that the licensee will permit the inspection during all reasonable hours of the establishment by any officer, agent, or employee of the Department of Health and Human Services authorized by the Secretary for such purpose. § 601.33 Samples for each importation.

Random samples of each importation, obtained by the District Director of Customs and forwarded to the Director, Center for Biologics Evaluation and Research, shall be at least two final containers of each lot of product. A copy of the associated documents which describe and identify the shipment shall accompany the shipment for forwarding with the samples to the Director, Center for Biologics Evaluation and Research. For shipments of 20 or less final containers, samples need not be forwarded, provided a copy of an official release from the Center for Biologics Evaluation and Research accompanies each shipment.

[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]

Subpart E-Accelerated Approval of Biological Products for Serious or Life-Threatening III

nesses

SOURCE: 57 FR 58959, Dec. 11, 1992, unless otherwise noted.

§ 601.40 Scope.

This subpart applies to certain biological products that have been studied for their safety and effectiveness in

treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy). §601.41 Approval based on a surrogate

endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.

FDA may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and wellcontrolled. The applicant shall carry out any such studies with due diligence.

§ 601.42 Approval with restrictions to assure safe use.

(a) If FDA concludes that a biological product shown to be effective can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to assure safe use of the biological product, such as:

(1) Distribution restricted to certain facilities or physicians with special training or experience; or

(2) Distribution conditioned on the performance of specified medical procedures.

(b) The limitations imposed will be commensurate with the specific safety concerns presented by the biological product.

§ 601.43 Withdrawal procedures.

(a) For biological products approved under §§ 601.40 and 601.42, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if:

(1) A postmarketing clinical study fails to verify clinical benefit;

(2) The applicant fails to perform the required postmarketing study with due diligence;

(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the biological product;

(4) The applicant fails to adhere to the postmarketing restrictions agreed upon;

(5) The promotional materials are false or misleading; or

(6) Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use.

(b) Notice of opportunity for a hearing. The Director of the Center for Biologics Evaluation and Research will give the applicant notice of an opportunity for a hearing on the Center's proposal to withdraw the approval of an application approved under §601.40 or §601.41. The notice, which will ordinarily be a letter, will state generally the reasons for the action and the proposed grounds for the order.

(c) Submission of data and information. (1) If the applicant fails to file a written request for a hearing within 15 days of receipt of the notice, the applicant waives the opportunity for a hearing.

(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the FEDERAL REGISTER in accordance with §§ 12.32(e) and 15.20 of this chapter.

(3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing.

(d) Separation of functions. Separation of functions (as specified in §10.55 of this chapter) will not apply at any point in withdrawal proceedings under this section.

(e) Procedures for hearings. Hearings held under this section will be conducted in accordance with the

provisions of part 15 of this chapter, with the following modifications:

(1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs.

(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of the Center may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation.

(f) Judicial review. The Commissioner's decision constitutes final agency action from which the applicant may petition for judicial review. Before requesting an order from a court for a stay of action pending review, an applicant must first submit a petition for a stay of action under §10.35 of this chapter.

§601.44 Postmarketing safety reporting.

Biological products approved under this program are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products.

8601.45 Promotional materials.

For biological products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.

§ 601.46 Termination of requirements.

If FDA determines after approval that the requirements established in § 601.42, § 601.43, or §601.45 are no longer necessary for the safe and effective use of a biological product, it will so notify the applicant. Ordinarily, for biological products approved under §601.41, these requirements will no longer apply when FDA determines that the required postmarketing study verifies and describes the biological product's clinical benefit and the biological product would be appropriate for approval under traditional procedures. For biological products approved under

§ 601.42, the restrictions would no longer apply when FDA determines that safe use of the biological product can be assured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30.

Subpart F-Confidentiality of
Information

§ 601.50 Confidentiality of data and information in an investigational new drug notice for a biological product. (a) The existence of an IND notice for a biological product will not be disclosed by the Food and Drug Administration unless it has previously been publicly disclosed or acknowledged.

(b) The availability for public disclosure of all data and information in an IND file for a biological product shall be handled in accordance with the provisions established in § 601.51.

(c) Notwithstanding the provisions of §601.51, the Food and Drug Administration shall disclose upon request to an individual on whom an investigational biological product has been used a copy of any adverse reaction report relating to such use.

[39 FR 44656, Dec. 24, 1974]

§ 601.51 Confidentiality of data and information in applications for establishment and product licenses.

(a) For purposes of this section the biological product file includes all data and information submitted with or incorporated by reference in any