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U.S. Department of Health and Human Services

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Export under section 802(b)(2) of the FD&C Act

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Sep 24, 2008

 

By Fax and Certified Mail

Ann Price
Director, Regulatory Affairs
Antigenics, Inc.
3 Forbes Road
Lexington, MA 02421

Dear Ms. Price:

We are in receipt of your submission dated April 14, 2008, and additional submissions dated June 4, 2008, August 13, 2008, September 2, 2008, and September 16, 2008, which were received in our office on April 16, 2008, June 12, 2008, August 18, 2008, September 2, 2008, and September 17, 2008, respectively. Your April 14, 2008, submission was about the export of Oncophage®, an autologous tumor-derived therapeutic vaccine, to the Russian Federation (Russia) under section 802(b)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 381(b)(2). In support of this export, Antigenics, Inc. (Antigenics) submitted the following documents to the Food and Drug Administration (FDA)1:

  1. Registration Certificate issued by the Ministry of Health and Social Development of the Russian Federation (Ministry of Health), Federal Service on Surveillance in Healthcare and Social Development (Federal Service), April 14, 2008, submission (April Submission), Appendix 1;
  2. Federal Law N 86-ФЗ of June 22, 1998, as amended on January 2, 2000, December 20, 2001, January 10, 2003, June 30, 2003, August 22, 2004, and December 29, 2004, April Submission, Appendix 2 (copies in Russian and English);
  3. GOST R 52249-2004, National Standard of the Russian Federation, Rules for the Production and Quality Control of Pharmaceuticals – Good Manufacturing Practice for Medicinal Products (GMP), April Submission, Appendix 3 (copies in Russian and English (excerpts));
  4. Order N 736, October 30, 2006, Regarding approval of the administrative regulation of Roszdravnadzor for implementation of the official activities on state registration of medical products, April Submission, Appendix 4 (copies in Russian and English (excerpts));
  5. Order N 736, October 30, 2006, Regarding approval of the administrative regulation of Roszdravnadzor for implementation of the official activities on state registration of medical products, June 4, 2008, submission (June Submission), Appendix 1 (copies in Russian and English);
  6. Order N 266, June 19, 2003, updated October 18, 2006, Concerning approval of rules of clinical practice in the Russian Federation, June Submission, Appendix 2 (copies in Russian and English (only partially translated));
  7. Order N 969, April 4, 2006, “ Statement of a temporary regulations for out-off-staff experts of Roszdravnadzor on purpose of evaluation of the submitted documents and data on quality, effectiveness and safety of medicinal drugs [sic]”, June Submission, Appendix 3 (copies in Russian and English);
  8. Order N 266, June 19, 2003, updated October 18, 2006, Concerning approval of rules of clinical practice in the Russian Federation, September 2, 2008, submission (September Submission), Appendix 1 (copy in English);
  9. GOST R 52249-2004, National Standard of the Russian Federation, Rules for the Production and Quality Control of Pharmaceuticals – Good Manufacturing Practice for Medicinal Products (GMP), September Submission, Appendix 2 (copy in English)); and
  10. Certification regarding Oncophage®, dated September 16, 2008, signed by Kerry Wentworth.

I. Introduction

Pursuant to section 802(b)(2) of the FD&C Act, an unapproved new drug (including an unlicensed biological product) may be directly exported to a country that is not listed in section 802(b)(1)(A) of the FD&C Act, if the following criteria are met:

  • The drug complies with the laws of the country to which it would be exported and it has a valid marketing authorization by the responsible authority in that country, § 802(b)(2)(A);
  • FDA determines that all of the following requirements are met in that country:2
    • There are statutory or regulatory requirements which require the review of the drug for safety and effectiveness by an entity of the government of the country, and which authorize the approval of only those drugs which have been determined to be safe and effective by experts employed by or acting on behalf of such entity and qualified by scientific training and experience to evaluate the safety and effectiveness of drugs on the basis of adequate and well-controlled investigations, including clinical investigations, conducted by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, § 802(b)(2)(B)(i);
    • There are statutory or regulatory requirements that the methods used in, and the facilities and controls used for the manufacture, processing, and packing of drugs in the country are adequate to preserve their identity, quality, purity, and strength, § 802(b)(2)(B)(ii);
    • There are statutory or regulatory requirements for the reporting of adverse reactions to drugs and procedures to withdraw approval and remove drugs found not to be safe and effective, § 802(b)(2)(B)(iii);
    • There are statutory or regulatory requirements that the labeling and promotion of drugs must be in accordance with the approval of the drug, § 802(b)(2)(B)(iv); and
  • The requirements of § 802(f) are met.

II. Requirements of Section 802(b)(2)(A)

Section 802(b)(2)(A) of the FD&C Act imposes two conditions on the export of an unapproved drug to an unlisted country. First, the drug must comply with the laws of the country to which it is being exported and, second, the drug must have a valid marketing authorization in that country. It is the responsibility of the exporter, here Antigenics, to ensure that each shipment of drug complies with these conditions. FDA does, however, recommend that firms intending to export drugs under section 802(b)(2) of the FD&C Act provide documentation to FDA showing that the drug complies with the foreign country’s laws and has a valid marketing authorization. See Guidance for Industry: Exports Under the FDA Export Reform and Enhancement Act of 1996, July 23, 2007, Section VII.F. We acknowledge that, according to the registration certificate attached to your submission, the responsible authority for the issuance of marketing authorizations for drugs in Russia resides in the Federal Service in the Ministry of Health and that the Federal Service has issued a registration certificate of pharmaceutical product for the pharmaceutical product Oncophage® to be imported and distributed in Russia by the United States manufacturer, Antigenics. Registration Certificate, April Submission, pp. 5-9 (Appendix 1) (copy of registration certificate). We also acknowledge your certification that Oncophage® complies with the laws of Russia, the country to which it will be exported. Certification regarding Oncopahge®, dated September 16, 2008.

III. Requirements of Section 802(b)(2)(B)

Section 802(b)(2)(B) describes four components of a drug regulatory system that must be provided for in the statutes or regulations of a country for an unapproved drug to be exported to that country under section 802(b)(2). These components are: (1) a process for premarket review and approval of drugs; (2) good manufacturing practice controls; (3) requirements for adverse drug reaction reporting and the authority to remove drugs found to be unsafe or ineffective; and (4) requirements concerning drug advertising and promotion. FDA has determined that Russia's laws governing the regulation of drugs contain these four components.

    A. Section 802(b)(2)(B)(i)

First, for a drug to be exported under section 802(b)(2) of the FD&C Act, FDA must make a determination concerning the country’s approval framework for drugs that involves several interrelated elements. These elements are:

  • that there are statutory or regulatory requirements which require the review of drugs for safety and effectiveness;
  • that this review must be conducted by an entity of the government of the country;
  • that the statutory or regulatory requirements authorize the approval of only those drugs which have been determined to be safe and effective;
  • that there are statutory or regulatory requirements that the determination of safety and effectiveness be made by experts employed by or acting on behalf of such entity and qualified by scientific training and experience to evaluate the safety and effectiveness of drugs;
  • that there are statutory or regulatory requirements that the determination of safety and effectiveness be based on adequate and well-controlled investigations, including clinical investigations; and
  • that there are statutory or regulatory requirements that the investigations be conducted by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs.

            1. Review of Drugs for Safety and Effectiveness by an Entity of the Government

According to Article 1 of Federal Law N 86-ФЗ, the Russian Federal government regulates the “development, production, manufacturing, non-clinic and clinic trials of drugs and other actions in the field of drugs distribution, quality, effectiveness, and safety control, sales of drugs and other actions in the field of drugs distribution.” April Submission, p. 12 (Appendix 2); see also Federal Law N 86-ФЗ, articles 5.2 & 8, April submission, pp. 14-15 (Appendix 2). This regulation of drugs includes registration of drugs prior to distribution. Federal Law N 86-ФЗ, article 19, April submission, pp. 18-19 (Appendix 2) (“Drugs may be produced, sold and used in the territory of the Russian Federation if only being registered by the federal executive body authorized for providing state control and supervision in the field of drugs distribution.”); see also Federal Law N 86-ФЗ, article 5.1(1), April Submission, p. 13 (Appendix 2). According to the registration certificate submitted by Antigenics, the entity of the Russian government responsible for drug approvals is the Federal Service. April Submission, pp. 5-9 (Appendix 1).

Russian law sets out the information that must be submitted in the application for registration, including information on the components of the drug, proposed indications for use and labeling, good manufacturing practice (GMP), and proposed pharmacopeia information, methods for quality control, and results of the non-clinical, pharmacological, toxicological, and clinical trials of the drug, and information on the registration of the drug in other countries. Federal Law N 86-ФЗ, Article 19.9, April Submission, p. 19 (Appendix 2). The Russian regulations promulgated by Order N 736, entitled “Regarding approval of the administrative regulation of Roszdravnadzor for implementation of the official activities on state registration of medical products,” also address the review process. Order N 736, Article 3.3, June Submission, Appendix 1, pp. 4-6; see also Order N 736, Addendum N 3, June Submission, Appendix 1, pp. 14-15 (detailed list of information needed “to carry out examination of drug quality, effectiveness and safety”). In particular, Articles 3.3.5 and 3.3.6 of Order N 736 discuss the review of information related to safety and effectiveness. Order N 736, Articles 3.3.5 & 3.6.6, June Submission, Appendix 1, p. 5; see also Order N 736, Addendum N 1, June Submission, Appendix 1, pp. 12-13 (flowchart of review process).

Based on the translated documents submitted by Antigenics, FDA determines that, in Russia, there are statutory or regulatory requirements which require the review of drugs for safety and effectiveness and require that this review be conducted by an entity of the government of the country. This determination is based on FDA’s assessment of the translated laws and regulations that were submitted by Antigenics and does not reflect an assessment of the implementation of these regulatory requirements by any entity of the Russian government.

        2. Approval Only of Drugs Determined to be Safe and Effective

Russian law and regulation require a positive finding about safety and effectiveness in order to issue a registration certificate for a drug.3 Order N. 736, article 3.3.8(3), June Submission, Appendix 1, p. 6 (the reasons for objection to state registration include “unsafeness, inefficacy or …failure to prove safety and effectiveness of the drug”); Order N 736, Addendum N 1, June Submission, Appendix 1, pp. 12-13.

Based on the translated documents submitted by Antigenics, FDA determines that, in Russia, there are statutory or regulatory requirements that authorize the approval of only those drugs which have been determined to be safe and effective. This determination is based on FDA’s assessment of the translated laws and regulations that were submitted by Antigenics and does not reflect an assessment of the implementation of these regulatory requirements by any entity of the Russian government.

        3. Determination by Qualified Experts

Like U.S. laws and regulations governing approval of drugs,4 the translated Russian laws and regulations that FDA reviewed do not explicitly require that decisions on applications for market authorization be made by qualified experts. The need for expert qualifications, however, is implicit in the nature of the scientific and medical decisions that are required to be made to register a drug in Russia.5

Based on the translated documents submitted by Antigenics, FDA determines that, in Russia, there are statutory or regulatory requirements which require that the determination of safety and effectiveness be made by experts employed by or acting on behalf of such entity and qualified by scientific training and experience to evaluate the safety and effectiveness of drugs. This determination is based on FDA’s assessment of the translated laws and regulations that were submitted by Antigenics and does not reflect an assessment of the implementation of these regulatory requirements by any entity of the Russian government.

        4. Adequate and Well-Controlled Investigations Conducted by Qualified Experts

The translations reviewed by FDA do not use the term “adequate and well-controlled investigations, including clinical investigations,” to describe the basis for a registration determination. However, the Russian laws and regulations require the submission of non-clinical and clinical tests in an application for registration of a drug. In addition, the Russian laws and regulations also contain standards that address the quality and reliability of clinical investigations in a manner that is similar to the standards represented by the term “adequate and well-controlled investigations” in U.S. law and regulations.

As discussed above, see Section III.A.1, Federal Law N 86-ФЗ and Article 3.3.3 and Addendum 3 of Order N 736 specify what investigations must be submitted as part of an application for registration, including the result of non-clinical and clinical trials. According to Article 37 of Federal Law N 86-ФЗ, non-clinical and clinical investigations are conducted for the “purpose of getting scientific assessment and evidence of effectiveness and safety of drugs….” Federal Law N 86-Ф3, Articles 36.1 & 37.1, April Submission, p. 24 (Appendix 2). Order N 266, entitled “Concerning approval of rules of clinical practice in the Russian Federation,” sets forth Russia’s rules for conducting and reporting clinical trials and is intended, in part, “to ensure the reliability and accuracy of information obtained during research,” Order N 266, Article 1.2, September Submission, Appendix 1, p. 2.

The chart below lists the provisions of 21 C.F.R. 314.126, FDA’s regulation on adequate and well-controlled clinical investigations, and the Russian requirements on clinical trials that are similar to them.

21 C.F.R. 314.126 Russian Requirements (all citations to Order N 266, September Submission, Appendix 1, unless otherwise noted)
21 C.F.R. 314.126(a) Articles 1.2, 1.3, 1.9, 1.10; Federal Law N 86-ФЗ, Articles 37-39 (April Submission, pp. 24-25 (Appendix 2))
21 C.F.R. 314.126(b)(1) Articles 1.10, 1.12, 20.1-20.4, 2 (definitions of ensurance of correspondence of the clinical trial, report on clinical trial, protocol, standard procedures), 1.4, 19.1
21 C.F.R. 314.126(b)(2) Articles 1.2, 1.3, 2 (definitions of randomization, “blind” method of research, standard procedures), 7.5, 7.14, 11.2
21 C.F.R. 314.126(b)(3) Articles 1.12, 7.5, 7.13, 20.1; Federal Law N 86-ФЗ, Article 39.3 (April Submission, p. 25 (Appendix 2))
21 C.F.R. 314.126(b)(4) Articles 1.2, 2 (definition of randomization, “blind” method of research, standard procedures), 8.7, 11.2, 20.1
21 C.F.R. 314.126(b)(5) Articles 7.6, 7.12, 7.16, 7.18, 7.22, 8.7, 11.2, 12.6, 13.2, 14.1, 14.2, 17.1, 17.6, 17.8, 2 (definition of documentation, “ensurance” of correspondence of the clinical trial, direct access, blind method of research), 18.1-18.6
21 C.F.R. 314.126(b)(6) Articles 1.2, 1.3, 2 (definition of documentation, individual subject chart, “ensurance” of correspondence of the clinical trial, “blind” method of research), 7.5, 7.14, 7.22, 8.5-8.10, 11.1, 11.4 -11.6, 13.2, 14.1, 15.1, 17.1-17.4, 17.8, 18.1, 20.1
21 C.F.R. 314.126(b)(7) Articles 1.2, 1.3, 1.1020.1-20.4, 1.2, 1.3, 1.10
21 C.F.R. 314.126(d) Articles 12.1-12.2

These rules also specify the scientific qualifications of the persons conducting, monitoring, and verifying clinical trials. See, e.g., Order N 266, Articles 7.2, 7.8, 7.9, 17.2, 18.2, September Submission, Appendix 1, pp. 9-10, 15-16.

Based on the translated documents submitted by Antigenics, FDA determines that, in Russia, there are statutory or regulatory requirements which require that the determination of safety and effectiveness be based on adequate and well-controlled investigations, including clinical investigations, conducted by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs. This determination is based on FDA’s assessment of the translated laws and regulations submitted by Antigenics and does not reflect an assessment of the implementation of these regulatory requirements by any entity of the Russian government.

    B. Section 802(b)(2)(B)(ii)

Second, under section 802(b)(2)(B)(ii) of the FD&C Act, FDA must determine that Russia possesses s tatutory or regulatory requirements that the methods used in, and the facilities and controls used for the manufacture, processing, and packing of drugs in the country are adequate to preserve their identity, quality, purity, and strength.

Article 13 of Federal Law N 86-ФЗ authorizes production and quality control rules for drugs. Federal Law N 86-ФЗ, Article 13.1, April Submission, p. 15 (Appendix 2). In addition, Russian law states that violations of the rules of production and quality control are punishable by disciplinary, administrative, and criminal liability. Federal Law N 86-ФЗ, Article 18, April Submission, p. 18 (Appendix 2). Russia has adopted a GMP standard, see GOST R 52249-2004, National Standard of the Russian Federation, Rules for the Production and Quality Control of Pharmaceuticals – Good Manufacturing Practice for Medicinal Products (GMP), see September Submission, Appendix 2, which “complies to EC Guide to Good Manufacturing Practice for Medicinal Products,” id. at p. 21. This standard addresses the methods used in and facilities used for the production, packaging and holding of drugs, see, e.g., GOST R 52249-2004, Articles 1.2, 3, 5, September Submission, Appendix 2, pp. 22, 26-28, 32-35, and are “intended to guarantee the highest possible quality and safety of pharmaceuticals and assure that they have been manufactured in strict compliance with their structural formula (composition) without foreign inclusions, being adequately marked, packed and will preserve their qualities during application time,” id. at p. 21.

Based on the translated documents submitted by Antigenics, FDA determines that, in Russia, there are statutory or regulatory provisions that require that t he methods used in, and the facilities and controls used for the manufacture, processing, and packing of drugs in the country be adequate to preserve their identity, quality, purity, and strength. This determination is based on FDA’s assessment of the translated laws and regulations that were submitted by Antigenics and does not reflect an assessment of the implementation of these regulatory requirements by any entity of the Russian government.

    C. Section 802(b)(2)(B)(iii)

Third, under section 802(b)(2)(B)(iii) of the FD&C Act, FDA must determine that there are statutory or regulatory requirements for the reporting of adverse reactions to drugs and procedures to withdraw approval and remove drugs found not to be safe or effective.

Article 41.1 of Federal Law N 86-ФЗ provides that the government must be notified about side effects and the nature of any drug interaction with other drugs that do not conform to the labeling information. Federal Law N 86-ФЗ , Article 41.1, April Submission, p. 26 (Appendix 2). There is a specific “form of notice” that is to be used to report possible harmful side effects. April Submission, p. 26 (Appendix 2) (note following Article 41). Persons who learn of side effects but do not report them appear to be subject to disciplinary, administrative, or criminal liability. Federal Law N 86-ФЗ , Article 41.2, April Submission, p. 26 (Appendix 2). Order N 736 provides more detail on reporting of side effects, including a flow chart showing how the Federal Service will assess severe or unexpected side effects. Order N 736, Article 3.5 June Submission, Appendix 1, pp. 10-11, seealso Order N 736, Addendum N 5, June Submission, Appendix 1, pp. 18-19.

Russian regulation provides for suspension or revocation of the registration of a drug if the drug is found to be no longer safe or effective or if it no longer meets the terms of its registration. Order N 736, Articles 3.5, June Submission, Appendix 1, p. 8; seealso Order N 736, Addendums N 1 & 4, June Submission, Appendix 1, pp. 12-13, 16-17.

Based on the translated documents submitted by Antigenics, FDA determines that, in Russia, there are statutory or regulatory requirements for the reporting of adverse reactions to drugs and procedures to withdraw approval and remove drugs found not to be safe or effective. This determination is based on FDA’s assessment of the translated laws and regulations that were submitted by Antigenics and does not reflect an assessment of the implementation of these regulatory requirements by any entity of the Russian government.

    D. Section 802(b)(2)(B)(iv)

Fourth, under section 802(b)(2)(B)(iv) of the FD&C Act, FDA must determine that there are statutory or regulatory requirements that the labeling and promotion of drugs must be in accordance with the approval of the drug.

Article 16 of Federal Law N 86-ФЗ specifies the information that must be on a drug’s outside packaging, e.g., name and international non-proprietary name, manufacturer, lot number, instructions for use, expiration date, indications for use, contraindications, side effects, interactions with other drugs, dosing and other methods of application. Federal Law N 86-ФЗ , Article 16, April Submission, pp. 16-17 (Appendix 2). Federal Law N 86-ФЗ also appears to control advertising and promotion of registered drugs, stating that information is “to be given according to the requirements of the state information standard” [i.e., the approved labeling]. Federal Law N 86-ФЗ , Article 43, April Submission, pp. 26-27 (Appendix 2).

Based on the translated documents submitted by Antigenics, FDA determines that, in Russia, there are statutory or regulatory requirements that the labeling and promotion of drugs must be in accordance with the approval of the drug. This determination is based on FDA’s assessment of the translated laws and regulations that were submitted by Antigenics and does not reflect an assessment of the implementation of these regulatory requirements by any entity of the Russian government.

III. Conclusion

Based on the translated documents provided in your submissions and for the reasons set forth above, FDA has determined that, in Russia, there are statutory or regulatory requirements as specified in section 802(b)(2)(B) of the FD&C Act. If there are any changes to the Russian statutes, orders, regulations, rules, or addendums, this determination may no longer apply. To ensure the export of Oncophage® continues to comply with all requirements in section 802(b)(2)(B), Antigenics should notify FDA of changes in the marketing status of Oncophage® in Russia and changes to Russian law that could affect FDA's determination in this letter. Also, again, please be advised that this determination is based on FDA’s assessment of the translated laws and regulations that were submitted by Antigenics and does not reflect an assessment of the implementation of these regulatory requirements by any entity of the Russian government. Finally, please note that the appropriate Russian governmental entities are responsible for application of Russian laws to the importation and distribution of this product in Russia; the FDA acknowledgment and determinations contained in this letter are not intended to supplant the application of Russian law to Oncophage®.

Be advised that any exports under section 802 of the FD&C Act must also comply with the additional requirements of section 802(b)(2), described above in section II, as well as the requirements of section 802(f) and (g) of the FD&C Act, including the recordkeeping and notification requirements. FDA’s implementing regulations can be found at 21 C.F.R. 1.101.

Sincerely,

----/s/----

Leslie Kux
Deputy Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

______________________________________________________________

1 FDA is basing its determinations on the translated documents provided by Antigenics; FDA has not conducted additional searches or translations to determine if the documents and translations provided by Antigenics are correct, complete, and current. All references to Russian regulatory requirements in this document refer to the translations submitted by Antigenics. If FDA later has reason to believe that these translations are, in any material way, incorrect, incomplete, or outdated, FDA will take the necessary steps to amend or revoke its determinations. FDA may also pursue other remedies as it deems appropriate.

2 An FDA determination that the requirements listed in section 802(b)(2)(B) (i) – (iv) are met in a country is a limited determination and does not apply beyond export under section 802. For example, an “802(b)(2) (B) determination” is not a finding of “equivalence” between the importing country and the United States (or any other country). In addition, an 802(b)(2)(B) determination does not constitute a determination about whether an unapproved drug meets any criterion for approval under U.S. laws.

3 Russian law defines “safety of drugs” to mean “characteristics of drugs based on the comparative analysis of their effectiveness and evaluation of risk of harm for health,” and “effectivenss of drugs” to mean “characteristics of positive influence of drugs on the disease.” Federal Law N 86-Ф3, Article 4, April Submission, p. 13 (Appendix 2).

4 The U.S. statutory standards for approving drugs can be found at section 505 of the FD&C Act. 21 U.S.C. 355. For drugs that are also biologics products, as is the case here, the approval standard of section 351 of the Public Health Service Act applies. 42 U.S.C. 262. The regulations addressing approval of drugs and biologics can be found at 21 C.F.R. Part 314 and 21 C.F.R. Part 601, respectively. None of these statutory or regulatory provisions speak to the qualifications of the FDA employees that make drug or biologic approval determinations.

5 In addition to the required review by the Federal Service, the Russian regulations refer to the receipt of the views of experts before a drug can be registered. Order N 736, Articles 3.3.6 & 3.3.8(3), June Submission, Appendix 1, pp. 5, 6. There also are regulations that address the qualifications and duties of experts that may be consulted to assist in the review of a drug registration, e.g., degrees needed and length of experience. Order N 969, “ Statement of a temporary regulations for out-off-staff experts of Roszdravnadzor on purpose of evaluation of the submitted documents and data on quality, effectiveness and safety of medicinal drugs [sic],” June Submission, Appendix 3, pp. 61-63.

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