EFFECTIVE DATE: Submit either electronic or written comments on this proposed rule by November 20, 2014. See section V of this document for the proposed effective date of any final rule that may publish based on this proposal.
ADDRESSES: You may submit comments by any of the following methods:
Submit electronic comments in the following way:
* Federal eRulemaking Portal: http://www.regulations.gov. Follow the instructions for submitting comments.
Submit written submissions in the following ways:
* Mail/Hand Delivery/Courier (for paper submissions): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include Docket No. FDA-2014-N- 1110 for this rulemaking. All comments received may be posted without change to http://www.regulations.gov, including any personal information provided. For additional information on submitting comments, see the "Request for Comments" heading in section X of the SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the "Search" box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Lori J. Churchyard, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.
Purpose and Coverage of the Proposed Rule
The proposed rule would eliminate the codified GST /1/ regulations for biological products. FDA is proposing this action because the existing codified GST regulations are duplicative of requirements that are also specified in biologics license applications (BLAs) or are no longer necessary or appropriate to help ensure the safety, purity, and potency of licensed biological products. FDA is taking this action as part of its retrospective review of its regulations to promote improvement and innovation, in response to Executive Order (E.O.) 13563 of January 18, 2011.
FOOTNOTE 1 For purposes of this proposed rulemaking, the terms "general safety test" or "GST" refer to the requirements found under Title 21 of the Code of Federal Regulations (CFR), subchapter F, parts 600 through 680 (21 CFR parts 600 through 680), specifically 21 CFR 610.11, 21 CFR 610.11a and 21 CFR 680.3(b). END FOOTNOTE
Summary of the Major Provisions of the Proposed Rule
The proposed rule would remove the requirements contained in 21 CFR 610.11, 610.11a, and 680.3(b) from the regulations. Section 610.11 concerns a GST for the detection of extraneous toxic contaminants in biological products intended for administration to humans. Section 610.11a concerns the GST regulations for inactivated influenza vaccine. Section 680.3(b) concerns GST regulations for allergenic products. Removal of these regulations would not remove GST requirements specified in individual BLAs, however. A biological product manufacturer would continue to be required to follow the GST requirements specified in its BLA unless the BLA were revised to eliminate or modify the test through a supplement in accordance with 21 CFR 601.12(c). FDA would review proposed changes to a manufacturer's approved biologics license on a case-by-case basis so that we could ensure that any such action is appropriate.
Costs and Benefits
FDA is proposing this action because the existing codified GST regulations are duplicative of requirements that are also specified in BLAs, or are no longer necessary or appropriate to help ensure the safety, purity, and potency of licensed biological products. Because this proposed rule would impose no additional regulatory burdens, this regulation is not anticipated to result in any compliance costs and the economic impact is expected to be minimal.
On January 18, 2011, President Barack Obama issued E.O. 13563, "Improving Regulation and Regulatory Review" (76 FR 3821, January 21, 2011). One of the provisions in the E.O. is the affirmation of retrospective reviews of existing significant regulations. As one step in implementing the new E.O., FDA published a notice in the Federal Register on April 27, 2011 (76 FR 23520), entitled "Periodic Review of Existing Regulations; Retrospective Review Under E.O. 13563." In that notice, FDA announced that it was conducting a review of existing regulations to determine, in part, whether they can be made more effective in light of current public health needs and to take advantage of, and support, advances in innovation that have occurred since those regulations took effect. As part of this initiative, FDA is proposing to eliminate the codified GST regulations as specified in this rule. We believe this action is appropriate because in many instances, the GST regulations duplicate requirements that are also specified in the BLA required for biological products intended for human use under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262), or they are outmoded or otherwise unnecessary to help ensure the continued safety, purity, and potency of biological products. For a number of years, FDA has not codified specific requirements for licensed biological products, in part because codifying specific requirements for biological products can diminish the ability of the Agency and industry to respond to technological developments. Instead the Agency has described the required tests for particular products in manufacturers' BLAs.
The GST is one of several tests listed in part 610, General Biological Product Standards, that is intended to help ensure the safety, purity, and potency of biological products administered to humans. Manufacturers of biological products are currently required to perform this test for general safety on biological products intended for administration to humans under SEC 610.11, on inactivated influenza vaccines under SEC 610.11a, and on allergenic products under SEC 680.3(b), unless exempted by regulation or an exemption is granted under SEC 610.11(g)(2).
The GST was intended to be a final check designed to detect any toxic contaminants present in the final product. The test was cited as early as 1909 (Ref. 1), and appeared in the first Code of Federal Regulations in 1938, before the establishment of Current Good Manufacturing Practices (cGMPs) for drug manufacture in the CFR, which occurred in 1963. The GST was subsequently revised to, among other things, "reflect the best current testing procedures established by the scientific community as well as to promote uniformity and specificity in the safety testing of licensed biological products" (March 15, 1976, 41 FR 10888).
A product that meets the requirements for general safety will comply with the criteria found in SEC 610.11(d) of the GST regulation, i.e., injected animals survive the test period; they do not exhibit any response that is not specific for or expected from the product and which may indicate a difference in quality of the product; and they weigh no less at the end of the test period than they did at the time of injection.
While originally a useful approach, as time has passed, the Agency has periodically explored the utility and efficiency of this approach. In the Federal Register of May 14, 1996 (61 FR 24227), FDA published a final rule exempting certain biotechnology-derived and synthetic biological products from a number of regulations applicable to biological products, including the GST (see SEC 601.2(c)). This action was in response to technical advances that greatly increased the ability of manufacturers to control the manufacture of, and to more fully analyze the physical and biological characteristics of, many biotechnology-derived biological products.
Approximately 2 years later, in the Federal Register of April 20, 1998, FDA issued a direct final rule (DFR) and a companion proposed rule (63 FR 19399 and 19431, respectively) to expand the exceptions in SEC 610.11(g) to include "cellular therapy products" because, among other reasons, the Agency believed that the procedures and materials used to manufacture these products are stringently controlled and monitored. In addition, FDA provided for in the DFR and the companion proposed rule an administrative procedure for manufacturers of other biological products to request and obtain exemptions from conducting the GST. FDA took this action ". . . because the GST may not be relevant or necessary for biological products . . . currently in various stages of development" and as part of FDA's continuing efforts at that time "to reduce the burden of unnecessary regulations on biological products without diminishing the protection of the public health" (63 FR 19399 at 19400) (FDA refers readers to the preamble of the April 20, 1998, proposed rule should they wish to obtain additional details on the history of this rulemaking).
In the Federal Register of August 5, 1998 (63 FR 41718) (August 1998 Notice), FDA published a DFR confirming in part, and withdrawing in part, the provisions in the DFR that published April 20, 1998. Specifically, FDA confirmed a revision to SEC 610.11(g)(1) to add "cellular therapy products" to the list of products exempted from the GST. However, because the Agency received significant adverse comments concerning SEC 610.11(g)(2), the provision of the rule that required administrative procedures for requesting an exemption from the GST regulations, SEC 610.11(g)(2) was withdrawn. As discussed in the August 1998 Notice, the comments were applied to the corresponding portion of the companion proposed rule and considered in developing the final rule.
After considering the comments to the DFR and companion proposed rule, in the Federal Register of March 4, 2003 (68 FR 10157 at 10158) (March 2003 Final Rule), FDA again provided for an administrative procedure under which manufacturers of biological products may request and obtain exemptions from conducting the GST ( SEC 610.11(g)(2)). In the preamble to the March 2003 Final Rule, FDA again noted that the GST may not be relevant or necessary for certain biological products (68 FR 10157).
Accordingly, SEC 610.11 currently includes a provision allowing manufacturers to request an exemption from the GST. Note that this exemption provision requires manufacturers to provide supporting documentation when making their request (see 68 FR 10157 through 10159). Specifically, when requesting such an exemption, manufacturers must submit information as part of a BLA or supplement to an approved BLA establishing that because of the mode of administration, the method of preparation, or the special nature of the product, a test for general safety is unnecessary to assure the safety, purity, and potency of the product, or cannot be performed ( SEC 610.11(g)(2)).
Since FDA issued the March 2003 Final Rule, it has become increasingly clear that the codified GST regulations are too restrictive for certain additional biological products because they specify particular methodologies or requirements when alternatives may be available that provide the same or greater level of assurance of safety. Thus, the Agency believes that the regulations may no longer reflect the best current testing procedures established by the scientific community as a general matter (although the testing procedures may still be appropriate in certain circumstances) and that the more efficient way of prescribing testing requirements for particular products would be to allow such requirements to be specified in the BLA to enhance flexibility to make appropriate changes to testing methods.
II. Appropriate Controls Would Remain in Place
FDA believes that if this rulemaking becomes finalized as proposed, we would be able to continue to ensure that appropriate controls remain in place. For example, manufacturers of all products derived from inherently toxic substances would be required to continue to use the safety tests that are prescribed in their BLAs to control and monitor toxicity. These product-specific tests (performed in animals, cell cultures, or other systems) in conjunction with physical, chemical, and biological characterization tests define and monitor the production process and alert manufacturers to potential problems. Because these tests are tailored to the proprietary manufacturing process and are appropriate for the detection of intrinsic or extraneous toxic contaminants for a particular product or product class, they are more appropriately specified in the manufacturer's BLA or BLA supplement than codified as regulations.
Furthermore, we anticipate that the proposal to eliminate the codified GST regulations would encourage the implementation of the principles of the "3Rs," to reduce, refine, and replace animal use in testing, thus addressing the need to minimize the use of animals in such testing and promoting more humane, appropriate, and specific test methods for assuring the safety of biological products. /2/
FOOTNOTE 2 Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Authorization Act of 2000 (42 U.S.C. 2851-3). Additional information on the Federal Government's implementation of the principles of the 3Rs may be found at the ICCVAM Web site at http://ntp.niehs.nih.gov/go/iccvam. END FOOTNOTE
If the proposed rule is finalized and the GST regulations are eliminated, manufacturers would continue to be required to perform a particular safety test for certain products that present specific safety concerns, for example, testing for a specific toxicity, as set forth in an approved BLA or BLA supplement. As discussed previously, although this rulemaking proposes to eliminate the codified GST from the biologics regulations, FDA recognizes that all manufacturers that currently conduct a GST have this test described in their BLAs for their licensed products. As a result, if this proposed rule is finalized, these manufacturers would continue to be required to perform the GST unless the manufacturer's BLA were revised through a supplement to eliminate or modify the test. FDA would review these proposed changes to a manufacturer's approved BLA on a case-by-case basis so that we could ensure that any such action is appropriate. Thus, the removal of these biologics regulations, should this proposed rule be finalized, would not automatically revise a manufacturer's BLA or BLA supplement.
The requirements for a licensed biological product manufacturer to report changes in its product, product labeling, production process, quality controls, equipment, facilities, or responsible personnel, as established in its approved BLA, are detailed in SEC 601.12. Under this regulation, manufacturers must report each change to the Agency in one of several different types of submissions. The applicable submission category depends on the potential for the change(s) at issue to have an adverse effect on the identity, strength, quality, purity, or potency of the particular biological product as it may relate to the safety or effectiveness of the product. A BLA supplement for a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as it may relate to the safety or effectiveness of the product must be submitted under SEC 601.12(c) (Changes requiring supplement submission at least 30 days prior to distribution of the product made using the change).
As a general matter, should a manufacturer wish to no longer perform the GST described in its BLA, the Agency would consider the discontinuation of the GST to have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as it may relate to the safety or effectiveness of the product. Accordingly, a manufacturer who desires to discontinue the GST in the approved BLA or utilize an alternative method other than the GST approved in its BLA must submit a BLA supplement reporting the change in accordance with SEC 601.12(c). Within 30 days of the date FDA receives the submission, FDA will determine if the change has been reported in the proper category and will notify the manufacturer if it has not. If FDA has not notified the manufacturer otherwise within 30 days after FDA receives the supplement, the manufacturer may distribute its product using the change described in the supplement. If, however, FDA determines that the information submitted in the supplement fails to demonstrate the continued safety or effectiveness of the product made using the change, FDA will try to resolve the problems with the manufacturer. For example, in the event that the Agency determines that for a particular manufacturer's unique product a GST is still necessary to assure the continued safety or effectiveness of the product (e.g., for products with concerns related to residual toxin activity/reversion to toxicity, or if the alternative method proposed is unacceptable), the Agency would notify the manufacturer of its decision within 30 days following receipt of the supplement and would work with the manufacturer to resolve the issue.
III. Highlights of the Proposed Rule
The proposed rule would remove SUBSEC 610.11, 610.11a, and 680.3(b), the regulations that require that manufacturers of biological products perform a specified test for general safety of biological products. FDA is taking this action because the existing codified GST regulations are duplicative, outmoded, or are otherwise unnecessary to help ensure the continued safety, purity, and potency of licensed biological products.
IV. Legal Authority
FDA is issuing this regulation under the biological products provisions of the PHS Act (42 U.S.C. 262 and 264), and the drugs and general administrative provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 321 et seq.). Under these provisions of the PHS Act and the FD&C Act, we have the authority to issue and enforce regulations designed to ensure that biological products are safe, effective, pure, and potent, and to prevent the introduction, transmission, and spread of communicable disease.
V. Proposed Effective Date
FDA is proposing that any final rule that may issue based on this proposal be effective 90 days after the date of its publication in the Federal Register .
VI. Analysis of Impacts
FDA has examined the impacts of the proposed rule under E.O. 12866, E.O. 13563, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 13563 direct Agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, and other advantages; distributive impacts; and equity). The Agency believes that this proposed rule is not a significant regulatory action as defined by E.O. 12866.
The Regulatory Flexibility Act requires Agencies to analyze regulatory options that would minimize any significant impact of a rule on small entities. Because this proposed rule generally increases flexibility for safety testing and would result in the reduction of certain regulatory burdens and does not add any new regulatory responsibilities, the Agency proposes to certify that the final rule will not have a significant economic impact on a substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires that Agencies prepare a written statement, which includes an assessment of anticipated costs and benefits, before proposing "any rule that includes any Federal mandate that may result in the expenditure by State, local, and tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more (adjusted annually for inflation) in any one year." The current threshold after adjustment for inflation is $141 million, using the most current (2013) Implicit Price Deflator for the Gross Domestic Product. FDA does not expect this proposed rule to result in any 1-year expenditure that would meet or exceed this amount.
This rule proposes to amend the biologics regulations by removing GST regulations for biological products found in SUBSEC 610.11, 610.11a and 680.3(b). FDA is proposing this action because the current codified GST regulations are duplicative of requirements that are also specified in biologics licenses, or are no longer necessary or appropriate to help ensure the safety, purity, and potency of licensed biological products. The removal of the GST regulations for biological products would not remove GST requirements specified in individual biologics license applications, however. All manufacturers that currently conduct a GST are already required, as part of the requirements specified in their biologics license applications, to perform the GST and would thus continue to be required perform the GST unless the BLA were revised to eliminate or modify the test through a supplement in accordance with SEC 601.12(c). Because this proposed rule would impose no additional regulatory burdens, this regulation is not anticipated to result in any compliance costs and the economic impact is expected to be minimal.
VII. The Paperwork Reduction Act of 1995
This proposed rule refers to previously approved collections of information that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520). The collections of information in SEC 601.12 have been approved under OMB control number 0910-0338. Therefore, FDA tentatively concludes that the proposed requirements in this document are not subject to review by OMB because they do not constitute a "new collection of information" under the PRA.
VIII. Environmental Impact
The Agency has determined under 21 CFR 25.30(h) that this action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.
FDA has analyzed this proposed rule in accordance with the principles set forth in E.O. 13132. FDA has determined that the proposed rule, if finalized, would not contain policies that would have substantial direct effects on the States, on the relationship between the National Government and the States, or on the distribution of power and responsibilities among the various levels of government. Accordingly, the Agency tentatively concludes that the proposed rule does not contain policies that have federalism implications as defined in the E.O. and, consequently, a federalism summary impact statement is not required.
X. Request for Comments
Interested persons may submit either electronic comments regarding this document to http://www.regulations.gov or written comments to the Division of Dockets Management (see ADDRESSES). It is only necessary to send one set of comments. Identify comments with the docket number found in brackets in the heading of this document. Received comments may be seen in the Division of Dockets Managementbetween 9 a.m. and 4 p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.
FDA has placed the following reference on display in the Division of Dockets Management (see ADDRESSES) and may be seen by interested persons between 9 a.m. and 4 p.m., Monday through Friday and are available electronically at http://www.regulations.gov.
1. Anderson, J. F., "The Influence of Concentration (Gibson's Method) On the Presence of Tetanus Toxin in Blood Serum," Journal of Experimental Medicine: 1909 September 2; 11(5): 656-658.
List of Subjects
21 CFR Part 610
Biologics, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 680
Biologics, Blood, Reporting and recordkeeping requirements.
Therefore under the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, and under authority delegated to the Commissioner of Food and Drugs, it is proposed that 21 CFR parts 610 and 680 be amended as follows:
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
1. The authority citation for 21 CFR part 610 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 264.
SEC 610.11 [Removed and Reserved]
2. Remove and reserve SEC 610.11.
SEC 610.11a [Removed and Reserved]
3. Remove and reserve SEC 610.11a.
PART 680--ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS
4. The authority citation for 21 CFR part 680 continues to read as follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.
SEC 680.3 [Amended]
5. Remove and reserve paragraph (b).
Dated: August 18, 2014.
Associate Commissioner for Policy and Planning.
[FR Doc. 2014-19888 Filed 8-21-14; 8:45 am]
BILLING CODE 4164-01-P