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  1. Clinical Trials and Human Subject Protection

New Drug and Antibiotic Regulations

21 CFR Parts 71, 170, 171, 180, 201, 310, 312, 314, 330, 430, 431, 433, 510, 511, 514, 570, 571, 601, 812, 1003, and 1010
New Drug and Antibiotic Regulations
[Docket No. 82N-0293]
50 FR 7452

February 22, 1985

AGENCY: Food and Drug Administration.

ACTION: Final rule.

SUMMARY: The Food and Drug Administration (FDA) is revising its regulations governing the approval for marketing of new drugs and antibiotic drugs for human use. FDA is taking this action to speed up the availability of beneficial drugs to consumers by improving the efficiency of the agency's approval process for new drugs and antibiotic drugs, while improving the already high level of public health protection the drug approval and surveillance processes now provide. The improvements will help applicants prepare and submit higher quality applications and permit FDA to review them more efficiently and with fewer delays. This will benefit both consumers and applicants by permitting earlier availability and marketing of new drugs and antibiotics. This action is one part of a larger effort by FDA to review all facets of the agency's drug approval process.

DATES: These final regulations are effective May 23, 1985, except 21 CFR 314.80 Postmarketing reporting of adverse drug experiences is effective August 22, 1985. FDA will, however, accept applications until February 24, 1986 that are in the format required under either the current regulations or this final rule. For additional information concerning these effective dates see IV. "Paperwork Reduction Act of 1980" appearing in the preamble of this document.

FOR FURTHER INFORMATION CONTACT: Steve H. Unger, Center for Drugs and Biologics (HFN-362), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-5220.

I. Introduction

This final rule completes the first phase of efforts by the Department of Health and Human Services (HHS) to revise Federal regulations governing the new drug approval process. This phase of the regulations (called the NDA Rewrite) finalizes new procedures in 21 CFR Part 314 for FDA review of new drug and antibiotic applications for marketing. This action completes the rulemaking process begun on October 19, 1982 (47 FR 46622). The second phase of these regulatory revision efforts (called the IND Rewrite) covers FDA procedures in 21 CFR Part 312 for reviewing investigational new drug applications. This second phase is nearing completion, following the publication of proposed regulations in the Federal Register of June 9, 1983 (48 FR 26720). A third phase of improving the drug approval process involves noncodified guidelines on application format and on fulfulling testing requirements. Together with other regulatory and administrative reforms, the IND/NDA Rewrite and related guidelines represent a major effort on the part of FDA to improve the entire process of drug approval regulation. This effort was begun by FDA through concept papers made available for public comment (44 FR 58919, October 12, 1979) and a related public meeting on November 9, 1979. It was accelerated and intensified at the request of the President's Task Force on Regulatory Relief.

The objectives of the NDA Rewrite final rule are to establish an efficient, but thorough, drug approval process in order both: (a) To facilitate the approval of drugs shown to be safe and effective; and (b) to ensure the disapproval of drugs not shown to be safe and effective. These regulations are also intended to improve FDA's surveillance of marketed drugs. Accordingly, the final regulations enable FDA to act as both a public health promoter, by facilitating the approval of important new safe and effective therapies, and as a public health protector, by keeping off or taking off the market drugs not shown to meet safety and efficacy standards.

In preparing the final rule, FDA carefully reviewed approximately 120 comments received from pharmaceutical manufacturers, trade associations, health professionals and professional societies, consumers and consumer organizations, and Congress. In addition, FDA held a series of meetings with agency employees in order to gain their views as part of the internal decisionmaking process. The agency also considered the recommendations of the Congressionally sponsored Commission on the Federal Drug Approval Process. In preparing the final rule, therefore, the agency has considered the views of virtually all persons having an interest in the drug approval process.

Like both the NDA and IND proposals, the NDA final rule has been reviewed by a special task force appointed by the Secretary of Health and Human Services, and chaired by the Commissioner of Food and Drugs, whose specific charge has been to review these regulations in accordance with Executive Order 12291 (46 FR 13193, February 19, 1981), the mandate of the President's Task Force on Regulatory Relief, and the policy objectives outlined above. Many of these issues were also reviewed by a separate FDA task force, which the Commissioner also chaired.

The NDA final rule is designed to complement the proposed IND regulations, especially in terms of fostering a continuous dialogue between FDA and applications throughout the drug development and approval process. For example, one of the major improvements over present practice suggested in the IND proposal was to allow any drug sponsor an opportunity to attend an "end-of-Phase 2" meeting with FDA officials in order to agree on a plan for Phase 3 clinical investigations. As stated in that proposal, FDA believes that such meetings can significantly shorten the period of subsequent NDA review. The IND proposal also encourages "Pre-NDA" meetings between FDA and applicants to discuss format and modes of presentation in the marketing application. These meetings will be especially necessary as applicants learn how to prepare marketing applications under the new format. As described further below, the NDA Rewrite final rule encourages such dialogue to continue throughout the NDA review period as well.

The new NDA regulations will be supplemented by a series of guidelines. These guidelines are intended to provide applicants with guidance on application format and on how to fulfill testing requirements. The format guidelines will address the overall summary and each of the different technical sections of the application. The guidelines on how to fulfill testing requirements will focus on the areas of animal toxicity testing and chemistry and manufacturing controls, as previously announced in the preamble to the IND Rewrite proposal (48 FR 26720, 26721). These guidelines are in addition to the overall 25 clinical guidelines that FDA prepared in the middle and late 1970's concerning the design of adequate and well-controlled studies on different classes of drugs. Finally, FDA plans to issue a guideline regarding the reporting of adverse drug experiences on marketed drugs, a draft of which has already been made available for public comment (48 FR 4049; January 28, 1983). FDA intends to continue to solicit public comment on draft guidelines before they are published in final form. For example, notices announcing the availability of several draft guidelines concerning how to fulfill chemistry and manufacturing controls requirements have already been published (see the Federal Register of February 1, 1984 (49 FR 4040) and May 7, 1984 (49 FR 19412 and 19413)). FDA hopes to have all these guidelines publicly available, at least in draft form, before the new regulations become effective, although the agency does not view the existence of draft or final guidelines as being a prerequisite for implementing this final rule.

The IND/NDA Rewrites and related guidelines are part of a larger, overall effort to improve the drug development and approval process. For example, FDA will continue to recognize the high priority given to new drug and antibiotic application reviews, to increase the efficiency in the management review of applications, and to strengthen the agency's scientific base. In addition, with the passage of the Orphan Drug Act of 1983, the agency's Office of Orphan Products Development is actively involved in facilitating the development of new drug and other products intended to treat rare diseases.

Highlights of this final rule, the agency's economic analysis, and responses to general comments are contained in the following introductory sections. The remainder of this preamble is devoted to a section-by-section analysis of comments received, responses to them, and contents of the final regulations.

II. Highlights of the Final Rule

As noted above, the guiding principle in the NDA Rewrite final rule is that the drug approval process should be efficient, but thorough, in order to facilitate the approval of drugs shown to be safe and effective, and ensure the disapproval of drugs not shown to be safe and effective. The regulations are also intended to improve FDA's surveillance of marketed drugs. In response to comments and further internal deliberations, the final rule has modified certain provisions of the proposal in order to meet these objectives better. The major provisions of the final rule are summarized as follows:

1. Application format. The final rule incorporates the proposed revisions designed to make the application format more amenable to efficient agency review. Thus, like the proposal, the new format requires an overall summary of the entire application and separate, detailed technical sections that each contain individual summaries and analyses of the specific information needed by the particular reviewing disciplines: clinical, pharmacology, chemistry, statistics, and biopharmaceutics (as well as microbiology for anti-infective drugs). The new format will therefore permit parallel review by each of the five (or six) disciplines. In addition, detailed technical sections that synthesize the important information about the drug will greatly facilitate review by agency officials. The final rule also provides applicants the option of submitting the chemistry section (if it is complete) 90 to 120 days prior to submission of the main application in order to expedite review and permit early resolution of deficiencies.

2. Safety update reports. The final rule also incorporates the general requirement contained in the proposal for applicants to submit new safety information learned about a drug while an application is being reviewed by FDA. The final rule modifies the timing and frequency of these reports in order to focus FDA evaluation of them at key points in the review process. Thus, under the final rule, safety update reports will be required 4 months following the initial submission of the application, following receipt of an "approvable" letter, and at other times upon FDA request. These safety update reports will ensure that approval decisions reflect the most up-to-date safety information available.

3. Case report forms and data tabulations. The final rule follows the general principle enunciated in the proposal that an efficient agency review of individual patient data should be based primarily on well-organized, concise, data tabulations, and that reliance on the more lengthy case report forms should be reserved for those instances where a more detailed review is necessary. Accordingly, the final rule provides: (i) That case report forms will be routinely required where the patient dropped out or died during a clinical study (because these forms are likely to disclose the most serious safety problems); (ii) that individual patient data tabulations will be required for the remaining patients; and (iii) that additional case report forms will be requested by FDA when needed to conduct a proper review of the application. In response to comments, the final rule clarifies that FDA reviewers, with the concurrence of the division director, will have access to whatever additional case report forms are needed to conduct a proper review. The preamble explains that this may include requests for full case reports from the most critical studies, but that these reports will ordinarily be requested early in the review process so as not to cause undue delay. These data submission requirements should promote a more focused, efficient review of the application without compromising the thoroughness of that review. FDA estimates that this approach will result in a 75 percent reduction, on average, in the number of case report forms now required to be submitted to the agency in order to obtain approval.

4. Time frames for FDA review. The final rule incorporates the time frames contained in the proposal pertaining to the agency's review of applications. Accordingly, the final rule gives the agency 180 days from receipt of an application to issue either an "approval" letter, an "approvable" letter, or a "not approvable" letter. This time period may be extended when major amendments are received, although the extension would only be for the extra time needed to review the amendments. The final rule, like the proposal, also defines the procedure and time frame for "filing" an application within the meaning of section 505(c) of the act (21 U.S.C. 355(c)). Codification of these time frames demonstrates the agency's commitment to reviewing applications promptly in accordance with the statutory mandate.

5. Action letters. The final rule also incorporates provisions contained in the proposal which clarify the meaning of its three action letters: approval letters, approvable letters, and not approvable letters. Like the proposal, the final rule clarifies that only an approval letter grants permission for marketing of a drug. In addition, the final rule adopts the proposed policy that the agency will issue an approval letter, rather than an approvable letter, when the only deficiencies in the application concern editorial or other minor changes in the labeling, with approval conditioned on the deficiencies being corrected, as requested, before the drug is marketed.

6. Foreign data. The final rule incorporates the proposed policy that an application based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved by FDA if: (i) The foreign data are applicable to the U.S. population and U.S. medical practice; (ii) the studies have been performed by clinical investigators of recognized competence; and (iii) the data may be considered valid without the need for an on-site inspection by FDA or, if FDA considers such an inspection to be necessary, FDA is able to validate the data through an on-site inspection or other appropriate means. These criteria assure the quality of any drug products so approved, while at the same time removing the need to conduct repetitive clinical testing in this country in those instances where adequate data have been generated abroad.

7. Communication between FDA and applicants. The final rule greatly expands upon the proposed provision concerning communication between FDA and applicants. The final rule, with greater emphasis than the proposal, encourages dialogue between FDA and applicants about scientific and medical issues that arise during the review process. This includes notifying applicants of easily correctable deficiencies found in an application shortly after those deficiencies are discovered, providing an opportunity for an informal meeting mid-way through the review process and again after FDA's review is completed, and expressly permitting telephone calls and other informal meetings as the need may arise. This provision builds on portions of the IND Rewrite proposal that encouraged such communication during the testing phase of the drug development process.

8. Dispute resolution. The final provision on dispute resolution has been significantly revised in order to build upon the general principles noted above with respect to communication between FDA and applicants. For administrative and procedural issues, the final rule establishes an ombudsman whose function will be to investigate what has happened and to facilitate a timely and equitable resolution. For scientific and medical disputes, the final rule provides that applicants should seek resolution through an "end-of-review conference" with appropriate agency staff and management representatives, and at other informal meetings as the need may arise. The final rule also provides for the participation of outside experts at these informal meetings when feasible. This procedure supersedes the appeals process described in the NDA (and IND) Rewrite proposals because that process was seen as being too formal and was not effective during the pilot period.

9. Supplements. The final rule, like the proposal, establishes different categories of supplements to approved applications concerning manufacturing and controls changes. The rationale for the categories is that changes that could affect the safety or effectiveness of a final drug product should be preapproved by FDA, but that other changes may be implemented by a firm while notifying FDA either concurrently or in the next annual report. Although some changes have been placed in different categories than originally proposed, the final rule should still result in a 20 percent reduction in the number of manufacturing and controls supplements that require prior approval by the agency. Thus, the final rule will enable drug manufacturers to implement some kinds of manufacturing changes significantly more promptly without compromising drug safety and effectiveness.

10. Postmarketing surveillance. The final rule modifies the proposal in several ways in order to focus FDA review more directly on the more serious adverse drug experiences. Under the final rule, 15 working day "alert reports" will be required for all adverse drug experiences that are both serious and unexpected, and for any significant increase in frequency of an adverse drug experience that is both serious and expected (rather than only unexpected fatal and life-threatening experiences, as had been proposed). Other adverse drug experiences, as specified in the final rule, will be required to be reported at quarterly intervals in the first 3 years following approval, and annually thereafter. The quarterly reporting requirement reflects the fact that close surveillance of a new drug's side effects is especially important during the first 3 years of marketing. Although the quarterly/annual reporting of adverse drug experiences is less frequent than the proposed period of 30 working days, FDA believes that such quarterly/annual reporting is consonant with the agency's need to review reports of expected or nonserious adverse drug experiences.

III. Economic Analysis

The agency has examined the economic consequences of these regulations in accordance with Executive Order 12291 and the Regulatory Flexibility Act. A final regulatory impact analysis has been prepared and placed in file with the Dockets Management Branch (HFA-305), Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857.

The regulations are expected to shorten the total elapsed time required to approve the average application, including resubmission, from about 27 months to 21 months -- an average savings of 6 months. The average approval time for applications involving important new chemical entities is projected to improve from about 19 months to 17 months -- an average savings of 2 months. The faster approval and smaller savings for new chemical entities reflect the special priority already accorded these applications. Faster approvals for applications would benefit both consumers and pharmaceutical manufacturers. Consumers would have earlier access to important new drugs that have the potential to extend life, avoid hospitalization, or provide other significant health benefits. Firms developing new drugs would realize faster return on their research investments, thereby encouraging further investment in subsequent pharmaceutical research. The regulatory impact analysis examines some measures of these various benefits, although none are amenable to simple quantification in monetary terms.

Nonetheless, these benefits are substantial. For example, a 2-month speed-up in the approval of 15 therapeutically significant applications per year would result in about 500,000 additional prescriptions for these important drugs in the first year following FDA approval. The number of persons benefiting from these additional prescriptions would probably exceed 200,000, after adjusting the total for renewal and repeat prescriptions. Some of these individuals should receive very significant medical benefits such as avoidance of surgery, cure or stabilization of a life-threatening disease, or relief of a physical handicap. Many individuals should also save money as compared to alternate treatments.

The accelerated availability of new drugs to consumers will also increase industry revenues. However, the increase will not be as great as gross sales because some of the new drugs will displace less effective or more costly drugs.

Changes in the cost of the new drug application process itself will be minor. Increases include $1.2 million annually for detailed NDA summaries, $0.5 million annually for NDA safety update reports, and $0.4 million annually for increased adverse experience reports for approved NDA's; decreases include $0.4 million for less routine paperwork for NDA's, $1.6 million for reduced supplements for approved NDA's, and $1.6 million for reduced supplements for approved ANDA's. These latter two decreases relate to applications to change postmarketing manufacturing procedures for NDA's or ANDA's in minor ways. The net decrease of $1.5 million is about $1.0 million less than the cost savings estimated in the preliminary analysis, attributable primarily to cost estimates for safety update reports and adverse experience reports that were not calculated at the proposal stage.

The agency also concludes that these regulations will have a favorable impact on small firms because of cost savings associated with abbreviated applications, the type of application most frequently held by small firms. Due to the elimination of requirements for submitting certain postmarketing supplements, FDA estimates a savings of $540 for each abbreviated application. While this impact is favorable, it will not be a significant savings for any one firm. Therefore, the agency certifies, in accordance with the Regulatory Flexibility Act, that this rule will not have a significant economic impact on a substantial number of small entities.

IV. Paperwork Reduction Act of 1980

In accordance with the Paperwork Reduction Act of 1980 (44 U.S.C. Chapter 35), the reporting and recordkeeping requirements in § § 314.50, 314.55, 314.70, 314.71, 314.72, 314.80, 314.81, 314.90, 314.110, 314.120, 314.126, 314.200, 314.300, and 314.420 in these regulations will be submitted for approval to the Office of Management and Budget (OMB). Interested persons desiring to submit comments on the collection of information requirements pursuant to the Paperwork Reduction Act and its implementing regulations (5 CFR Part 1320) should direct them by April 15, 1985, to the Office of Information and Regulatory Affairs, OMB, Rm. 3002, New Executive Office Bldg., Washington, DC 20503, Attn: Bruce Artim. These requirements will not be effective until FDA obtains OMB approval. FDA will publish a notice concerning OMB approval of these requirements in the Federal Register prior to May 23, 1985. V. Comments on Proposed Rule

General Comments

1. FDA received approximately 120 comments on the proposed rule. These comments were received from pharmaceutical manufacturers, trade associations, health professionals and professional societies, consumer and consumer organizations, and Congress. A number of the proposed changes were generally supported by these diverse groups, especially those improving the application format, establishing time frames for FDA review of applications, and requiring safety update reports for pending applications. Other items considered especially beneficial by consumers included the requirement for a description of the foreign marketing history of the drug and the proposal concerning postmarketing survelliance. In addition, industry comments found especially beneficial the adoption of a single set of regulations for both antibiotics and nonantibiotic drugs, the reductions in supplements and other reports, and the clarified definitions and procedures for FDA's issuance of action letters.

2. The major concerns raised by consumers and consumer organizations was the fear that two of the proposed changes could possibly result in the marketing of drugs that are not safe or effective, as required by law. The issues of concern in this regard were the proposal to eliminate the routine submission of most case report forms, and the proposal concerning the acceptance of foreign data.

FDA shares the view that any changes made in the new drug regulations should not in any way lower the safety and effectiveness of marketed drugs, and FDA has carefully reviewed each section of the final regulations to ensure that that result does not occur. With respect to case report forms, the final rule ensures that FDA reviewers will have access to any case report forms necessary to conduct a proper review of the drug's safety and effectiveness. With respect to foreign data, FDA carefully reviewed its proposed policy, and explains in this preamble why the agency does not believe that fears about a possible lowering of drug quality are warranted. The agency intends to administer the policy with this concern in mind. Both of these issues are discussed in more detail in the section-by-section analysis.

3. Comments received from the pharmaceutical industry raised three kinds of objections. First, industry comments believed that the proposed regulations were deficient in not addressing several areas that the industry believes are important, such as granting sponsors a right to bring disputed matters to an outside advisory committee, providing an ombudsman to resolve minor procedural disputes, expanding communication between FDA and applicants, and codifying substantive provisions of the standards for safety and effectiveness.

Second, industry comments suggested that, although many of the proposed revisions represented movement in the right direction, FDA should make more dramatic changes in the drug approval process in order to achieve adequate regulatory reform. For example, some industry comments urged replacing both case report forms and detailed tabulations with briefer summaries, placing even greater reliance on foreign data and requiring many fewer supplements to approved applications.

Finally, while agreeing with the concept of strengthened postmarketing surveillance, industry comments generally stated that the specific reporting requirements proposed were excessive and did not provide a corresponding public health benefit. These comments stated that the reporting requirements should be better tailored to the relative importance of the adverse drug experiences involved.

In response to these comments, FDA has added to the final rule major sections on communication between FDA and applicants and on dispute resolution, including establishment of an ombudsman. The final rule also contains a detailed statement on the agency's use of advisory committees, although the agency has not provided, for the reasons stated in that discussion, applicants with rights to advisory committee reviews of issues. With respect to codifying substantive standards for safety and effectiveness, FDA believes that current statutory and regulatory provisions contain the necessary flexibility to administer these provisions to the wide variety of drugs subject to FDA's approval authority. The agency has, moreover, undertaken to provide further guidance with respect to the efficacy standard through the publication of guidelines for over 25 classes of drugs. Finally, in the IND Rewrite proposal, FDA stated its intent to make "end-of-Phase 2" meetings available for all IND's. These meetings provide a mechanism for agency reviewing officials and sponsors, with input from outside experts, to agree on an overall plan for Phase 3 investigations and the objectives and design of particular studies necessary to demonstrate the safety and effectiveness of the drug. (See 48 FR 26732.) FDA believes that this in-depth, case-by-case approach, will greatly facilitate the drug development process by providing sponsors with specific information about safety and effectiveness requirements in a timely manner.

Second, FDA generally disagrees with the industry comments that suggested that specific provisions in the proposal did not go far enough in providing regulatory relief. As described further below, FDA believes that case report forms and tabulations provide information, viewed as necessary, that may not be obtained through summaries alone; that further changes in the foreign data policy are not now appropriate; and that significant further changes in the area of supplements could possibly adversely affect the assurance of FDA regulation of marketed drugs.

Finally, FDA agrees that improvements in postmarketing surveillance should focus high priority reporting requirements on the more important adverse drug experiences. Accordingly, as described further below, the final rule provides for more stringent reporting requirements for adverse drug experiences that are both enexpected and serious, and less stringent requirements for the others.

4. Several comments urged FDA to adopt more specific and detailed regulations that give clear guidance to the regulated industry and to FDA personnel. According to these comments, these regulations should include detailed requirements for FDA actions, broad admonitions about normative conduct, requirements for agency documentation of decisions, and internal review mechanisms. Comments objected to FDA relying upon guidelines, internal manuals, memoranda, and other similar informal mechanisms to handle practices and procedures because they are too imprecise, subject to change, and of questionable authority. However, if FDA does decide to rely heavily on staff manual guides, one comment urged FDA to establish and codify a policy stating that such guides are binding upon the agency.

Many comments addressed further the issue of guidelines. Several comments argued that it was hard to discern the proposal's true impact without reviewing the guidelines FDA intends to use to implement the regulations and, accordingly, that FDA should reopen the administrative record once the guidelines are available. Moreover, these comments believe FDA should limit the use of guidelines to those situations where negotiation and alternative methods are clearly necessary or desirable, such as in clinical trials of different diseases. Several comments also asked FDA to provide notice and comment procedures on draft guidelines and staff and compliance manuals before final ones are prepared. Finally, some comments objected to FDA's reliance on guidelines because such documents often remain internal working documents and, according to these comments, are applied less consistently than the regulations. Finally, one comment urged that the final rule, or another proposal, should address procedural issues in the application review process, such as the designation of a primary review team early in the process, the need for meetings, concurrent review of an application by members of a review team, the finality of each part of the review once it is completed, and the importance of a tracking system to determine the history and current location and status of all submissions to FDA.

FDA believes its proposal provided adequate notice of the rights and responsibilities of both applicants and the agency in the drug approval process. FDA believes the more detailed regulations urged by these comments would add very little to the structure of the new drug approval process provided by FDA's combination of regulations, guidelines, and staff guides, while making the process more inflexible and difficult to change. The agency believes the proposal struck a proper balance between the need for regulatory requirements, the use of guidelines to help persons comply with those requirements, and the use of staff manuals to direct agency employees. FDA recognizes that the prompt issuance of clear guidelines will be most helpful to applicants and, thus, the agency is taking steps to expedite the development of guidelines and to clarify for its staff the role of guidelines in the regulatory process. Because FDA recognizes the significant contribution the industry, the medical community, and other members of the public can make to the development of scientifically sound guidelines, the agency routinely solicits comments on its guidelines either as draft or as final documents. With respect to the guidelines developed to implement this final rule, FDA intends to issue them as draft guidelines and to seek comments on them before they are made final. FDA believes it has provided adequate notice for this rulemaking proceedings and does not intend to reopen the administrative record on the regulations after the guidelines (or draft guidelines) are issued. Finally, FDA believes that administrative steps short of codification, such as staff manual guides, are appropriate for many management issues.

5. Several comments suggested that FDA implement many of its proposed procedural improvements in the new drug approval process immediately following the closing of the comment period (for example, changes in the content and format of an application, time frames for filing and reviewing an application and amendments, provisions on communications between the agency and applicants, and procedures for action letters).

Although FDA implemented several changes at the time it published the proposal (i.e., implementation of the informal appeals process; changes in the procedures for submitting samples; and the policy to notify applicants about deficiencies in chemistry, manufacturing, and controls information within 90 days of the beginning of the review of an application), the agency believes there is insufficient justification to implement other new requirements in advance of traditional effective date periods. FDA also notes that certain changes in the regulation (such as the procedures for action letters) simply codify current practice and so that immediate implementation of the final rule would not have had measurable impact.

6. One comment suggested that FDA impose user fees on industry for services FDA performs, particularly the costs of on-site inspections of domestic and foreign facilities. Another comment suggested that the agency incorporate into a final rule requirements for the evaluation of important new drugs in children before or at the time of approval of the application.

FDA believes these complex issues are sufficiently unrelated to the regulatory improvements in the new drug approval process that are implemented by the final rule that full consideration of them now would unnecessarily delay implementation of the rule. The agency is, however, exploring each of these issues separately and welcomes further discussion of them.

Effective Date

7. FDA received several comments recommending various effective dates for the final rule. Several comments suggested an effective date for the final rule of 180 days or 1 year, but also suggested that FDA accept applications up to the effective date in either the old, proposed, or new formats. A medical association suggested that FDA clarify how the regulations will apply to studies already in progress and to studies completed but not submitted before the effective date of the regulations. Finally, one comment urged that FDA not issue a final rule amending its new drug application regulations until after it has published and received comments on its proposal to revise the investigational new drug regulations.

FDA has concluded that these final regulations will become effective May 23, 1985, except § 314.80 Postmarketing reporting of adverse drug experiences will become effective August 22, 1985. FDA will, however, accept applications until February 24, 1986, that are in the format required under either the current regulations or this final rule. The separate effective date for the reporting of adverse drug experiences reflects the time FDA believes applicants may need to adapt to the new regulations. As noted above, with respect to application format, FDA has followed the suggestion to permit applications to be submitted in the format prescribed by either the current regulations or this final rule (but not the proposed rule). This 1-year period also covers the submission of case report forms and data tabulations. FDA believes this 1-year period of optional formatting will facilitate a smooth transition from the old to the new regulations. Within the parameters described above, the effective dates apply to studies in progress or not yet submitted to FDA.

Although FDA will accept for 1 year applications in the format required under the current regulations, the substantive requirements of the regulations will apply to pending and approved applications on and after May 23, 1985 under this final rule. For example, the requirements and procedures for amendments, communication between FDA and applicants, dispute resolution, withdrawal by the applicant, safety update reports, supplements, records and reports, time frames for FDA action, action letters, adequate and well-controlled studies, and withdrawal of approval will apply after 90 days to all applications regardless of the format in which they appear.

Finally, in the Federal Register of June 9, 1983 (48 FR 26720), FDA proposed to revise its regulation governing the investigational use of new drugs. The comment period on the proposal closed August 8, 1983, and the agency is reviewing those comments. FDA does not believe that the IND rulemaking proceeding should further delay these final regulations because the two sets of regulations address different stages of the new drug development and approval process, and can be implemented separately in a satisfactory manner.

8. FDA has added to the final rule a new section that states the agency's intention that the regulations be applied in a manner that facilitates the approval of safe and effective new drugs, ensures that drugs not shown to be safe and effective are not marketed, and provides for an effective system for FDA's surveillance of marketed drugs. Definitions (§ 314.3)

9. Several comments objected to the agency's proposed definition of the term "drug substance," claiming that the definition is overbroad and would wrongly subject the following to FDA regulation as new drugs: foods, vitamins, minerals, amino acids, other nutritional substances, and intermediates used in the synthesis of the drug substances.

FDA does not believe that the proposed definition of "drug substance" has the broad reach attributed to it by the comments. The proposed definition does not subject substances to FDA regulation as new drugs that do not fall within the definition of "new drug" in section 201(p) of the act (21 U.S.C. 321(p)). Moreover, the proposed definition is consistent with the definition of "drug" in section 201(g)(1) of the act and the agency's definition of "active ingredient" in § 210.3(b)(7) (21 CFR 210.3(b)(7)) of FDA's current good manufacturing practice regulations. FDA has, however, revised the definition in the final rule to make clear that it does not apply to intermediates used in the synthesis of the drug substance.

Application Form (§ 314.50(a))

10. One comment suggested that the proposed changes in the format for an application, under which a reviewer would receive only an overall summary and a technical section devoted to the reviewer's own discipline, would make it harder for a reviewer to consider relevant data that appear only in another reviewer's technical section. The new application format should not have the result suggested by this comment.

The application summary is intended to provide reviewers with adequate information about subjects outside their own review disciplines. Moreover, reviewers will also have access to other technical sections in the archival copy of the application, which will be maintained as a reference copy in the reviewing division's document room. Thus, reviewers will have access to whatever data they need for their reviews.

11. Several comments suggested that the regulations should make it clearer that the revised new drug and antibiotic application form is intended to serve essentially as a check list of basic information about the new drug and the application.

FDA agrees that the application form should serve only as a capsule listing of the contents of the application and the most basic information about the drug. This purpose will be self-evident from the revised form itself and, for that reason, no changes in this regard have been made in the regulations.

12. One comment objected to the requirement that the application form contain the established name, proprietary name, and code of the drug product. The reason for the objection was that some of the information may not yet exist when the application is filed. Two comments also sought clarification of the term "code" and asked whether it referred to the chemical name, shipping code, or marketing code.

The reason that names and codes used for the drug product must be submitted on the application form is to provide reviewers with easy identification of the product formulations to which the application refers. The term "code" would apply to any designation of a drug that would help identify it. To the extent one of the listed identifiers is not available, it would not need to be provided.

13. One comment suggested that the agency should establish procedures providing for the early submission and review of the chemistry, manufacturing, and controls section and/or the preclinical data section before submission of the clinical data and other sections. According to the comment, these early submissions would expedite ultimate approval by permitting early review and resolution of deficiencies in these technical areas.

FDA has revised the final rule (to be elaborated on by a staff manual guide) to provide for the early submission of chemistry, manufacturing, and controls information, at the option of the applicant. During the IND period, applicants will be permitted to submit information about fully developed chemistry, manufacturing, and controls procedures and specifications 90 to 120 days in advance of the submission of the main application. Chemistry, manufacturing, and controls submissions would not be accepted less than 90 days before the submission of the main application, as they would come too late to improve the speed of the review process significantly. Similarly, such submissions would not be accepted more than 120 days before submission of the main application because they would be premature and would likely not be sufficiently complete or final for review purposes. (Because review of preclinical data is not a common source of delay in the review process, the final rule does not provide for their early submission.)

The final rule expands upon past practice which had been to limit such early submissions only to drugs offering therapeutic advances. The agency notes, however, that in expanding the permissibility of such early submissions to other drugs, FDA's ability to review them early will depend upon available resources. Full applications are viewed as having higher priority, as are early submissions of chemistry, manufacturing, and controls information for drugs offering therapeutic advances. Nevertheless, this change in the final rule provides a mechanism for speeding the review of at least some applications for which a mechanism does not presently exist.

14. One comment suggested that FDA clarify the status of its paper NDA policy in the final rule.

FDA has revised the final rule to include a description of the "paper NDA." This is an application for a duplicate of a marketed drug product which relies primarily on published literature to provide substantial evidence of effectiveness and adequate scientific evidence of safety for the claimed indications. A complete description of FDA's paper NDA policy appears in the Federal Register of May 19, 1981 (46 FR 27396).

Summary (§ 314.50(c))

15. Several comments endorsed the requirement for an overall summary, but urged that it should resemble more a brief summary than a lengthy treatise.

FDA agrees in part. As stated in the proposal, the summary is intended to facilitate review of the application. If a more complete summary of any specific section of the application is needed to provide the necessary information for review purposes, it should appear in the appropriate technical section. FDA also will not refuse to file an application or delay its approval if the summary is inadequate, provided the data contained in the technical sections of the application show that the drug is safe and effective. Applicants should recognize, however, that a superficial, poorly written, or incomplete summary will not serve its intended function of facilitating review and could even prolong the review process if it is confusing. The summary, therefore, should include critical details of study design, sufficient numerical data (tabular or graphic) to provide a quantitative understanding of the data, and a forthright discussion of any problem areas. Althought the preamble to the proposal suggested that a typical summary should be 50 to 200 pages long, length will likely vary according to the nature of the drug and the quantity and type of information available. Fifty pages should not be viewed as a minimum requirement, nor 200 pages a maximum; applicants should instead be guided by the circumstances surrounding the particular application at hand.

16. FDA received several comments concerning the proposed requirement that the overall summary contain a fully annotated copy of the draft labeling. One comment asked that FDA require annotations to drug labeling only for claims about safety and effectiveness. Another comment asked for clarification about how omissions from labeling should be annotated. The comment also objected to the requirement that the labeling bear annotations to the information in both the summary and the technical sections of the application, suggesting that such a requirement is redundant. A third comment suggested that the summary should contain only a brief summary of the labeling information about the drug, and that copies of the labeling itself (including labels, packages, and package inserts) should not be required. Finally, one comment found the proposal unclear about whether labeling should be included in the clinical or chemistry sections of the application, and whether reviewers would receive copies of labeling.

Assessment of the adequacy of labeling is a critical part of FDA's review of a new drug application. In determining whether the data and information in an application support the claims made in the product's labeling, it is helpful to know the precise information that the sponsor considers supportive. By providing reviewers with an annotated copy of the proposed labeling for the drug, and by directing the reviewer to both the summarized and detailed data supporting the labeling, the sponsor can assure that critical supporting data are not ignored and that confusion (with its inevitable delay) about the basis for labeling does not arise.

As indicated, FDA believes that annotations referring to both the technical sections and the overall summary will best facilitate review. The inclusion of annotations to the summary will be particularly important to the reviewers who do not receive the technical sections, and to others, such as FDA's managers and advisory committee members, who will not review all of the technical data. These reviewers also may wish to consider certain matters in detail, however, and the references to technical sections will facilitate this. By law, "specimens" of the labeling are required to be submitted, and brief summaries, as suggested by one comment, are not viewed as adequate. The agency's guideline on preparing a summary will clarify more fully the kinds of information that should appear in annotated labeling, and how omissions from the labeling should be annotated.

Finally, an annotated copy of the labeling will appear in the summary, which will be provided to each reviewer. In addition, copies of labels and other labeling pieces will be contained in the archival copy of the application where they will be available to all reviewers, as necessary.

17. One comment supported FDA's proposal to use the application summary to prepare the summary basis of approval (SBA) document that is made publicly available following approval of the application. Another comment suggested that FDA work with the applicant during the preparation of the SBA and allow the applicant to review the SBA before it is released to ensure the protection of proprietary information.

Although FDA believes applicants can play a large role in the development of the SBA through the preparation of the summary, the SBA necessarily reflects FDA's judgment, and not the applicant's, of what data and information in the application support approval of the drug product. FDA believes that an applicant's review of the SBA to identify proprietary information is unnecessary because FDA has traditionally not included such information in the SBA.

18. One comment suggested that applicants should not ordinarily be required to submit a completely revised summary with a resubmitted application, and should be permitted, to the extent possible, to submit only an addendum to the original summary. FDA agrees that an addendum to a summary is appropriate if minor changes are made to an application. Significant submissions, however, such as providing additional data in response to a "not approvable" letter, would necessitate a revised summary that again reflects a clear and concise description of the information in the application.

19. One comment asked FDA to clarify its requirement for the "marketing history" of a drug by other persons.

This requirement is limited to the marketing of the drug outside of the United States, and it is intended that it will be met with brief information concerning where and when the drug has been marketed, for what indications, and any significant safety or effectiveness problems that developed during such foreign marketing. The agency has revised this provision to require also a list of countries in which applications for marketing are pending. This information will facilitate FDA contacts with foreign drug regulatory officials about the drug.

Chemistry, Manufacturing, and Controls Section (§ 314.50(d)(1))

20. FDA received several favorable comments concerning proposed changes in the chemistry section of the application. For example, one comment was pleased that the proposal generally reflected the format and level of detail of manufacturing and controls data required by the European Economic Community to market a drug product. Another comment agreed with FDA's proposal to eliminate requirements for information available to the agency under its current good manufacturing practice (CGMP) regulations, stating that this change will substantially lessen the burden of preparing an application without compromising safety or effectiveness.

21. FDA received several comments regarding the agency's proposal to permit references in the chemistry technical section to compendial monographs. One comment urged FDA to go even further and not require detailed descriptions of drug substances subject to compendial monographs if the source of the substance is identified and CGMP's are followed in manufacturing it. A comment supported the proposal, believing that it reflects FDA's willingness to rely upon the compendia as authoritative sources of pharmaceutical quality standards. Two other comments suggested that the agency should also permit references to the Food Chemicals Codex, the British Pharmacopeia, and other compendia.

The agency is issuing this provision essentially as proposed, with one clarification. Although FDA believes that references to the official compendia may be relied upon under proper circumstances to provide required information, new developments in drug synthesis and advances in analytical technology may introduce new concerns about the chemistry of drug substances that are not adequately addressed by current compendial monographs. In those cases, FDA may need additional information about a drug substance to ensure that additives or byproducts of the synthetic process are properly controlled. Although a reference to official compendia will often satisfy the requirements, FDA has revised the final rule to state that FDA may require that additional information be submitted to permit the proper review of the application. This is particularily the case for tests for impurities and adulterants that might be present depending upon the source of material and the manner of processing the applicant employs. While compendial monographs are intended to assure the identity, strength, quality, and purity of the drug, they are not intended to include in each monograph a test for every impurity or adulterant. Thus, FDA concludes that additional information about drug substances subject to compendial monographs will sometimes be required.

The regulation limits the compendial sources that may be referenced to "official compendia" because a special relationship exists between FDA and the official compendia (United States Pharmacopeia/National Formulary) under the act, where FDA is authorized to enforce compendial standards (see section 502(g) of the act (21 U.S.C. 352(g)).

22. Several comments addressed the proposed requirements for documentation of raw materials and reagents used in the manufacture of the drug substance. One comment thought the requirements were ambiguous. A second comment criticized the proposal as continuing to require too much information about the method of synthesis, isolation, and purification of a drug substance. This comment suggested that either the regulations or a guideline should make it clear that an applicant need only submit such information that applies after a pivotal intermediate used to produce the drug substance is identified. Another comment asked for clarification of the requirement for the submission of specifications and analytical methods for components of a drug product (regardless of whether they appear in the finished product) and whether it includes raw materials used in the drug substance.

FDA believes that complete information about raw materials, reagents, in-process controls, and methods used in the manufacture of a drug substance are needed (particularly for a new chemical entity) to characterize fully the drug substance. The level of detail required, however, will vary according to the nature of the drug and FDA's familiarity with it. To provide flexibility, the regulation itself is general in nature, and FDA will prepare a guideline on the chemistry technical section to aid applicants in determining the appropriate level of data and information on a drug substance needed in a particular case.

23. One comment suggested that the agency should only require information about components of a drug substance that remain, in some measure, in the drug product or which could have an adverse effect on safety or effectiveness.

FDA disagrees with this comment. Information about components that do not appear in the finished drug substance or drug product is important in determining whether the specifications and analytical methods are appropriate to assure the identity, strength, quality, and purity of the drug substance and the bioavailability of drug products made for it. This information is also important to assure batch-to-batch reproducibility of the drug substance. Although these components do not appear in the finished drug substance or drug product, they may, or changes in them may, significant affect the finished drug product.

24. Several comments suggested that the final rule should explicitly recognize current practice, under which applications may provide for alternative sources of inactive ingredients and alternative manufacturing procedures, including the following: (1) Reasonable alternatives for any material used in the synthesis of the new drug substance, (2) alternative methods or variations of methods of synthesis within reasonable limits which do not affect the characteristics of the substance, and (3) reasonable quantitative variations in the ingredients in the product.

FDA agrees with these comments, and has revised the final rule to provide for identifying such alternatives. Generally, an alternative method or variation should include a description of the circumstances under which the alternative or variation will be used. Comparable specifications and analytical data for the material produced by the alternative methods or variations must also be submitted.

25. Several comments addressed the inclusion of bioavailability-related information in the chemistry section. One comment objected to the addition of bioavailability to the statutory standards of identity, strength, quality, and purity -- standards that, according to the comment, adequately cover the physical and chemical parameters affecting bioavailability. The comment also pointed out tht bioavailability is covered under its own technical section. Another comment objected to the requirement to provide specifications and analytical methods to ensure bioavailability because the methodology may not exist. A third comment suggested that references to the bioavailability of drug products made from a drug substance be deleted from the paragraph on the drug substance because it appears in the paragraph on the drug product.

FDA believes that these comments misunderstood the proposed requirements. The final rule, like the proposal, does not require the chemistry section of an application to contain information about the bioavailability of the drug product. That information is contained in the human pharmacokinetics and bioavailability section. What is required in the chemistry section is that an applicant provide specifications and analytical methods for the drug substance and the drug product that will assure the ultimate bioavailability characteristics of the drug product. For example, if the bioavailability of the drug product depends on the crystalline form of the drug substance used in the drug product, the chemistry technical section must contain the necessary specifications and analytical methods to ensure that the substance has the necessary crystalline form. This requirement for specifications and analytical methods pertains to both the drug substance and drug product, because specifications at either or both stages could be pertinent to bioavailability, but it does not apply to intermediates and raw materials used in the manufacturing of the drug substance. If specifications and methods are unnecessary for assuring bioavailability, they need not be supplied. Although it might be argued that the standard of "quality" adequately covers the physical and chemical parameters affecting bioavailability, there is no good reason not to be explicit about the requirements for information about drug chemistry that, although they pertain to bioavailability, must be evaluated by FDA's chemistry reviewers.

26. One comment suggested that the phrase "specifications related to stability" should be deleted from the requirements for the drug substance because expiration dates on drug substances are not required.

Like the previous comments on specifications relating to bioavailability, FDA believes this comment misunderstood the proposal. Although expiration dates for drug substances are not required, establishment of a specification for stability of the drug substance may in some cases be needed to assure the quality of the drug product. If there is no such specification, it need not be supplied.

27. One comment suggested that references to process controls should not be required because they are adequately regulated under the CGMP regulations. According to this comment, requiring this information in an application and requiring agency approval before changes can be made takes away manufacturers' flexibility for establishing procedures for in-process tests and for determining the significance of testing results.

The agency disagrees with this comment. FDA believes that a review prior to marketing of in-process controls is needed to determine whether appropriate tests and limits are established (for example, for solvents and particle size) which may affect physiological or pharmacological activity.

28. One comment urged that the agency codify its current policy that methods validations will not delay approval of an application.

FDA views itself as bound by its current policy, unless changed, regardless of whether it is included in the regulations. Moreover, the policy is of a type that the agency would more likely cast as a guideline, given its length and complexity, than as a regulation. In addition, the agency memoranda on this subject, which have been made public, adequately describe the policy and, thus, FDA does not believe that codifying the policy is necessary.

Nonclinical Pharmacology and Toxicology Section (§ 314.50(d)(2))

29. Several comments objected to FDA's proposal to require a description of studies of nonclinical pharmacological actions of the drug for possible therapeutic indications for which the applicant is not seeking approval. These objections are premised on the belief that the information would be irrelevant to the drug's proposed indications, that the requirement would delay submission of an application while the applicant gathered the information, and that time and effort of reviewers would be wasted, particularly if the information were to lead them to speculate about other potential, new indications.

FDA agrees in part with these comments, but believes the purpose of this section was not well described in the proposal. Information about pharmacological effects other than the primary effect related to the proposed use is not usually critical to evaluating the effectiveness of the drug, but these pharmacologic properties are pertinent to a full understanding of the drug's effects, e.g., they may help explain side effects and drug interactions. Such information also is pertinent to investigational use of the drug, so it should be unnecessary for an applicant to perform new analyses to meet the requirement. The agency has revised the final rule to make this requirement clearer.

30. Several comments addressed the form of submission of data from animal studies. One comment requested clarification as to whether the revised regulations are intended to continue the current practice under which individual animal data are only reported in tabulations, and the "raw data" (laboratory notebook, worksheets, and other documentation relating to individual animals) are not submitted unless FDA has reason to request them in a particular case. Another comment suggested that FDA require summaries instead of tabulated individual data from long-term toxicity and carcinogenicity studies in order to reduce the size of the application.

The nonclinical pharmacology and toxicity section of the application is intended to continue current practices with respect to the submission of individual animal data. Thus, applicants are not required to submit laboratory notebooks, worksheets, and other documentation relating to individual animals (although those materials are subject to record retention requirements under the good laboratory practice (GLP) regulations (21 CFR Part 58)). Although summaries that contain tabulations and graphs are helpful for describing long-term toxicity and carcinogenicity studies, FDA believes that full tabulations of individual animal data are necessary to conduct a proper review of these important safety-oriented studies.

31. Several comments questioned the implication in the proposal that all pharmacological studies are subject to the agency's GLP regulations. These comments noted that those regulations apply only to nonclinical safety studies and not to other animal studies, such as nonclinical pharmacology studies. Other comments suggested that the regulation should require only a description of "significant" deviations from the GLP regulations, or a "statement of differences" for studies that were not in "substantial" compliance with them.

FDA agrees that the proposal might be read to imply that all pharmacological studies are subject to FDA's GLP regulations. The agency has revised the final rule to clarify that an application is only required to contain a statement regarding compliance with GLP's for a "nonclinical laboratory study" as defined in 21 CFR 58.3(d). FDA, however, has not made the other suggested change. Because the GLP regulations describe minimum standards for nonclinical laboratory studies, FDA believes that it is appropriate that the application contains a description of deviations from those requirements. The agency advises that such studies may still be relied upon, depending on the nature of the deviations.

Human Pharmacokinetics and Bioavailability Section (§ 314.50(d)(3))

32. One comment urged that this section contain a comparison analysis of human and animal pharmacokinetic data and the rationale for setting the specifications for the drug substance and drug product based upon the results of bioavailability studies.

FDA does not agree that the final rule should require a comparison of human and animal pharmacokinetic data. Animal pharmacokinetic data are generally most relevant during the investigational phases of drug development, where they permit the establishment of parameters for the safe use of the drug in human subjects. After human pharmacokinetic data are collected, however, they alone are usually adequate for review of an application. An applicant is free, however, to provide a comparison analysis of the animal and human data if the applicant believes it results in a clearer presentation. At the same time, the agency agrees with the suggestion for inclusion of the rationale for specifications and analytical methods for the drug substance and drug product needed to assure the bioavailability, and FDA has revised the final rule to add that requirement. The rationale for establishing specifications and analytical methods, with the data and information supporting the rationale, is needed to determine whether the proposed specifications or methods will assure the bioavailability of the drug substance or drug product.

33. One comment objected to the statement in the preamble that bioavailability data are needed to assure batch-to-batch consistency and to reevaluate product reformulations or changes in manufacturing processes. The comment argued instead that simpler methods, such as in vitro dissolution, are adequate.

The ability of in vitro dissolution data to determine the bioavailability of a batch of a drug product depends, in FDA's view, on whether the data can be correlated with in vivo data. Generally in vivo bioavailability data and in vitro dissolution data are examined and, if possible, in vitro dissolution methods and specifications are set for the product. Subsequent batch-to-batch consistency is assured by testing each batch by the in vitro method and evaluating the results against the in vitro specifications. Thus, bioavailability data are often needed to establish the simpler in vitro tests.

34. One comment urged that the summarizing discussion and analysis be clearly required at the beginning of the pharmacokinetics and bioavailability section because it brings together information not necessarily present in each of the bioavailability and bioequivalence studies. This comment also suggested that this section should require that the analytical and statistical methods used in each study be described in the report of the study, and not grouped together in a separate section as the proposal suggests. Moreover, the comment believed that each study should be evaluated as an entity because that is the way reports of studies are prepared. The comment asserted that breaking reports in this section apart is likely to lead to errors.

FDA believes this comment misunderstood the proposal. The regulation is intended to describe in general terms the kinds of data and information that are required to appear in this section and the applicant is free to present it in the format that provides the clearest presentation, which may include either an opening or closing summary. Because FDA agrees that, in most instances, the analytical and statistical methods used in each study should be described in the study report, the agency has revised the regulation to suggest that use of that format is usually preferable. Again, however, FDA believes the applicant should use a format that provides the clearest presentation and permits the most efficient review.

Clinical Data Section -- General (§ 314.50(d)(5))

35. One comment objected to the requirement that the results of each human clinical pharmacology study be compared with the animal pharmacology and toxicology data. The comment explained that most toxicology studies use doses higher than those used in human studies and often for longer periods of time, and that animal pharmacology studies may include disease states in animals not present in clinical studies. Thus, according to this comment, applicants should only be required to compare the results of clinical pharmacology studies with the "major findings" of animal pharmacology and toxicology studies. Another comment urged that this requirement be limited to information related to the intended use of the drug under its proposed labeling and to possible side effects to ensure that the applicant and the agency do not become sidetracked on issues related to potential new indications for the drug.

The agency does not agree that it is necessary to limit the comparison between clinical pharmacology data and animal data, as suggested by the comment. The proposal's call for "a brief comparison of the results of human [pharmacology] studies with the animal pharmacology and toxicology data" is intended to require an examination of the clues to potential usefulness or toxicology in humans provided by animal data. With respect to the second comment, virtually all of the pharmacologic properties of a drug are pertinent to the intended use of the drug, even those properties that are not the ones leading to the drug's intended use. The human results should thus be compared to all pertinent animal observations. If no human observations concerning a particular property exist, of course, no comparison can be made.

36. Noting that a controlled clinical study on a drug may not be relevant to the indications proposed in the application, one comment suggested that the final rule should only require a description and analysis of each controlled clinical study pertinent to the proposed indications for the drug and that other controlled studies should be included in the general description of other data or information relevant to an evaluation of the safety and effectiveness of the drug. This comment also suggested that the regulations require only that the applicant describe, and not analyze, data from studies that are not controlled.

FDA has revised the final rule to require description and analyses of controlled clinical studies pertinent to a proposed use of the drug. The agency notes, however, that § 314.50(d)(5)(iv) still calls for "a description and analysis of any other data or information relevant to an evaluation of the safety * * * of the drug product" not a "general description" as implied by the comment, and does require some analysis of controlled studies not pertinent to the proposed uses of the drug. FDA continues to believe that the usefulness of sources of data, such as clinical trials of drug uses other than those proposed, depends on a reasonably detailed description and analysis of the safety of those trials. The agency notes, however, that the proposal did not require analyses of uncontrolled studies, but only a description of them, which accords with the comment's suggestion. Finally, FDA has revised the final rule to include a requirement for a brief description of pertinent studies that have been discontinued or are ongoing.

37. One comment objected to a requirement for safety data from epidemiological studies of related drugs, believing that the requirement is vague and potentially subject to an overbroad application.

The agency does not believe that information about related drugs, such as epidemiologic data, can be ignored in evaluating a new drug. An applicant developing a new member of an already established drug class usually is, and should be, conscious of the experience with other members of the class. Such information may be relevant to labeling and may help focus the evaluation of the data submitted. FDA does not believe that the requirement will be applied unreasonably.

38. On its own initiative, the agency has made two additional changes in the final rule. First, FDA has added an explicit requirement for the applicant to synthesize, in an integrated summary, the data which it believes provide substantial evidence of effectiveness of the drug for its proposed uses (§ 314.50(d)(5)(v)). FDA believes that this requirement was implicit in the proposed requirements for an overall summary to help the agency prepare the SBA document, but has determined that a specifically focused discussion in the clinical section will significantly facilitate review. Second, the final rule also requires an applicant to explain briefly why a study is not considered adequate and well-controlled. This will enable the agency reviewers to determine what conclusions can be validly drawn from those studies.

Safety Update Reports (§ 314.50(d)(5)(vi)(b))

39. FDA received several comments on the proposed "safety update reports," which are designed to advise FDA of new safety information that becomes available while the application is being reviewed by the agency. The proposal would have required such reports at 4-month intervals and upon receipt of an approvable letter. Although most of the comments addressing this issue favored the concept of safety update reports, concerns were raised that the reporting intervals were too frequent and that the data being requested were more than were necessary. Concerns were also raised that, if not properly limited, the requirement for safety update reports could delay the approval process by creating an ongoing need to review more data.

FDA believes that the basis for the proposed safety update reports, which is to ensure that drug approvals are based on the most up-to-date safety information available, is sound. FDA has, however, revised the final rule to ensure that reporting obligations are no greater than are needed, so that the requirement does not unduly delay approvals.

First, FDA has defined more precisely the type of information that needs to be reported. Whereas the proposal simply said "new safety information," the final rule specifies "new safety information * * * that may reasonably be expected to affect the statement of contraindications, warnings, precautions, and adverse reactions contained in the draft labeling." Thus, under the final rule, the only information that must be submitted in a safety update report is safety information that is different from that previously submitted and that may warrant revision in the draft labeling. It should be emphasized that (1) "new" information includes both adverse effects that were never seen before and a material change in the frequency or severity of effects that were recognized previously; and (2) case report forms for patients who die or who leave a study prematurely because of an adverse event are always required (unless the requirement is waived). Thus, for example, new safety information that suggests that an adverse effect occurs at a higher rate than previously thought would be required because it might change a precaution to a warning in the labeling.

Second, FDA has revised the reporting intervals so that safety update reports will be required (1) 4 months after the initial submission; (2) following receipt of an approval letter: and (3) at other times as requested by FDA. The first safety update report is important because it is designed to let reviewers know if any major new data are available that could affect their recommendations regarding approval of the drug. This first report covers a much longer period than 4 months because it also covers the time period between the "data lock point" and submission of the application, during which time the applicant is preparing the application for submission to the agency. The report following an approvable letter is intended to provide the agency with the most current information available immediately before approval. Moreover, it parallels the normal submission of final printed labeling so that FDA reviewers can be assured that the labeling is up-to-date. In addition, FDA may request safety update reports at other times, such as before an advisory committee meeting or before an approval letter where an unusual amount of time may have passed since issuance of the approvable letter. This may also include the situation where the agency intends to issue an approval (instead of an approvable) letter based on draft labeling, and a special request for a final safety update report will prevent undue delay. Thus, by replacing the "every 4 months" requirement with discretionary requests by the agency, the regulations allow applicants to submit interim reports only when the agency believes they are necessary for review and approval of the application.

FDA does not believe this policy will delay the approval process. As noted above, the reports themselves are tied to information pertinent to labeling, and will be in a familiar format, permitting prompt review. Moreover, FDA expects that major changes in safety information will not be common. If an applicant, however, does obtain new safety information that is so significant that it could affect the overall risk/benefit determination of the drug for one or more indications, a further extension of the review process will inevitably be necessary. The guideline on the clinical section of the application will describe the format of both original safety reports and updates.

Samples and Labeling (§ 314.50(e))

40. Several comments suggested that requiring four samples is excessive and that FDA should request only the actual amount needed.

FDA's experience is that four samples are needed to perform necessary testing. One sample is tested by each of two FDA laboratories, for purposes of replication, and the two remaining samples are held as reserve samples for each of those laboratories in the event that additional testing is necessary. In addition, the final rule represents a significant reduction from past practice in the amount of samples applicants must submit to support approval of an application. Samples are no longer required, for example, of the finished dosage forms used in the clinical investigations, nor of the new drug substance used in manufacturing those dosage forms. FDA has revised the final rule to increase from two to three copies of the analytical methods and related descriptive information FDA needs to test the samples. One copy is needed for each of the FDA laboratories assigned to test the samples and a third copy is needed for the agency's headquarters files.

41. One comment urged that samples be required earlier in the review process, specifically either at the time the application is submitted or when the application is filed. This suggestion was aimed at ensuring that necessary testing is completed on time and does not delay approval of the application.

FDA disagrees with this comment. Under the final rule, the FDA reviewer will contact the applicant to request samples and provide laboratory assignments after a preliminary review of the analytical procedures indicates that the procedures are satisfactory. The date of filing is not appropriate because the review necessary to determine whether an application is complete and can be filed is not as detailed as the review needed to determine whether analytical procedures are satisfactory. The procedure in the final rule will prevent the premature submission of samples and will ensure that methods validation testing is not conducted on outdated samples. The procedure should not, however, delay the review process so long as applicants make every effort to provide the samples when requested. Moreover, as noted above, it is FDA's policy not to delay approval of a drug solely because methods validation has not been completed.

42. Several comments questioned whether, by combining requirements for samples and labeling, the proposal implied that labeling should be submitted only upon request. Another comment asked FDA to clarify what it means by "related descriptive information" and noted that the proposal would not have required submission of results of the applicant's tests on samples.

FDA has revised the final rule to state that copies of the product's label and labeling should be submitted with the application, and not only upon request. The final rule also states that "related descriptive information" includes a list describing each submitted sample; a list of proposed regulatory specifications; a detailed description of the methods of analysis; supporting data for accuracy, specificity, precision, and ruggedness; and complete results of the applicant's tests on each sample.

43. One comment urged that the current exclusion for sterility and pyrogen testing samples, which was not contained in the proposal, be retained. Although FDA agrees that sterility and pyrogen testing samples are often unnecessary, particularly if the testing procedures are ones generally recognized as valid (for example, procedures established in the official compendia), new testing procedures may be developed (for example, the limulus amebocyte lysate test for pyrogens) that warrant FDA review. Accordingly, the final rule requires their submission, but FDA will consider waiver requests on a case-by-case basis.

44. One comment suggested that the final rule should follow the current practice and require the submission of only one finished market package.

FDA has revised the final rule to eliminate the suggestion that four samples of the finished market package are required. Samples of the finished market package are required to be submitted only if FDA requests them and, although the agency generally requests only one sample, two are sometimes needed. The final rule provides this flexibility.

Case Report Forms and Tabulations (§ 314.50(f))

45. FDA received many comments on the proposed submission of individual clinical data using a combination of case report forms and tabulations. A number of the comments misunderstood the meaning of the terms used and their interrelationship. For example, some comments erroneously equated "case report forms" with "raw data," while other comments mistakenly understood "tabulations" to be the same as "summaries." Before addressing the specific comments, therefore, these terms need to be clarified in the context of the current regulations and the NDA Rewrite proposal.

a. Raw data. The "raw data" from a clinical study are the clinical investigator's own records of the individual patients. These records include the patient charts, hospital records, x-rays or other laboratory test results, and notes of the attending physician. These raw data, even under current regulations, are not routinely submitted to FDA as part of a new drug application, but instead remain in the files of the clinical investigator or hospital for FDA audit, if necessary.

b. Case report forms. These are the documents that the clinical investigator sends to the drug sponsor that list all the data collected on each individual patient. There is 1 case report for every patient in each study, and case reports typically vary from 5 to 50 pages in length. Under current regulations, all case reports must be submitted to FDA as part of a marketing application. Because such applications frequently contain data on from 1,000 to 3,000 patients, case reports consume a great many volumes in a typical application.

c. Tabulations. These are tabular listings of the individual patient data, as taken from the case report forms. The tabulations are prepared by the drug sponsor, usually using an automated data processing system. By using tabulations, the results from a study of a given medical parameter (e.g., blood pressures for an anti-hypertensive drug) can be presented on one or two pages. These tabulations contain the very same numbers as the case report forms on which they are based, and the data are clearly identified by individual patient. Thus, tabulations are ordinarily a more concise and efficient representation of the data contained on the case report forms.

d. Summaries. These are usually narrative documents, often interwoven with summary tables and graphic presentations of data, that present the results of a study, using the analyses deemed appropriate. Summaries are the most common means of communication in science, and most scientific journal articles are summaries in this sense, as are the descriptions and analysis called for in the clinical section of the application. Summaries, however, are by their nature interpretive documents that select certain data as being important. Thus, summaries reflect a point of view about what the data mean, and the point of view and data selections are always shaped by the judgment of the writer.

e. Current requirements. Current regulations require the routine submission of all case report forms. Use of tabulations is voluntary with the applicant. Recognizing the inherent difficulty of relying on the case report forms themselves to find individual data elements, it is extremely common for applicants to submit tabulations voluntarily in some form to make the review of the data more efficient. Applicants use such tabulations in their own analyses, subjecting them to a variety of statistical procedures to develop analyses and summary tables presented for each study report.

f. The proposal. Based on the agency's positive experience with tabulations, FDA proposed to substitute tabulations for case report forms as the primary focus of the data review. Under the proposal, some case report forms would still be required routinely (i.e., for patients who died during or who dropped out of a clinical study due to an adverse event) because these cases are the ones most likely to reveal significant safety problems and demand individual case-by-case review. Also under the proposal, FDA would have access to additional case reports whenever a legitimate need existed. Thus, the intent of the proposal was to focus the agency's review on a more concise and efficient mode of data presentation, while still providing the agency with complete individual patient data. The proposal also contained a requirement for summaries, but only to complement and integrate the individual patient data contained in the case reports and tabulations.

46. FDA received a considerable number of comments on this provision, concerning primarily the concept of how data should be submitted (i.e., summaries versus tabulations versus case report forms). Comments on both these subjects covered a wide spectrum. Several comments argued that all case report forms should be routinely required, on the ground that FDA needed this "raw data" to conduct a full scientific review. In contrast, other comments suggested that even the review of tabulations would be more time consuming than necessary, and that FDA should instead rely on summaries alone.

FDA believes that the proposal to require data submission through a combination of summaries, tabulations, and case report forms allows a scientific review that is both thorough and efficient. FDA believes that, for many purposes, tabulations can provide adequate information for review because these tabulations will be required to contain the same individual patient data listed on the case report forms. As described above, even case report forms are not actually "raw data" (but instead constitute individual patient data as transposed by the clinical investigator from the doctor's charts), so concerns raised about the agency no longer requiring "raw data" are misplaced.

FDA also disagrees with the suggestion that it rely on summaries alone, without a routine submission of individual patient data (either as case report forms or tabulations). As noted above, summaries are, by their very nature, interpretive documents. Although summaries are extremely useful in reviewing applications, FDA believes they need to be complemented by the underlying data (either in tabulations or case report forms) for the agency to be able to conduct a thoroughly independent and objective review.

In response to these comments, however, FDA has reevaluated the proper mix of tabulations and case report forms that should be required. Although FDA believes that tabulations will be extremely useful in promoting a more efficient review process, the agency also recognizes that there are some inherent limitations on the use of tabulations and that, in certain instances, direct reference to case reports will be necessary. Theses may include, for example, instances where important narrative or other information on the case report form is not amenable to tabular presentation, or where case reports are desired to spot check the accuracy of the tabulations.

Accordingly, in order for the agency to conduct a scientific review that is both thorough and timely, a complete set of case report forms will ordinarily be needed for the most critical studies. In order to choose these appropriately, and at a time when they can be provided without causing delay, FDA reviewers will designate, approximately 30 days after receipt of an application, the critical studies for which case reports will be requested. These studies will ordinarily also be the ones utilized by the Division of Scientific Investigations in conducting its on-site data audits, and that division will make use of the same case reports, whenever possible, in order to eliminate the need for duplicate submissions.

FDA believes this policy is consistent with its overall goal of improving the efficiency of the drug review process. By relying more heavily on summaries and tabulations, FDA's initial review will be focused onto a more concise form of data presentation. This initial review, however, may trigger the need to review certain patient histories in more detail, especially those from the most critical studies, and case reports provide the basis for that more detailed review. Requests for full case reports from certain critical studies does not necessarily imply the need for a case-by-case review of every patient; instead, such requests are intended to ensure that FDA reviewers can make reference to, when needed, case report forms for those patients requiring further review. By making such requests approximately 30 days into the review process, delay is unlikely to occur.

Even with this modification, FDA estimates that there will be an average reduction of about 75 percent in the number of case reports that are routinely requested, when compared to the current requirement of full submission. As reviewers become more comfortable with tabulations, and applicants become more skillful in making them usable, it is possible that requests for case reports will decrease. The regulation itself is general in nature so as to accommodate both the present expectation and any future changes.

47. Several comments that opposed the substitution of tabulations for most case report forms were concerned that this change could enhance the possibility that FDA would receive inaccurate data.

FDA does not believe that this change will decrease the accuracy of the data received or undermine the agency's ability to assure data accuracy. First, FDA's Division of Scientific Investigations routinely conducts a data audit on two or more critical studies in each marketing application. Such data audits compare the data on case report forms to the raw data retained by the clinical investigators. The policy of conducting these audits will continue. In addition, as noted above, medical reviewers may need to spot check the accuracy of tabulations for the most critical studies by comparing them to the data in the case report forms, and FDA can request the submission of case reports for that purpose.

48. FDA received a number of comments on the proposed standard that additional case reports could be obtained whenever a "legitimate need" existed to conduct an adequate review of the application. Comments generally believed that this provision was vague. Many interpreted it as an attempt to discourage requests for additional case report forms. Several comments, on the other hand, were concerned that the provision would lead to excessive requests and urged that the final rule contain explicit criteria for justifying request, and that requests should be made in writing with a supporting rationale.

FDA had modified this provision in the final rule to reflect the agency's central concern -- namely, to permit the agency access to case report forms when it believes that they are needed to conduct a proper review of the application. The agency did not intend the phrase "legitimate need" to imply a barrier, and the final rule has been modified to contain more neutral language. FDA recognizes the concern expressed by several comments that some reviewers may be prone to request more case reports than the applicant believes are necessary. Although there will inveitably be differences among reviewers, FDA believes that assuring the reasonableness of requests for case report forms is the responsibility of FDA management. To strike what FDA believes is the appropriate balance between these competing interests, the final rule provides that all requests for additional case reports (other than those required to be routinely submitted) must be approved by the director of the division responsible for reviewing the application. Any applicant that feels it is being asked for an excessive number of case reports may raise the matter directly with the releveant division director or with the ombudsman.

FDA notes that the need for additional case reports will likely vary according to the type of drug under review. For example, case reports appear to contribute significantly less to the efficacy review of an anti-hypertensive drug because blood pressures can quite adequately be complied in a tabulation, patient dropouts are usually few, and most patients entered into a trial are analyzed. Conversely, FDA believes that case reports may be critical to the review of controlled studies for an antibiotic drug. This is because the efficacy determination for an antibiotic turns largely on which patients were included and which were excluded from the study analysis, and the reasons for inclusion or exclusion often involve close judgments that cannot readily be shown in a tabulation. FDA will advise applicants, either in guidelines or in "pre-NDA" conferences, of particular case report needs for particular drug classes.

49. Several comments addressed the time aspect involved in FDA requesting additional case report forms or tabulations. One comment was concerned that the proposal might actually delay the review process, because reviewers would have to wait for the submission of additional case report forms. Another comment suggested that the 30 days for the submission of case report forms, as provided in the proposal, may not be adequate. A third comment suggested that, if additional case reports or tabulations are submitted more than 30 days following an FDA request, any extension to the review period should be limited to the number of days the submission was late.

FDA does not believe that this requirement will cause delay in the review process. Case report forms are still required to be maintained by drug sponsors, and the time needed to respond to requests should be relatively short. Moreover, applicants, who themselves seek an expeditious review, have an incentive to respond to such requests quickly. Finally, as noted above, the agency's policy of identifying needed case report forms early in the review process should also help reduce delay. When applicants do take more than 30 days to respond, the agency considers it reasonable to extend the review period in accordance with § 314.60. The length of such extension will involve not only the time taken to respond, but also other factors, such as the stage of the review process and the reasons for the request. For example, case reports requested to investigate data discrepancies may require a longer extension than requests for case reports to provide information not contained in the tabulations.

50. Several comments urged that FDA require the routine submission of case report forms for deaths and dropouts only for patients who receive the investigational drug, and that case reports for patients on placebo or a reference drug not be included. In addition, one comment asked whether the term "adverse event" in this section of the proposal would include a patient who dropped out of the study because of a "lack of expected pharmacological effect."

FDA believes that case report forms for deaths and dropouts are particularly useful for determining safety problems with a drug. In determining whether these events were drug-related, FDA's evaluation necessarily includes comparing safety problems for patients who took the test drug with patients in the control group who also died or dropped out of the study. Thus, the agency believes that this provision of the final rule should not distinguish between patients in a study on the basis of whether they actually received the investigational drug, and the final rule has been so revised. The term adverse event in this context (as distinguished from its use in § 314.80 concerning postmarketing surveillance) does not include "lack of expected pharmacologic effect."

51. Several comments addressed the level of detail required in the tabulations. A number of comments objected to requiring "every datum" obtained on each patient so that FDA reviewers can reanalyze the data already analyzed by the applicant. These comments preferred tabulating data on categories of patients, which is the standard procedure used in submitting papers to scientific journals. Another comment took the opposite view and suggested that the tabulations include full listings of individual patient data. One comment simply asked that FDA clarify the level of detail needed.

As a general rule, FDA believes that individual patient information that is important enough to be recorded on a case report form would be pertinent to the agency's review of the drug's safety and effectiveness. As noted earlier, the tabulations are intended to present essentially the same information as the case reports, except in a more efficient form.

Nevertheless, the agency recognizes that not all individual patient information will be needed for the agency to conduct a proper review of the application. The regulation, for example, exempts from submission tabulated data on effectiveness derived from uncontrolled Phase 2 and Phase 3 studies. This is because the agency's effectiveness review relies upon adequate and controlled studies, as required by law.

The regulation further provides that the applicant may delete additional tabulations which the agency agrees, in advance, are not pertinent to a review of the drug's safety or effectiveness. Upon request, FDA will discuss with the applicant in a "pre-NDA" conference those tabulations that may be appropriate for such deletion. The regulation also provides that, barring unforeseen circumstances, tabulations agreed to be deleted at such a conference will not be requested during FDA's review.

Other Information (§ 314.50(g))

52. One comment suggested that applicants be permitted to submit English language abstracts that appear in original publications in foreign languages and that they be required to submit an English translation of the full publication only upon request.

The agency believes that it is not unreasonable to ask an applicant who relies upon an original literature publication in a foreign language to submit both the foreign publication and an English translation of it. Otherwise, FDA would not be able to review the full presentation. This is not a new requirement.

53. Several comments addressed the provision whereby applicants could submit the archival copy of the application on microfiche. Comments generally suggested that limiting submissions to microfiche is too restrictive and that FDA should permit microfilm and other data storage forms. One comment suggested that roll microfilm is more economical and easier to make hard copies from than microfiche. Some comments stated that most applicants already submit copies of raw data on indexed microfilm to Canadian drug approval authorities, and that the same form should be acceptable in this country. One comment also suggested that case report forms should be permitted on microfiche or roll microfilm.

FDA has revised the final rule to provide that applicants may submit the relevant portion of an application on microfiche or, if FDA agrees, on another suitable microform system. This change would permit the use of new microform technologies while ensuring that the submission would be in a form usable by FDA. Although other currently available systems (such as indexed roll microfilm) have some advantages over other microform systems, they also have significant disadvantages when used under the circumstances of an FDA application review because of the difficulty in locating specific information even in well-indexed systems. Decisions on using alternative microform systems will be made on a case-by-case basis, as will decisions on whether a microform system may be used for case reports and tabulations.

Abbreviated Applications (§ 314.55)

Note. -- On September 24, 1984, the President signed into law the Drug Price Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417). A primary purpose of this law is to greatly expand the universe of drugs for which FDA will accept abbreviated applications. Pursuant to section 105(b) of the new law, on November 26, 1984, FDA began accepting such applications. Section 105(a) of the new legislation provides FDA with 1 year from the date of enactment to promulgate new implementing regulations. Section 105(b) further provides that, until such time as FDA has new implementing regulations in place, the currently existing regulations will be effective, absent a conflict with the new statute. Because the provisions in this final rule governing abbreviated applications merely restate, in slightly different form, the current regulations on this subject, FDA considers these provisions of the final rule to have the same effect under section 105 of the new law as do the current regulations governing abbreviated new drug applications.

54. One comment asked how the standard of "very closely related" in proposed § 314.56(c) for determining whether an abbreviated application is suitable differs from the standard of "identical, related, and similar drug products" in § 310.6 (21 CFR 310.6) for applying FDA's efficacy conclusions in the Drug Efficacy Study Implementation (DESI) project.

In the Federal Register on January 21, 1983 (48 FR 2751), FDA amended its new drug regulations to clarify its policy on when abbreviated new drug applications are suitable and will be accepted. That rule states that, when FDA finds that an abbreviated application is suitable for a drug product, the finding will apply only to drug products "identical" to the product that was the subject of the finding. At the same time, FDA established a petition procedure under which prospective applicants may ask FDA to determine whether an abbreviated application is suitable for similar or related products. Such decisions on suitability will be made on a case-by-case basis, and abbreviated applications will be accepted only if the safety and efficacy data on the first product are applicable to the product that is the subject of the petition. FDA has revised § 314.55 to conform to the text of that final rule.

In the preamble to the January 21, 1983 final rule, FDA addressed the relationship of this provision to the DESI policy contained in § 310.6. As stated in that preamble, a DESI finding of effectiveness for one drug product does not automatically apply to all similar or related products. Rather, "There will be * * * areas where the judgments of experts must determine the applicability of efficacy findings. The determination will be based on the chemical structure of the drug, recommended use, route of administration, its pharmacological properties and any other information available on the action or properties of the drug." (48 FR 2751 at 2753.) It is through the petition procedure described in § 314.55 that this determination will be made.

Application Development File

55. FDA has removed from the final regulations the proposed provision on the application development file (proposed § 314.57). The provision would have established a mechanism for prospective applicants of abbreviated applications to obtain agency comments on their formulation data, dissolution data, bioequivalence protocols, and pilot studies before conducting bioequivalence tests. FDA has determined that a codified procedure is unnecessary because less formal procedures for providing guidance to potential applicants exist. For example, FDA provides applicant with guidance on developing bioavailability studies through guidelines, meetings between applicants and agency staff, and general correspondence. Moreover, many applicants now rely upon contract laboratories to conduct bioavailability studies, and these laboratories are generally familiar with the requirements for performing acceptable bioequivalence studies. The agency also believes that providing general prospective guidance on bioavailability studies, as opposed to application-specific review, will consume significantly less agency resources while providing adequate guidance to potential applicant.

Amendments to an Unapproved Application (§ 314.60)

56. Several comments asked that FDA inform an applicant if the agency considers a submission to be a major amendment and the approximate amount of time the division needs to review it. Some of these comments urged FDA to reply within 30 days after the agency receives the amendment. Other comments urged that the final rule clarify that the maximum extension will be 180 days. One comment suggested that, if an amendment is made in response to an agency request, FDA should inform the applicant within 30 days of whether the response was adequate.

As stated in the proposal, the director of the reviewing division will inform an applicant that submits a major amendment if an extension is needed. The agency has clarified the final rule to state explicitly that the division director will also inform the applicant of the amount of time the division needs to review the amendment. The agency will strive to make such notifications as timely as possible. FDA has added a statement to the final rule to clarify that the maximum extension of the review period will be 180 days. Finally, FDA may notify the applicant of particular deficiencies found in the amendment and request further clarification or, depending upon the deficiency, may respond to it in an action letter. In this respect, agency comments on an amendment will be handled in the same way as on any other part of the application.

Supplements and Other Changes to an Approved Application (§ 314.70)

57. FDA views the requirements under which applicants can make manufacturing and controls changes in their approved applications as an area in which it can significantly reduce regulatory burdens on the drug industry without compromising public health protection. Currently, nearly all changes in the conditions originally approved in the application are subject to prior FDA approval in a supplemental application, with the few exceptions listed in the regulations. In the same manner suggested by the proposal, the final rule changes this scheme significantly by reducing the number of changes that require supplements and listing those changes (instead of the exceptions) in the regulations. Thus, the final rule retains the three proposed regulatory categories: (1) prior approval, for those changes in marketed drugs which could affect FDA's previous conclusions about the safety and effectiveness of the drug; (2) changes requiring supplements concurrent with the change but on which FDA prior approval is not necessary; and (3) annual reports for changes that do not fall into one of those two categories. The final rule, like the proposal, specifically lists the kinds of changes falling into the first two categories. The final rule also lists examples of changes that can be described in the annual report, but the list is not intended to be exhaustive because the annual report is the residual category.

In the proposed rule, FDA identified several areas where it believed applicants could make changes in their approved applications under less restrictive conditions than currently required. Since then, FDA has conducted an exhaustive examination of its current practices with respect to supplements and has determined that, although significant improvements can be made in this area, for the reasons stated below, not all of the proposed changes have been implemented. As a result, FDA has realigned the specific types of changes among the three categories and is returning several kinds of changes to the prior approval category that, under the proposal, could have been reported to FDA following implementation. At the same time, however, FDA will permit annual reporting of some changes that, under the proposal, would have required prior approval. Under the final rule, FDA estimates that there will be a reduction in approximately 20 percent of manufacturing and controls supplements that now require prior approval, all in areas not likely to affect the safety or effectiveness of the finished drug product. Although FDA proposed to permit the following changes without prior approval, the agency is retaining in the final rule the current prior approval requirements for changing a contract laboratory or labeler, establishing new procedures for reprocessing a batch of a drug product that fails to meet specifications, changing the synthesis of a drug substance, and changing the facility or establishment for manufacturing the drug substance in certain instances. FDA has concluded that prior approval of these changes is needed because they can significantly affect existing agency safety and effectiveness conclusions about a product.

First, FDA has concluded that it should preapprove the ability of a contract laboratory or labeler to comply with CGMP regulations, for such compliance relates directly to the ability of the laboratory or labeler to produce a drug of acceptable quality and/or properly labeled. Second, with respect to the prior approval requirement for reprocessing a batch that fails to meet specifications, many critical factors affect the acceptability of reprocessed batches; for example, the reason for the original batch failure, the storage conditions of the original batch, the tests performed on the reprocessed batch, and the stability of the reprocessed batch. Prior approval of reprocessing procedures will best ensure that rejected batches are not blended with accepted batches, that stability data are used to support recovery or reprocessing operations, and that original control tests are adequate to monitor the reprocessed batch.

Third, prior approval to change the synthesis of the drug substance is needed to assure the safety and effectiveness of the finished product, as is the use of a new facility to manufacture it in certain instances. A change in the synthesis and the many changes in equipment and procedures that occur with a change in manufacturing facilities may significantly affect the finished product. For example, such a change may affect the particle size, crystalline form, stability, or dosage form dissolution of the drug and, thus, affect the bioavailability of the finished product. The method of synthesis of a drug substance is also linked to specifications needed to monitor its strength and purity. Prior approval will ensure that applicants who make a change in synthesis reexamine the adequacy of specifications in light of that change. A product from a different route of synthesis may yield a different purity profile and may require in vivo testing because the limits for specific impurities are normally developed with reference to their toxicity and pharmacological properties. Finally, impurities may also affect the stability of the finished product. In sum, given the significance these changes may have on product safety and integrity, FDA belives it necessary to maintain premarket approval with respect to them.

With respect to changing the facility or establishment that manufactures the drug substance, prior approval will be required where: (1) the manufacturing process in the new facility or establishment differs materially from that in the former facility or establishment, or (2) the new facility or establishment has not received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process. However, the final rule also provides that an applicant may change the facility or establishment that manufactures the drug substance, without obtaining prior FDA approval, if: (1) The manufacturing process in the new facility or establishment does not differ materially from that in the former facility or establishment, and (2) the new facility or establishment has received a satisfactory CGMP inspection within the previous 2 years covering that manufacturing process. If those two criteria are met, the applicant may implement the change concurrent with submission to FDA of a supplement. In that instance, the supplement is to be plainly marked, "Special Supplement -- Changes Being Effected."

FDA has also identified certain changes, in addition to those proposed, that may be reported to FDA on an annual basis rather than in a supplement. These include certain changes in the container and closure system for the drug product, and the addition or deletion of alternate analytical methods. These changes are described more fully below in response to comments on the proposal.

Finally, FDA has revised the final rule to provide a mechanism for applicants to obtain expedited review of supplements where special considerations exist. FDA generally reviews supplements subject to prior approval in the order in which they are received, taking into account other review priorities such as investigational new drug applications and applications for important new drugs. A longstanding and understandable concern of applicants is the cost of waiting for FDA to review and approve these supplements, particularly when extraordinary circumstances require a change in the conditions of approval; for example, when an unexpected event forces an applicant to use a different facility to continue manufacturing a product, or a technological breakthrough would greatly reduce costs. The agency has informally recognized the need to expedite such supplements, but believes that the regulations should specifically recognize this practice. Secondly, the agency has revised the final rule to permit applicants to request expedited review of a supplement for a change that requires prior approval. The agency emphasizes that expedited review is available only under extraordinary circumstances, for either public health or economic reasons, and is subject to the agency's discretion and available resources.

This section, like most of the final rule, will become effective May 23, 1985. If an applicant has submitted to FDA supplements for manufacturing and controls changes that do not require a supplement under the final rule, and those supplements have not yet been reviewed by FDA, the applicant should notify FDA in writing that it is withdrawing those supplements. Upon such notification to FDA, the applicant may proceed to implement those changes as permitted by the final rule.

58. Several consumer comments urged FDA to require prior approval of supplements for every change in an approved application to ensure the safety of the change.

FDA does not agree that prior approval of supplements for all changes in approved applications is necessary. For example, the deletion of an ingredient intended only to affect the color of the drug product is unlikely to affect safety or effectiveness. This is the type of change that, under the final rule, can be implemented by the applicant and submitted to FDA as part of the annual report. FDA believes its combination of prior approval requirements, requirements for supplements not requiring prior approval, and annual reporting requirements focus FDA's resources and attention on those issues that must be monitored closely and properly tailor the time of the reporting to the nature of the change.

59. Several industry comments stated that FDA's proposed reductions in its supplemental application requirements represent a major improvement over current practices. FDA received several comments, however, suggesting that, even with the proposed changes, the regulation of supplements would still be too restrictive. For example, several comments noted that the categories of changes are stated generally and might apply to many changes for which prior approval of a supplement should not be required. Another comment observed that, although the preamble suggested it would be unnecessary to explain batch control numbers in an original application, changes in the batch numbering system would be required in an annual report. Finally, one comment suggested that the agency should permit a single supplement to cover all similar and related products; for example, a packaging change that may affect as many as 100 products should require only a single supplement.

FDA does not agree that the categories of changes are stated too generally. It must be remembered that applicants are to inform FDA about only those changes that affect the information previously submitted in the application. Thus, the application itself is a guide to the kinds of information for which, if changed, the applicant must submit a supplement. Moreover, as described more fully in the proposal, FDA will no longer require an original application to contain information about manufacturing practices that FDA monitors under its current good manufacturing practice (CGMP) regulations, a regulatory change that will also eliminate the need to submit supplements that would require prior approval under current regulations. Because batch control numbers fall under the CGMP regulations, an explanation of batch control numbers is not required in either the original application or the annual report.

Finally, the agency does not agree that a single supplement would be adequate to cover a change affecting similar and related products. Eliminating multiple supplements in favor of a single supplement would not affect the review time and speed of approval because FDA now combines those supplements and performs a single review if the applicant adequately notes the relationship of multiple submissions. Moreover, except for the submission of a supplemental application form for each application, the applicant may now make a single submission of the technical data and information necessary for the agency to review the change. Individual application forms are needed, however, because they are the mechanism by which the change is noted in each application. When approved, the supplement is placed in the application and becomes a part of the permanent record. The submission of a single supplement to cover multiple applications would impose an added burden on FDA to document the changes and is more likely than the current system to result in a failure to include documentation of the change in each application.

60. One comment asked whether changes in the manufacturing site of the drug substance require prior approval. Another comment objected that use of a facility for packaging a drug product should not require prior approval if the container and closure system and quality control procedures are unchanged, and the facility has undergone a recent CGMP inspection. Moreover, according to this comment, changes in the manufacturing site or the manufacturer of a drug product should not require prior approval if the method of manufacture and specifications of the ingredients are the same as those identified in the application and the drug product meets all specifications in the application.

FDA is obligated to see that approved new drugs are manufactured under circumstances that ensure that the marketed drug does not differ from the drug approved by FDA and, thus, that the agency's conclusions about safety and effectiveness apply to it. To accomplish these objectives, the agency must continually monitor the applicant's manufacturing and control operations, including packaging operations, to determine the applicant's ability to produce a product of acceptable quality. This includes prior approval of facilities for the manufacture of the drug substance and drug product and for packaging the product. Compliance with product specifications is important, but it cannot supplant the review process. The use of a new facility to manufacture a drug substance or drug product, or to package the product, invariably involves changes in procedures that may affect the agency's conclusions about the safety and effectiveness of the product. FDA encourages manufacturers to advise it early about plans to begin manufacturing or packaging operations in a new facility. When that is done, the agency and the applicant can work together to ensure that the requirement for prior approval of the supplemental application does not delay an applicant's use of the facility. Moreover, as described in paragraph 57 above and § 314.70(c)(3) of the final rule, prior FDA approval is not required when the applicant uses a new facility or establishment to manufacture a drug substance if certain criteria are met. Finally, FDA believes that the comment's confidence in the use of specifications to ensure product quality is too great. Quality is built into a product through the method of manufacture and in-process controls; end product testing is not viewed by FDA as a substitute for adequate control of the manufacturing process.

61. One comment noted that FDA's list of changes that would require prior approval of a supplement includes changes that can now be made at the time a supplement is submitted, and that FDA should continue to permit immediate implementation of all changes for which that practice now exists. Comments urged FDA to retain the provision in the current regulations that permits a change to be made when a supplement is submitted if the change gives increased assurance that the drug will have the characteristics of identity, strength, quality, and purity which it purports or is represented to possess. One comment suggested that FDA go one step further and permit a change without prior approval if the change provides the same level of assurance that the drug will possess its represented characteristics.

FDA did not intend either to require prior approval of any change for which prior approval is not now required or to change current practice with respect to those changes already listed in the regulations (21 CFR 314.8(d)) as giving increased assurance that the drug will possess its represented characteristics. FDA has revised the final rule to retain the provision. The particular changes contained in the section can be made without prior approval because, by assuring to a greater degree that the drug will possess its represented characteristics, the change provides a public health benefit. A change that provides only the same level of assurance, however, does not provide such a benefit and, thus, the agency finds no basis for making the additional modification suggested by the comment.

62. One comment suggested that the proposal is more restrictive than current requirements in proposing that the "method of manufacture of the drug product, including changing or relaxing an in process control" must be approved by FDA before the change is made. Another comment objected to the phrase "the method of manufacture" because it is too broad and could apply to any change in the procedure for the manufacture of a drug product. One comment suggested that this requirement be revised to apply to changes that "make a significant change to the method of manufacture of the drug product, including changing or relaxing an in process control; for this section a significant change in method of manufacture should be defined as a change resulting in altered product specifications or altered in process controls."

As discussed above, a change in the method of manufacture should be made in the context of the original method of manufacture described in the application and approved by the agency. Moreover, the final rule omits the current requirements under which changes in manufacturing practices covered by FDA's CGMP regulations must be described in a supplement. This change already eliminates the need to seek prior approval for the kinds of changes in the method of manufacture that FDA believes are not significant.

63. One comment suggested that the requirement for prior approval of a new regulatory analytical method is inconsistent with the preamble statement that changes in analytical methods for the drug substance may be made and reported in the next annual report unless there is also a change in synthesis. An applicant suggested that a change in an analytical method should be allowed without prior approval when results are comparable to the approved method. Another comment urged FDA to permit the substitution of a less discriminating analytical method with a more stringent method without prior approval to reward innovation, reduce costs, and introduce benefit from technological advances. Several comments suggested that the agency should permit without prior approval a change in the container and closure system if the applicant demonstrates stability equivalence with the approved container and closure system under an approved stability protocol or where there is no significant alteration in the material of the components.

FDA notes that the comment is correct about the inconsistency in references to changes in analytical methods for drug substances. The preamble statement was incorrect; a change in a regulatory analytical method for a drug substance requires prior FDA approval because it is the method FDA relies upon to determine whether the product meets legal requirements. An applicant may, however, tighten the limits on a specification, or add a new specification without prior FDA approval, if the change is described in the next annual report. FDA is also persuaded that prior approval is unnecessary when adding or deleting an alternate analytical method because FDA will continue to rely upon the regulatory methods, and changes in alternate analytical methods will let applicants take advantage of technological changes. This change will eliminate a large number of supplements, particularly with respect to abbreviated applications.

FDA has also closely examined its supplement requirements with respect to containers and closures. FDA agrees with the comment that an applicant should be permitted to change the container and closures within a particular container and closure system, put the change into effect, and notify FDA about the change in the annual report, if the applicant first determines that the approved and proposed container systems have equivalent stability profiles under an accepted protocol (that is, a protocol appearing in the official compendia or one that has received approval in the application, or a supplement to it). The agency is, however, returning to the prior approval category changes in the container size for nonsolid dosage forms because of the potential adverse effects a change in container size may have for liquids and other nonsolid dosage forms. For example, use of a larger container size for a multi-dose parenteral drug may result in an increase in the number of punctures of the vial stopper and, thus, may adversely affect the product's integrity in use over time.

64. Because CGMP regulations require manufacturers to have validated processes, ongoing stability testing programs, detailed written processes, and quality assurance units, comments urged FDA to permit applicants to make changes in packaging components, excipients, dyes, flavors, fragrances, preservatives, and other changes without prior approval if they do not result in changes in product specifications or performance, or product safety and efficacy. Some comments urged that the agency go even further in reducing the burden of supplements by permitting any change in manufacturing or controls without prior approval if it is properly validated using procedures already accepted by FDA.

FDA believes that these comments confuse the different objectives of the CGMP regulations and the drug approval process. The CGMP regulations establish primarily minimum standards for assuring that the drug is not contaminated during manufacture, and that the drug has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess. Somewhat differently, the new drug approval process and the supplemental application requirements are intended to ensure that the drug is safe, that its benefits outweigh its risks, and that it is effective. Thus, premarket review is still needed to determine whether a change in packaging components, excipients, dyes, flavors, fragrances, and preservatives will affect the safety and effectiveness of the drug. Indeed, because a color may affect a product's stability, FDA concludes that prior approval of the addition of a color is also needed to assure the safety and effectiveness of the product. With these concerns in mind the agency has revised the final rule to require (as it does now) prior approval of a supplement to add a color.

65. One comment suggested that, under the proposal, prior approval of a supplement would be required to delete claims or indications which may now be made upon submission of a supplemental application and without prior approval. The comment urged FDA to permit applicants to delete, without prior approval, any indication for use or claim for effectiveness considered by the applicant to be unsupportable as a result of the applicant's reconsideration of the data or considered by the applicant to present an unacceptable safety to efficacy ratio.

FDA agrees with the comment and has revised the final rule to continue the current practice of permitting the applicant to remove from labeling false, misleading, or unsupported indications for use or claims for effectiveness at the time a supplement describing the change is submitted.

66. FDA received several comments concerning FDA notification of certain changes in the annual report. The United States Pharmacopeial Convention (USPC) supported FDA's proposal to permit changes in an approved application without requiring a supplement if the changes are made to comply with a change in the compendia. Another comment suggested that the changes that may be described in the next annual report that were listed in the preamble to the proposal should be included in the regulation. One comment suggested that any attempt to list both those changes requiring supplements and those changes not requiring supplements would inevitably leave out some kinds of changes. Several comments suggested that the regulation should clearly identify the container size changes that may be made without a supplement if the applicant informs the agency in the next annual report. Finally, one comment asked that the final rule reflect the preamble statement that applicants would not be required to report changes in information not required in an original application; for example, information about manufacturing practices subject to CGMP regulations.

FDA appreciates the support of the USPC and notes that this change in the agency's supplemental application requirements is based upon close cooperation between FDA and the USPC in the development of compendial standards, including cooperation in the review of data and information supporting changes in standards. FDA has revised the final rule to add to the list of changes that may be described in the annual report. The list includes the following: Any change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied that does not involve a change in the dosage strength or dosage form; an editorial or similar minor change in labeling; the deletion of an ingredient intended only to affect the color of the drug product; an extension of the expiration date based upon full shelf-life data obtained from a protocol approved in the application; a change within the container and closure system for the drug product (for example, a change from one high density polyethylene to another), except a change in size for nonsolid dosage forms, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium; the addition or deletion of an alternate analytical method; a change in the size of a container for a solid dosage form, without a change in the container and closure system. FDA emphasizes, however, that the list is not intended to be exhaustive. All changes not falling under one of the two categories requiring supplements are to be described by the applicant in the next annual report to the application. Moreover, any change falling under one of the "supplement" categories that is made simply to comply with an official compendium is also to be described by the applicant in the next annual report. Although FDA believes it is impractical, if not impossible, to describe in the regulations every possible change that could occur in any application, the final rule lists the most significant and common changes that may be made and that are to be described in the annual report. Finally, FDA believes that a list of subjects, like changes under the CGMP regulations for which prior approval has been but is no longer required, would be of only historical interest and could be confusing.

67. One comment suggested that the agency permit applicants to add and update biopharmaceutic information in drug labeling in the annual report and without a supplement.

Drug labeling serves as the standard under which FDA determines whether a product is safe and effective. Substantive changes in labeling, which include changes in biopharmaceutic information, are more likely than other changes to affect the agency's previous conclusions about the safety and effectiveness of the drug. Thus, they are appropriately approved by FDA in advance, unless they relate to important safety information, like a new contraindication or warning, that should be immediately conveyed to the user.

68. One comment suggested that FDA create a fourth kind of supplement under which an applicant could implement a change 60 days after notifying the agency unless the agency advises otherwise within that time. Another comment suggested 30 days. These supplements might include changes in labeling or revisions to manufacturing or control procedures.

FDA has not adopted this suggestion because of the impact it would have on FDA's priorities. Were such a system instituted, FDA would be forced to rearrange its priorities to ensure that it acted within the required time frame, often with the effect of deferring action on other older and perhaps more important submissions that cannot be implemented without FDA approval. FDA recognizes applicants' concerns about obtaining timely review of supplements, and the agency is addressing this problem by eliminating unnecessary supplements which should, in turn, reduce any backlog. FDA now works closely with applicants who have a special need for timely review of a supplement and, as described above, FDA is establishing a procedure for applicants to request expedited review of certain supplements.

Procedures for Submission of a Supplement to an Approved Application (§ 314.71)

69. Noting that a supplemental application can sometimes be as significant as an original application, such as a supplement for a new indication, several comments found beneficial the application to supplements of all procedures and FDA actions on applications under proposed § § 314.100 through 314.170. The comments urged, however, that the agency clearly state that § 314.60 on amendments to unapproved applications, § 314.65 on voluntary withdrawal, and § 314.103 on dispute resolution also apply to supplements.

FDA has revised the final rule to clarify that all procedures applicable to an original application also apply to supplements.

70. One comment suggested that the final rule should specify what actions FDA will take in the event that the agency refuses to approve a supplement for a change that the applicant placed into effect at the time the supplement was submitted. The comment stated that FDA should provide a reasonable time for the applicant to correct the problem, including time to exhaust supplies of the drug or labeling affected by the change, unless a significant safety concern exists.

If FDA refuses to approve a supplement for a change that the applicant has already placed into effect, the agency must consider all the factors surrounding its refusal to approve the supplement, including the applicant's reasons for making the change and the alternatives available to the applicant to resolve the problem. Applicants should be aware that they institute such changes subject to agency approval and that, if circumstances warrant, may be required to discontinue the change immediately. Nonetheless, if circumstances permit, FDA agrees that applicants should be able to correct a problem at minimal expense and without unnecessary waste. Because circumstances can vary greatly, however, FDA is not persuaded that a general statement in the regulations would be appropriate.

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