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                Clinical Trials and Human Subject Protection

Clinical Trials and Human Subject Protection

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          Investigational New Drug Applications and New Drug Applications (9/8/1995)Clinical Trials and Human Subject Protection Investigational New Drug Applications and New Drug Applications (9/8/1995)
  
  	
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    Print[Federal Register: September 8, 1995 (Volume 60, Number 174)]
  [Proposed Rules] 
  [Page **46794**-46797]
  From the Federal Register Online via GPO Access [wais.access.gpo.gov]
  [DOCID:fr08se95-24]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
  Food and Drug Administration
  21 CFR Parts 312 and 314
  [Docket No. 95N-0010]
Investigational New Drug Applications and New Drug Applications
  AGENCY: Food and Drug Administration, HHS.
  ACTION: Proposed rule.
SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
  its regulations pertaining to investigational new drug applications 
  (IND's) and new drug applications (NDA's). The proposed rule would 
  clearly define in the NDA format and content requirements the need to 
  present effectiveness and safety data for important demographic 
  subgroups, specifically gender, age, and racial subgroups. The rule 
  would codify expectations that FDA has previously described in 
  guidance. The proposed amendments would also require IND sponsors of 
  drugs, including biological products, to characterize, in their annual 
  reports, the number of subjects in a clinical study according to age 
  group, gender, and race. The proposed rule does not address the 
  requirements for the conduct of clinical studies and would not require 
  sponsors to conduct any more studies than they have already conducted. 
  It also would not require the inclusion of particular numbers of 
  individuals from specific subgroups in any study or overall. The rule 
  refers only to the presentation of data already collected. The scope of 
  this proposal does not extend to requiring additional studies or data.
DATES: Written comments by December 7, 1995.
ADDRESSES: Submit written comments to the Dockets Management Branch 
  (HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
  Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Deborah A. Wolf, Center for Drug 
  Evaluation and Research (HFD-362), Food and Drug Administration, 7500 
  Standish Pl., Rockville, MD 20855, 301-594-1046.
SUPPLEMENTARY INFORMATION: The proposed rule would amend the NDA 
  content and format regulations at 21 CFR 314.50 to explicitly require 
  that sponsors submit effectiveness and safety data by gender, age, and 
  racial subgroups and other subgroups of the population of patients 
  treated, as appropriate, such as patients with renal failure or 
  patients with different levels of severity of disease. In the Federal 
  Register of July 22, 1993 (58 FR 39406), FDA published a guideline 
  entitled ``Guideline for the Study and Evaluation of Gender Differences 
  in the Clinical Evaluation of Drugs.'' The guideline provided guidance 
  on FDA's expectations regarding inclusion of both men and women in drug 
  development, analyses of clinical data by gender, assessment of 
  potential pharmacokinetic differences between genders, and conduct of 
  specific additional studies in women, where indicated. The preamble to 
  the guideline described the development of the agency's policy 
  regarding the evaluation of clinical data by gender. The guideline 
  noted that over the preceding decade there had been growing concern 
  that the drug development process did not produce adequate information 
  about the effects of drugs in women (58 FR 39406). Analyses of 
  published clinical trials in certain therapeutic areas had indicated 
  that there had been little or no participation by women in many of the 
  studies. There had also been little study of the effects of such 
  aspects of female
[Page 46795]
  physiology as the menstrual cycle and menopause or of the effects of 
  oral contraceptives and systemic progestins and estrogens on drug 
  action and pharmacokinetics.
The guideline also explained that concerns about the adequacy of 
  data on the effects of drugs in women have arisen in the context of an 
  increasing awareness of the need to individualize treatment in the face 
  of the wide variety of demographic, disease-related, and individual 
  patient-related factors that can lead to different responses in subsets 
  of the population. Optimal use of drugs requires identification of 
  these factors so that appropriate adjustments in dose, concomitant 
  therapy, or monitoring can be made. The guideline was part of FDA's 
  effort to address the need to gather and evaluate data from various 
  subpopulations in clinical drug trials. The agency had previously 
  addressed the need to develop information on the elderly in the 1989 
  guideline entitled, ``Guideline for the Study of Drugs Likely to be 
  Used in the Elderly.'' That guideline provided similar guidance 
  regarding inclusion of elderly patients in clinical trials and 
  assessment of clinical and pharmacokinetic differences between older 
  and younger patients.
In 1983 and 1989, FDA examined the relative numbers of individuals 
  from two important demographic subgroups, women and the elderly, in the 
  data bases of NDA's. The agency found that, in general, the proportions 
  of women and men included in the clinical trials were similar to the 
  respective proportions of women and men who had the diseases for which 
  the drugs were being studied, taking into account the age range of the 
  population studied. The General Accounting Office (GAO) conducted a 
  larger study of drugs approved during the period 1988 through 1991, and 
  found similar proportions. Women were found to typically represent a 
  majority of patients in NDA data bases of drugs used to treat 
  conditions more common, or more commonly treated, in women, and a 
  minority, generally a sizable one, in tests of drugs for conditions 
  that occur predominantly in males in the age range usually included in 
  the clinical trials.
Although women have been included in the later phases of clinical 
  trials, the agency believes that inclusion alone is not sufficient for 
  adequate assessment of potential gender differences. There must be an 
  effort to use the data to discover such differences, and the agency 
  found that this effort was not made. Various documents published by the 
  agency have reflected the need to examine gender as well as other 
  characteristics for their effects on drug response. FDA's regulations 
  on NDA content and format require the clinical data section of the NDA 
  to include, among other things, ``An integrated summary of the data 
  demonstrating substantial evidence of effectiveness for the claimed 
  indications. Evidence is also required to support the dosage and 
  administration section of the labeling, including support for the 
  dosage and dose interval recommended, and modifications for specific 
  subgroups (for example, pediatrics, geriatrics, patients with renal 
  failure)'' and an integrated summary of safety. (See 21 CFR 
  314.50(d)(5)(v) and (d)(5)(vi)(a)). The examples of subgroups listed in 
  Sec. 314.50(d)(5)(v) were not intended to be a complete list or to 
  limit the subgroups for which data should be submitted. In 1988, in a 
  guideline entitled, ``Guideline for the Format and Content of the 
  Clinical and Statistical Sections of New Drug Applications,'' FDA 
  discussed analyses of population subsets within NDA data bases to look 
  for differences in effectiveness and adverse reactions to drugs. The 
  guideline describes the population subsets to include subsets such as 
  different genders, age groups, and races, and other subsets such as 
  people receiving other drug therapy and people with concurrent 
  illnesses. See, ``Guideline for the Format and Content of the Clinical 
  and Statistical Sections of New Drug Applications'' at pages 32 and 40. 
  The guideline describes the need for clinical data beyond the specific 
  subgroups and categories of information set forth in the current 
  regulations.
The current wording of Sec. 314.50, while not intended to limit the 
  analyses to be carried out does not fully reflect the need to present 
  the safety and effectiveness data by subgroup and omits important 
  subgroups, including gender and racial groups. The proposal would make 
  explicit the agency's requirements concerning the data that are 
  presented in NDA's. It would make clear the need to present safety and 
  effectiveness data by gender, age, and racial subgroups to allow a 
  determination, to the extent the data permit, of whether these factors 
  affect results of treatment or alter dosing requirements.
FDA believes that it is important to make such an explicit 
  requirement. After the publication of the 1988 guideline, FDA and GAO 
  examined data bases for NDA's to see whether the analyses to which the 
  guideline refers were being conducted and submitted. Both of the 
  examinations found that in about half of the cases the data bases were 
  not being analyzed to determine whether there were differences in 
  response to drugs between the two genders or among different racial 
  groups and age groups. Thus, changes that the proposal would make to 
  Sec. 314.50 would codify what the agency has already identified as 
  important elements of clinical data.
FDA also believes that to codify the need for presentations of data 
  by subgroups will provide industry with clear information regarding 
  potential consequences of the absence of subgroup data. The agency's 
  regulation governing the filing of an application, which is set forth 
  in 21 CFR 314.101, provides that the Center for Drug Evaluation and 
  Research may refuse to file an NDA that, among other things, is not 
  submitted in the form required under Sec. 314.50 or that is incomplete 
  because it does not on its face contain information required under 
  section 505(b) of the Federal Food, Drug and Cosmetic Act. 21 CFR 
  314.101(d)(3). The refusal to file policy attempts to direct FDA's 
  resources to applications complete enough for review. The agency's 
  ``New Drug Evaluation Guidance Document: Refusal to File'' describes 
  situations in which FDA applies the provision in Sec. 314.101(d)(3) to 
  make refusal to file decisions. In particular, the document explains 
  that omission of critical data, information or analyses needed to 
  evaluate effectiveness and safety or provide adequate directions for 
  use is an appropriate basis for a refusal to file. Among the particular 
  considerations in refusal to file decisions is a ``clearly inadequate 
  evaluation for safety and/or effectiveness of the population intended 
  to use the drug, including pertinent subsets, such as gender, age, and 
  racial subsets.'' Thus, the proposal would allow sponsors to know from 
  the beginning that data that are not presented with regard to gender, 
  age, and racial groups are grounds for a refusal to file.
It is important to note that the rule does not address the 
  requirements for the conduct of clinical studies and that this proposal 
  would not require sponsors to conduct any more studies than they have 
  already conducted. It also does not require the inclusion of particular 
  numbers of individuals from specific subgroups in any study or overall. 
  The rule refers only to the presentation of data already collected. The 
  scope of this proposal does not extend to requiring additional studies 
  or data.
Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action 
  is of a
[Page 46796]
  type that does not individually or cumulatively have a significant 
  effect on the human environment. Therefore, neither an environmental 
  assessment nor an environmental impact statement is required.
Paperwork Reduction Act of 1980
This proposed rule contains information collections which are 
  subject to review by the Office of Management and Budget (OMB) under 
  the Paperwork Reduction Act of 1980. The title, description, and 
  respondent description of the information collection are shown below 
  with an estimate of the annual reporting and recordkeeping burden. 
  Included in the estimate is the time for reviewing instructions, 
  searching existing data sources, gathering and maintaining the data 
  needed, and completing and reviewing the collection of information.
Title: Investigational New Drug Applications and New Drug 
  Applications.
Description: The information submitted by respondents pursuant to 
  the proposed regulatory revisions would assist the agency in monitoring 
  the success of drug companies in enrolling in clinical drug trials 
  subjects representing various subgroups of the population expected to 
  use the drug being tested once it is approved and marketed and in 
  better evaluating the safety and efficacy profiles of drugs for various 
  subgroups.
Description of respondents: Businesses, nonprofit institutions, 
  small businesses.
Section
      Annual number of respondents
      Annual frequency
      Average burden per response
      Annual burden hours312.33(a)(2)
      1,616 (noncommercial)
      1
      2 hours
      3,232312.33(a)(2)
      362 (commercial)
      1
      8 hours
      2,896314.50
      50
      1
      40 hours
      2,000Total
      
      
      
      8,128
The agency has submitted a copy of this proposed rule to OMB for 
  review of these information collections. Send comments regarding this 
  burden estimate or any other aspect of this collection of information, 
  including suggestions for reducing this burden, to FDA's Dockets 
  Management Branch (address above) and to the Office of Information and 
  Regulatory Affairs, OMB, Washington, DC 20503.
Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive 
  Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
  Executive Order 12866 directs agencies to assess all costs and benefits 
  of available regulatory alternatives and, when regulation is necessary, 
  to select regulatory approaches that maximize net benefits (including 
  potential economic, environmental, public health and safety, and other 
  advantages; distributive impacts; and equity). The agency believes that 
  this proposed rule is consistent with the regulatory philosophy and 
  principles identified in the Executive Order. The proposed rule does 
  not require any change in the studies a drug manufacturer needs to 
  conduct or impose any requirements on the conduct of those studies. It 
  requires only a presentation of data already collected. In addition, 
  the proposed rule is not a significant regulatory action as defined by 
  the Executive Order and so is not subject to review under the Executive 
  Order.
This proposed rule would amend the IND regulations to enable FDA 
  and sponsors of drugs, including biological products, to monitor the 
  sponsor's success in studying the populations that are likely to 
  receive the drug once it is approved. Under the current IND regulations 
  in Sec. 312.33(a)(2) (21 CFR 312.33(a)(2)), sponsors are required to 
  submit an annual report that includes for each study, among other 
  things, ``The total number of subjects initially planned for inclusion 
  in the study, the number entered into the study to date, the number 
  whose participation in the study was completed as planned, and the 
  number who dropped out of the study for any reason.'' The proposed rule 
  would amend Sec. 312.33(a)(2) to require that the annual report include 
  the number of subjects entered into the study ``characterized by age 
  group, gender, and race.'' Reporting and reviewing this information 
  would not itself represent a need for new studies or patients. The 
  agency is aware that many clinical trials do not contain enough 
  patients from various subgroups to perform statistically rigorous 
  comparisons of outcomes between subgroups. The Regulatory Flexibility 
  Act requires agencies to analyze regulatory options that would minimize 
  any significant impact of a rule on small entities. The agency 
  certifies that the proposed rule will not have a significant economic 
  impact on a substantial number of small entities. Therefore, under the 
  Regulatory Flexibility Act, no further analysis is required.
Request for Comments
Interested persons may, on or before December 7, 1995, submit to 
  the Dockets Management Branch (address above) written comments 
  regarding this proposal. Two copies of any comments are to be 
  submitted, except that individuals may submit one copy. Comments are to 
  be identified with the docket number found in brackets in the heading 
  of this document. Received comments may be seen in the office above 
  between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects
21 CFR Part 312 
  Drugs, Exports, Imports, Investigations, Labeling, Medical 
  research, Reporting and recordkeeping requirements, Safety.
21 CFR Part 314 
  Administrative practice and procedure, Confidential business 
  information, Drugs, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
  Public Health Service Act, and under authority delegated to the 
  Commissioner of Food and Drugs, it is proposed that 21 CFR parts 312 
  and 314 be amended to read as follows:
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
1. The authority citation for 21 CFR part 312 continues to read as 
  follows: 
  Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of 
  the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 
  352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service 
  Act (42 U.S.C. 262).
[Page 46797]
2. Section 312.33 is amended by revising paragraph (a)(2) to read 
  as follows:Sec. 312.33  Annual reports.
  * * * * *
  (a) * * *
  (2) The total number of subjects initially planned for inclusion in 
  the study; the number entered into the study to date, characterized by 
  age group, gender, and race; the number whose participation in the 
  study was completed as planned; and the number who dropped out of the 
  study for any reason.
  * * * * *
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN 
  ANTIBIOTIC DRUG
3. The authority citation for 21 CFR part 314 continues to read as 
  follows: 
  Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701, 
  704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 
  331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).
4. Section 314.50 is amended by revising the second sentence and 
  adding two new sentences after the second sentence in paragraph 
  (d)(5)(v) and by adding two new sentences after the first sentence in 
  paragraph (d)(5)(vi)(a) to read as follows:
Sec. 314.50  Content and format of an application. 
  * * * * *
  (d) * * *
  (5) * * *
  (v) * * * Evidence is also required to support the dosage and 
  administration section of the labeling, including support for the 
  dosage and dose interval recommended. The effectiveness data shall be 
  presented by gender, age, and racial subgroups. Effectiveness data from 
  other subgroups of the population of patients treated, as appropriate, 
  such as patients with renal failure or patients with different levels 
  of severity of disease, shall also be presented.
  (vi) * * *
  (a) * * * The safety data shall be presented by gender, age, and 
  racial subgroups. Safety data from other subgroups of the population of 
  patients treated, as appropriate, such as patients with renal failure 
  or patients with different levels of severity of disease, shall also be 
  presented. * * *
  * * * * *
Dated: July 11, 1995.
  William B. Schultz,
  Deputy Commissioner for Policy.
  [FR Doc. 95-22297 Filed 9-7-95; 8:45 am]
  BILLING CODE 4160-01-F

                                                                                  Content current as of:
      09/18/2015Clinical Trials and Human Subject Protection

          
                        BIMO Inspection Metrics
          HSP/BIMO Initiative
          Good Clinical Practice (GCP) Inspection Collaboration with International Regulators for Drug Development
          ICH Guidance Documents
          Regulations: Good Clinical Practice and Clinical Trials
          Clinical Trials Guidance Documents


                        Clinical Investigations Compliance & Enforcement
          FDA's Role: ClinicalTrials.gov Information
          Good Clinical Practice Educational Materials
          Report Problems to FDA
          Reporting Complaints Related to FDA-Regulated Clinical Trials
          Good Clinical Practice Inquiries
 
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