(a) Standard submission deadline. In general, for applicable clinical trials subject to § 11.42, clinical trial results information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)) or in § 11.48, as applicable, must be submitted no later than 1 year after the primary completion date of the applicable clinical trial.
(b) Delayed submission of results information with certification if seeking approval, licensure, or clearance of a new use—(1) General requirements. If, prior to the results information submission deadline specified under paragraph (a) of this section, the responsible party submits a certification that an applicable clinical trial involves an FDA-regulated drug product (including a biological product) or device product that previously has been approved, licensed, or cleared, for which the manufacturer is the sponsor of the applicable clinical trial and for which an application or premarket notification seeking approval, licensure, or clearance of the use being studied (which is not included in the labeling of the approved, licensed, or cleared drug product (including a biological product) or device product) has been filed or will be filed within 1 year with FDA, the deadline for submitting clinical trial results information, as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)) or § 11.48, as applicable, will be 30 calendar days after the earliest of the following events:
(i) FDA approves, licenses, or clears the drug product (including a biological product) or device product for the use studied in the applicable clinical trial;
(ii) FDA issues a letter that ends the regulatory review cycle for the application or submission but does not approve, license, or clear the drug product (including a biological product) or device product for the use studied in the applicable clinical trial; or
(iii) The application or premarket notification seeking approval, licensure, or clearance of the new use is withdrawn without resubmission for not less than 210 calendar days.
(2) Two-year limitation. Notwithstanding the deadlines specified in paragraph (b)(1) of this section, the responsible party must submit clinical trial results information specified in paragraph (b)(1) of this section not later than the date that is 2 years after the date that the certification was submitted, except to the extent that paragraph (d) of this section applies.
(3) Additional requirements. If a responsible party who is both the manufacturer of the drug product (including a biological product) or device product studied in an applicable clinical trial and the sponsor of the applicable clinical trial submits a certification in accordance with paragraph (b)(1) of this section, that responsible party must submit such a certification for each applicable clinical trial that meets the following criteria:
(i) The applicable clinical trial is required to be submitted in an application or premarket notification seeking approval, licensure, or clearance of a new use; and
(ii) The applicable clinical trial studies the same drug product (including a biological product) or device product for the same use as studied in the applicable clinical trial for which the initial certification was submitted.
(c) Delayed submission of results with certification if seeking initial approval, licensure, or clearance.—(1) General requirements. If, prior to the submission deadline specified under paragraph (a) of this section, a responsible party submits a certification that an applicable clinical trial studies an FDA-regulated drug product (including a biological product) or device product that was not approved, licensed, or cleared by FDA for any use before the primary completion date of the trial, and that the sponsor intends to continue with product development and is either seeking, or may at a future date seek, FDA approval, licensure, or clearance of the drug product (including a biological product) or device product under study, the deadline for submitting clinical trial results information, as specified in § 11.48, will be 30 calendar days after the earlier of the date on which:
(i) FDA approves, licenses, or clears the drug product (including a biological product) or device product for any use that is studied in the applicable clinical trial; or
(ii) The marketing application or premarket notification is withdrawn without resubmission for not less than 210 calendar days.
(2) Two-year limitation. Notwithstanding the deadlines established in paragraph (c)(1) of this section, the responsible party must submit clinical trial results information specified in paragraph (c)(1) of this section not later than 2 years after the date on which the certification was submitted, except to the extent that paragraph (d) of this section applies.
(d) Submitting partial results information. (1) If clinical trial results information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)) or § 11.48, as applicable, has not been collected for a secondary outcome measure(s) or additional adverse event information by the primary completion date, the responsible party must submit the remaining required clinical trial results information for secondary outcome measure(s) or additional adverse event information for that clinical trial by the following deadlines:
(i) For secondary outcome measure(s), by the later of:
(A) One year after the date on which the final subject is examined or receives an intervention for the purposes of final collection of data for that secondary outcome measure, whether the clinical trial was concluded according to the pre-specified protocol or was terminated; or
(B) If a certification to delay results information submission has been submitted under paragraph (b) or (c) of this section, the date on which results information for the primary outcome measures is due pursuant to paragraph (b) or (c) of this section.
(ii) For additional adverse event information, by the later of:
(A) One year after the date of data collection for additional adverse event information, whether the clinical trial was concluded according to the pre-specified protocol or was terminated; or
(B) If a certification to delay results information submission has been submitted under paragraph (b) or (c) of this section, the date on which results information for the primary outcome measures is due pursuant to paragraph (b) or (c) of this section.
(2) Except, if clinical trial results information was submitted for the primary outcome measure(s) prior to the effective date of these regulations but data collection for all of the secondary outcome measure(s) or additional adverse event information is not completed until on or after January 18, 2017, clinical trial results information for all primary and secondary outcome measures and adverse event information for the clinical trial must be submitted as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C) and 42 U.S.C. 282(j)(3)(I)).
(3) For each submission of partial results information for a clinical trial, as specified in paragraph (d)(1) of this section:
(i) If any amendments were made to the protocol and/or statistical analysis plan as described in § 11.48(a)(5) since the previous submission of partial results information, the responsible party must submit a copy of the revised protocol and/or statistical analysis plan; and
(ii) If information about certain agreements as described in § 11.48(a)(6)(ii) has changed since the previous submission of partial results information, the responsible party must submit information to reflect the new status of certain agreements between the principal investigator and the sponsor.
(e) Extensions for good cause. (1) A responsible party may request an extension of the deadline for submitting clinical trial results information subject to paragraphs (e)(1)(i) and (ii) of this section or section 402(j)(3)(E)(vi) of the Public Health Service Act (42 U.S.C. 282(j)(3)(E)(vi)), as applicable, and may request more than one extension for the same applicable clinical trial.
(i) The responsible party must submit a request for an extension to ClinicalTrials.gov prior to the date on which clinical trial results information would otherwise be due in accordance with paragraph (a), (b), (c), (d), (e), or (f) of this section.
(ii) A request for an extension must contain the following:
(A) Description of the reason(s) why clinical trial results information cannot be provided according to the deadline, with sufficient detail to allow for the evaluation of the request; and
(B) Estimate of the date on which the clinical trial results information will be submitted.
(2) Decision and submission deadline. The Director will provide a response electronically to the responsible party indicating whether the requested extension demonstrates good cause and has been granted.
(i) If the extension request is granted, the responsible party must submit clinical trial results information not later than the date of the deadline specified in the electronic response.
(ii) If the extension request is denied, the responsible party must either appeal in accordance with paragraph (e)(3) of this section or submit clinical trial results information specified in § 11.48 by the later of the submission deadline specified in paragraph (a), (b), (c), (d), (e), or (f) of this section, as applicable, or 30 calendar days after the date on which the electronic notice of the denial is sent to the responsible party.
(3) Appealing a denied extension request. (i) A responsible party who seeks to appeal a denied extension request or the deadline specified in a granted extension must submit an appeal to the Director in the format specified at https://prsinfo.clinicaltrials.gov/ not later than 30 calendar days after the date on which the electronic notification of the granting or denial of the request is sent to the responsible party.
(ii) An appeal must contain an explanation of the reason(s) why the initial decision to deny the extension request or to grant the extension request with a shorter deadline than requested should be overturned or revised, with sufficient detail to allow for the evaluation of the appeal.
(iii) The Director will provide an electronic notification to the responsible party indicating whether the requested extension has been granted upon appeal.
(iv) If the Director grants the extension request upon appeal, the responsible party must submit clinical trial results information not later than the deadline specified in the electronic notification specified in paragraph (e)(3)(iii) of this section.
(v) If the Director denies the appeal of a denied extension request, the responsible party must submit clinical trial results information by the later of the deadline specified in paragraph (a), (b), (c), (d), (e), or (f) of this section, or 30 calendar days after the electronic notification of the denial of the appeal, specified in paragraph (e)(3)(iii) of this section, is sent to the responsible party.
(vi) If the Director denies an appeal of a denied deadline specified in a granted extension request, the responsible party must submit clinical trial results information by the later of the deadline specified in the notification granting the extension request, specified in paragraph (e)(2)(i) of this section, or 30 calendar days after the electronic notification denying the appeal, specified in paragraph (e)(3)(iii) of this section, is sent to the responsible party.
(f) Pediatric postmarket surveillance of a device product that is not a clinical trial. For each pediatric postmarket surveillance of a device product that is not a clinical trial as defined in this part, the responsible party must submit clinical trial results information as specified in § 11.48(b) or section 402(j)(C)(3) of the Public Health Service Act (42 U.S.C. 282(j)(C)(3)), as applicable, not later than 30 calendar days after the date on which the final report of the approved pediatric postmarket surveillance of a device product, as specified in 21 CFR 822.38, is submitted to FDA.
(a) For each applicable clinical trial, other than a pediatric postmarket surveillance of a device product that is not a clinical trial, for which clinical trial results information must be submitted under § 11.42, the responsible party must provide the following:
(1) Participant flow. Information for completing a table documenting the progress of human subjects through a clinical trial, by arm, including the number who started and completed the clinical trial. This information must include the following elements:
(i) Participant Flow Arm Information. A brief description of each arm used for describing the flow of human subjects through the clinical trial, including a descriptive title used to identify each arm;
(ii) Pre-assignment Information. A description of significant events in the clinical trial that occur after enrollment and prior to assignment of human subjects to an arm, if any; and
(iii) Participant Data. The number of human subjects that started and completed the clinical trial, by arm. If assignment is based on a unit other than participants, also include a description of the unit of assignment and the number of units that started and completed the clinical trial, by arm.
(2) Demographic and baseline characteristics. Information for completing a table of demographic and baseline measures and data collected by arm or comparison group and for the entire population of human subjects who participated in the clinical trial. This information must include the following elements:
(i) Baseline Characteristics Arm/Group Information. A brief description of each arm or comparison group used for describing the demographic and baseline characteristics of the human subjects in the clinical trial, including a descriptive title used to identify each arm or comparison group.
(ii) Baseline Analysis Population Information—(A) Overall Number of Baseline Participants. The total number of human subjects for whom baseline characteristics were measured, by arm or comparison group and overall.
(B) Overall Number of Units Analyzed. If the analysis is based on a unit other than participants, a description of the unit of analysis and the number of units for which baseline measures were measured and analyzed, by arm or comparison group and overall.
(C) Analysis Population Description. If the Overall Number of Baseline Participants (or units) differs from the number of human subjects (or units) assigned to the arm or comparison group and overall, a brief description of the reason(s) for the difference.
(iii) Baseline Measure Information. A description of each baseline or demographic characteristic measured in the clinical trial, including age, sex/gender, race, ethnicity (if collected under the protocol), and any other measure(s) that were assessed at baseline and are used in the analysis of the primary outcome measure(s) in accordance with § 11.48(a)(3). The description of each measure must include the following elements:
(A) Name and description of the measure, including any categories that are used to submit Baseline Measure Data.
(B) Measure Type and Measure of Dispersion: For each baseline measure submitted, an indication of the type of data to be submitted and the associated measure of dispersion.
(C) Unit of Measure. For each baseline measure for which data are collected, the unit of measure.
(iv) Baseline Measure Data. The value(s) for each submitted baseline measure, by arm or comparison group and for the entire population of human subjects for whom baseline characteristics were measured.
(v) Number of baseline participants (and units), by arm or comparison group and overall, if different from the Overall Number of Baseline Participants or Overall Number of Units Analyzed in § 11.48(a)(2)(ii)(A) and (B), respectively.
(3) Outcomes and statistical analyses. Information for completing a table of data for each primary and secondary outcome measure by arm or comparison group, including the result(s) of scientifically appropriate statistical analyses that were performed on the outcome measure data, if any. This information must include the following elements:
(i) Outcome Measure Arm/Group Information. A brief description of each arm or comparison group used for submitting an outcome measure for the clinical trial, including a descriptive title to identify each arm or comparison group.
(ii) Analysis Population Information—(A) Number of Participants Analyzed. The number of human subjects for whom an outcome was measured and analyzed, by arm or comparison group.
(B) Number of Units Analyzed. If the analysis is based on a unit other than participants, a description of the unit of analysis and the number of units for which an outcome was measured and analyzed, by arm or comparison group.
(C) Analysis Population Description. If the Number of Participants Analyzed or Number of Units Analyzed differs from the number of human subjects or units assigned to the arm or comparison group, a brief description of the reason(s) for the difference.
(iii) Outcome Measure Information. A description of each outcome measure, to include the following elements:
(A) Name of the specific outcome measure, including the titles of any categories in which Outcome Measure Data in § 11.48(a)(3)(iv) are aggregated.
(B) Description of the metric used to characterize the specific outcome measure.
(C) Time point(s) at which the measurement was assessed for the specific metric.
(D) Outcome Measure Type. The type of outcome measure, whether primary, secondary, other pre-specified, or post-hoc.
(E) Measure Type and Measure of Dispersion or Precision. For each outcome measure for which data are collected, the type of data submitted and the measure of dispersion or precision.
(F) Unit of Measure. For each outcome measure for which data are collected, the unit of measure.
(iv) Outcome Measure Data. The measurement value(s) for each outcome measure for which data are collected, by arm or comparison group and by category (if specified).
(v) Statistical Analyses. Result(s) of scientifically appropriate tests of the statistical significance of the primary and secondary outcome measures, if any.
(A) A statistical analysis is required to be submitted if it is:
(1) Pre-specified in the protocol and/or statistical analysis plan and was performed on the outcome measure data,
(2) Made public by the sponsor or responsible party prior to the date on which clinical trial results information is submitted for the primary outcome measures(s) studied in the clinical trial to which the statistical analysis applies, or
(3) Conducted on a primary outcome measure in response to a request made by FDA prior to the date on which clinical trial results information is submitted for the primary outcome measure(s) studied in the clinical trial to which the statistical analysis applies.
(B) Information for each statistical analysis specified in paragraph (a)(3)(v)(A) of this section must include the following elements:
(1) Statistical Analysis Overview: Identification of the arms or comparison groups compared in the statistical analysis; the type of statistical test conducted; and, for a non-inferiority or equivalence test, a description of the analysis that includes, at minimum, the power calculation and non-inferiority or equivalence margin.
(2) One of the following, as applicable:
(i) Statistical Test of Hypothesis: The p-value and the procedure used for the statistical analysis; or
(ii) Method of Estimation: The estimation parameter, estimated value, and confidence interval (if calculated).
(4) Adverse event information. (i) Information to describe the methods for collecting adverse events during an applicable clinical trial:
(A) Time Frame. The specific period of time over which adverse event information was collected and for which information is submitted in paragraph (a)(4)(iii) of this section.
(B) Adverse Event Reporting Description. If the adverse event information collected in the clinical trial is collected based on a different definition of adverse event and/or serious adverse event than defined in this part, a brief description of how those definitions differ.
(C) Collection Approach. The type of approach taken to collect adverse event information, whether systematic or non-systematic.
(ii) Information for completing three tables summarizing anticipated and unanticipated adverse events collected during an applicable clinical trial:
(A) Table of all serious adverse events grouped by organ system, with the number and frequency of each event by arm or comparison group;
(B) Table of all adverse events, other than serious adverse events, that exceed a frequency of 5 percent within any arm of the clinical trial, grouped by organ system, with the number and frequency of each event by arm or comparison group; and
(C) Table of all-cause mortality, with the number and frequency of deaths due to any cause by arm or comparison group.
(iii) Information for each table specified in paragraph (a)(4)(ii) of this section must include the following elements, unless otherwise specified:
(A) Adverse Event Arm/Group Information. A brief description of each arm or comparison group used for submitting adverse event information from the clinical trial, including a descriptive title used to identify each arm or comparison group.
(B) Total Number Affected. The overall number of human subjects affected, by arm or comparison group, by:
(1) Serious adverse event(s);
(2) Adverse event(s) other than serious adverse events that exceed a frequency of 5 percent within any arm of the clinical trial; and
(3) Deaths due to any cause.
(C) Total Number at Risk. The overall number of human subjects included in the assessment, by arm or comparison group, for:
(1) Serious adverse events;
(2) Adverse event(s) other than serious adverse events that exceed a frequency of 5 percent within any arm of the clinical trial; or
(3) Deaths due to any cause.
(D) Adverse Event Information. For the two tables described in paragraphs (a)(4)(ii)(A) and (B) of this section, a description of each type of serious adverse event and other adverse event that is not a serious adverse event and exceeds a frequency of 5 percent within any arm of the clinical trial, consisting of the following attributes:
(1) Descriptive term for the adverse event; and
(2) Organ system associated with the adverse event.
(E) Adverse Event Data. For the two tables described in paragraphs (a)(4)(ii)(A) and (B) of this section and for each adverse event listed in accordance with paragraph (a)(4)(iii)(D) of this section:
(1) Number of human subjects affected by such adverse event.
(2) Number of human subjects at risk for such adverse event.
(5) Protocol and statistical analysis plan. A copy of the protocol and the statistical analysis plan (if not included in the protocol), including all amendments that have been approved by a human subjects protection review board (if applicable) before the time of submission under this subsection and that apply to all clinical trial Facility Locations. The responsible party must include the Official Title (as defined in § 11.10(b)(2)), NCT number (as defined in § 11.10(a)) (if available), and date of the protocol and the statistical analysis plan on the cover page of each document. The responsible party may redact names, addresses, and other personally identifiable information, as well as any trade secret and/or confidential commercial information (as those terms are defined in the Freedom of Information Act (5 U.S.C. 552) and the Trade Secrets Act (18 U.S.C. 1905)) contained in the protocol or statistical analysis plan prior to submission, unless such information is otherwise required to be submitted under this part. The protocol and statistical analysis plan must be submitted in a common electronic document format specified at https://prsinfo.clinicaltrials.gov.
(6) Administrative information—(i) Results Point of Contact. Point of contact for scientific information about the clinical trial results information, including the following:
(A) Name or official title of the point of contact
(B) Name of the affiliated organization, and
(C) Telephone number and email address of the point of contact.
(ii) Certain Agreements. An indication of whether the principal investigator is an employee of the sponsor and, if not, whether there exists any agreement (other than an agreement solely to comply with applicable provisions of law protecting the privacy of human subjects participating in the clinical trial) between the sponsor or its agent and the principal investigator that restricts in any manner the ability of the principal investigator, after the primary completion date of the clinical trial, to discuss the results of the clinical trial at a scientific meeting or any other public or private forum or to publish in a scientific or academic journal information concerning the results of the clinical trial
(7) Additional clinical trial results information for applicable device clinical trials of unapproved or uncleared device products. (i) For an applicable device clinical trial of an unapproved or uncleared device product and for which clinical trial registration information has not been posted publicly on Clinical Trials.gov by the Director in accordance with § 11.35(b)(2)(i), the responsible party must provide the following data elements, as the data elements are defined in § 11.10(b): Brief Title; Official Title; Brief Summary; Primary Purpose; Study Design; Study Type; Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study; Intervention Name(s); Other Intervention Name(s); Intervention Description; Intervention Type; Device Product Not Approved or Cleared by U.S. FDA, if any studied intervention is a device product; Study Start Date; Primary Completion Date; Study Completion Date, Enrollment; Primary Outcome Measure Information; Secondary Outcome Measure Information; Eligibility Criteria; Sex/Gender; Age Limits; Accepts Healthy Volunteers; Overall Recruitment Status; Why Study Stopped; Name of the Sponsor; Responsible Party, by Official Title; Facility Name and Facility Location, for each participating facility in a clinical trial; Unique Protocol Identification Number; Secondary ID; Human Subjects Protection Review Board Status; and Record Verification Date.
(ii) The responsible party shall submit all the results information specified in paragraph (a)(7)(i) and must submit an affirmation that any information previously submitted to ClinicalTrials.gov for the data elements listed in paragraph (a)(7)(i) of this section have been updated in accordance with § 11.64(a) and are to be included as clinical trial results information.
(b) Pediatric postmarket surveillance of a device product that is not a clinical trial. For each pediatric postmarket surveillance of a device product that is not a clinical trial, the responsible party must submit a copy of any final report that is submitted to FDA as specified in 21 CFR 822.38. The responsible party may redact names, addresses, and other personally identifiable information or commercial confidential information contained in the final report prior to submission to NIH, unless such information is otherwise required to be submitted under this part. The final report must be in a common electronic document format specified at https://prsinfo.clinicaltrials.gov.
(a) Waiver request. (1) A responsible party for an applicable clinical trial with a primary completion date on or after January 18, 2017 may request a waiver from any applicable requirement(s) of this subpart C by submitting a waiver request in the format specified at https://prsinfo.clinicaltrials.gov/ to the Secretary or delegate prior to the deadline specified in § 11.44(a) for submitting clinical trial results information.
(2) The waiver request must contain:
(i) The NCT number, Brief Title, and Name of the Sponsor of the applicable clinical trial for which the waiver is requested;
(ii) The specific requirement(s) of this subpart C for which the waiver is requested; and
(iii) A description of the extraordinary circumstances that the responsible party believes justify the waiver and an explanation of why granting the request would be consistent with the protection of public health or in the interest of national security.
(3) The responsible party will not be required to comply with the specified requirements of this subpart for which a waiver is granted.
(4) The responsible party must comply with any requirements of this subpart for which a waiver is not granted or must submit an appeal as set forth in paragraph (b) of this section. The deadline for submitting any required clinical trial results information will be the later of the original submission deadline or 30 calendar days after the notification of the denial is sent to the responsible party.
(b) Appealing a denied waiver request. (1) A responsible party for an applicable clinical trial with a primary completion date on or after January 18, 2017 may appeal a denied waiver request by submitting an appeal to the Secretary or delegate in the format specified at https://prsinfo.clinicaltrials.gov/ not later than 30 calendar days after the date on which the electronic notification of the denial in paragraph (a)(4) of this section denying the request is sent to the responsible party.
(2) The responsible party is not required to comply with any requirements of this subpart for which a waiver is granted upon appeal.
(3) The responsible party must submit clinical trial results information to comply with any requirements of this subpart that are not waived upon appeal by the later of the original submission deadline or 30 calendar days after the notice of the denial upon appeal is sent to the responsible party.
(c) If a waiver is granted under paragraph (a) or (b) of this section:
(1) The Director will include a notation in the clinical trial record that specified elements of the requirements of this part have been waived.
(2) The Secretary will notify, in writing, the appropriate committees of Congress and provide an explanation for why the waiver was granted, not later than 30 calendar days after any waiver is granted.
(d) A responsible party for an applicable clinical trial with a primary completion date before January 18, 2017 may request a waiver from any applicable requirement(s) for clinical trial results information submission by submitting a waiver request, as specified in section 402(j)(3)(H) of the Public Health Service Act (42 U.S.C. 282(j)(3)(H)).