1. NIH and HHS Proposals: Clinical Trial Disclosure Rebecca J. Williams, Pharm.D., MPH Assistant Director, ClinicalTrials.gov National Library of Medicine, NIH December 9, 2014

2. 2 “Medical advances would not be possible without participants in clinical trials,” said NIH Director Francis S. Collins, M.D., Ph.D. “We owe it to every participant and the public at large to support the maximal use of this knowledge for the greatest benefit to human health. This important commitment from researchers to research participants must always be upheld.” http://www.nih.gov/news/health/nov2014/od-19.htm

3. NIH Policy Proposal Guide Notice: NOT-OD-15-019 NIH-funded awardees & investigators conducting clinical trials, funded in whole or in part by NIH NIH-funded clinical trials must be registered and have summary results, including adverse event information, submitted to ClinicalTrials.gov – NIH revised definition of clinical trial (Oct 2014) Broader than FDAAA “ACT” - includes Phase 1, all intervention types – Same type of registration and results data and in the same timeframes as the trials subject to FDAAA Submit comments by Feb 19, 2015 * 3 NIH Policy Proposal: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-019.htmlhttp://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-019.html Revised NIH Definition of “Clinical Trial”: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.htmlhttp://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html * Submit comments to: clinicaltrials.disseminationpolicy@mail.nih.govclinicaltrials.disseminationpolicy@mail.nih.gov

4. FDAAA: Notice of Proposed Rulemaking (NPRM)

5. Federal Rulemaking Process Consistent with the Administrative Procedures Act [5 U.S.C. 533] 5 Announce in Unified Agenda Agency develops draft NPRM Departmental (HHS) review OMB review Publish in Federal Register Public comment period (ends Feb 19, 2015) Agency response to comments Departmental review OMB reviewPublish final rule Congressional review Rule takes effect We are here

6. NPRM Background and Select Topics Proposed regulations to implement Title VIII of FDAAA fully, including: – Description of procedures for registering and submitting results of clinical trials to ClinicalTrials.gov – Clarifies definitions (e.g., “applicable clinical trial”) – Describes required protocol/results information – Addresses questions identified in FDAAA – Explains Effective and Compliance Dates Note: The NPRM is a proposal and does NOT change current requirements 6

7. Navigating the Federal Register Notice I – X. “Preamble”: Includes background on how decisions were made Section III.C. includes discussion of items considered, but not proposed Section IV. describes items proposed in XI. Codified, including specific form and manner for elements and subelements (e.g., menu options) Requests public comment generally, and on specific issues XI. Codified: Requirements proposed in the regulations format 7 https://federalregister.gov/a/2014-26197

8. Considered but do not propose Example: Disclosure of clinical trial registration information for applicable device clinical trials with uncleared/unlicensed products 1.Allow RP to give, voluntarily, the NIH permission to release clinical trial registration information 2.Allow someone with NCT Number to access a limited set of data elements Preamble: Neither appears to be permissible under the statute 8 NPRM: Section III.C.3

9. FDAAA: Applicable Clinical Trial Applicable Device Clinical Trial – “… comparing an intervention with a device … against a control …” Applicable Drug Clinical Trial – “… a controlled clinical investigation …” 9

10. NPRM: Control or Controlled Definition: “… data collected on human subjects in the clinical trial will be compared to concurrently collected data or to non-concurrently collected data (e.g., historical controls, including a human subject’s baseline data) …” Additional Details: – All multi-arm studies considered “controlled” – Many single-arm studies would implicitly meet definition (change from baseline, using participants as their own control; “response”) 10 NPRM: Section III.C.1; Section IV.A.5

11. Determining if a Trial is an ACT Interventional Study Type Other than Feasibility Study Phase Number of Arms > 2 OR Single Arm Controlled = Yes Controlled Not Combination product Intervention Type Yes Studies FDA- Regulated Device? Facility Location in U.S. OR Product Manufactured in U.S. OR FDA IDE Number FDA Jurisdiction - OR- Yes Pediatric Postmarket Surveillance of a Device? Interventional Study Type Other than Phase 1 Study Phase Number of Arms > 2 OR Single Arm Controlled = Yes Controlled Yes Studies FDA- Regulated Drug? Facility Location in U.S. OR Product Manufactured in U.S. OR FDA IND Number FDA Jurisdiction 11 Use registration data elements to determine if study meets definition of ACT Devices Drugs (and Biologics) NPRM: Section IV.B.2 and 4; IDE = Investigational Device Exemption; IND = Investigational New Drug application

12. NPRM: Protocol Data Elements Existing *Required data elements – Some exceptions: e.g., Oversight Authorities; Human Subjects Review Board details currently not made public (board - approval number, name, affiliation, contact) Most Optional data elements to be *Required – Some exceptions: e.g., Outcome Measure - Safety Issue? New data elements proposed – Mostly related to determining whether an ACT IV.C. describes menu options for elements 12 Source: What Changes From Current Practice Are Proposed in the NPRM? (Nov 2014) http://www.clinicaltrials.gov/ct2/manage-recs/resources#FDAAA2007

13. NPRM: Enroll or Enrolled Definition: “A human subject’s agreement to participate in a clinical trial, as indicated by the signing of the informed consent document(s)” Impacts Study Start Date definition: – “The estimated date on which the clinical trial will be open to enrollment of human subjects.” – “If the clinical trial has enrolled the first human subject, the actual date on which the first human subject was enrolled” – Note: new proposed format of Month Day Year 13 NPRM: Section IV.A.5; Section IV.B.4

14. NPRM: Human Subjects Protection Review Board Status Definition: “information to indicate whether a clinical trial has been approved by a human subjects protection review board or is exempt from human subjects protection review board approval,…” Additional Details: – Pull-down menu (e.g., “Submitted, Approved”) – Status required for all trials (including if IND/IDE) – Will be made public 14 NPRM: Section IV.B.4

15. NPRM: “Outcome” Definitions Primary – The outcome measure of greatest importance specified in the protocol, usually the one(s) used in the power calculation. Secondary – An outcome measure that is of lesser importance than a primary outcome measure, but is part of a pre-specified plan for evaluating the effects of the intervention or interventions under investigation in a clinical trial. 15 NPRM: Section IV.A.5; Section IV.B.4

16. NPRM: Outcome Measure Information Primary and Secondary Outcome Measure Information – Name of the specific measure – Description of the metric used to characterize the specific outcome measure – Time point(s) at which the measurement is assessed for the specific metric used 16 NPRM: Section IV.B.4

17. FDAAA: Completion Date Definition: “the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome, whether the clinical trial concluding according to the pre-specified protocol or was terminated” 17 Note: Currently called Primary Completion Date on ClinicalTrials.gov

18. NPRM: Completion Date Addition to FDAAA Definition: “In the case of … more than one primary outcome measure with different completion dates, this term refers to the data upon which data collection is completed for all of the primary outcomes.” – Note: new proposed format of Month Day Year 18 NPRM: Section IV.A.5; Section IV.B.4

19. Results Submission Additional Issues Addressed in NPRM 19 Topic To Be AddressedNPRM Proposal EXTEND RESULTS SUBMISSION DEADLINE? Extend the deadline for submitting results from 12 to 18 mos. NO. Little support from industry or patient groups NARRATIVE SUMMARIES? Include technical and lay summaries if Secretary determines can be included without being misleading or promotional. DEFERS DECISION. Invites additional public comment PROTOCOLS? Require submission of the full protocol or such information as may be necessary to help to evaluate the results of the trial. DEFERS DECISION. Invites additional public comment. RESULTS FOR UNAPPROVED PRODUCTS? Require results for trials of drugs and devices that have not been approved by FDA? If so, deadline for submitting those results. YES. Due within 12 months of completion date. May delay for up to 2 years w/ certification. 19 NPRM: Section III.C.5 to 8.

20. NPRM: Unapproved Products and Results Requires results submission for ACTs of products not approved, cleared, or licensed for any use Deadline: within 1 year of completion date – Certifications to delay deadline up to 2 years: Drug, biologic, or device is not yet approved by FDA for any use and is still under development Manufacturer is sponsor and will seek approval of new use within 1 year of certification – Extensions for “good cause” also available 20 NPRM: Sections IV.C.2 and 3

21. NPRM: “Initial Approval” and “New Use” Initial Approval – Finished product that is approved or licensed for marketing (not just active ingredient or moiety) – Original marketing application Exception: Only first 510(k) cleared is “initial clearance”; subsequent 510(k)s for the device type are considered “new use” New Use – Supplemental applications 21 NPRM: Section IV.C.3

22. NPRM: Participant Flow Arm Information Pre-assignment Information, if any Participant Data – Number of human subjects that started and completed the clinical trial, by arm 22 NPRM: Section IV.C.4

23. Results: Participant Flow 23 CONSORT Flow Diagram RemuverolPlacebo Started 10199 Completed 8081 Not Completed 2118 Adverse Event 108 Withdrawal by Subject 54 Lost to Follow-up 34 Protocol Violation 22 Pregnancy 10 ClinicalTrials.gov (current) Participants Randomized (n=200) Completed Week 24 (n=80) 79% Placebo (n=99) Remuverol (n=101) Completed Week 24 (n=81) 82% 21 Withdrawals Total 10 Adverse Events 5 Withdrawal by Subject 3 Lost to Follow-up 2 Protocol Violation 1 Pregnancy 18 Withdrawals Total 8 Adverse Events 4 Withdrawal by Subject 4 Lost to Follow-up 2 Protocol Violation 0 Pregnancy Overall Study Fictional parallel design study for illustration purposes

24. NPRM: Baseline Characteristics Arm/Group Information Overall Number of Baseline Participants Baseline Measure Information – Age; Gender – Any other measure(s) assessed at baseline and used in analysis of outcome measures (NEW) – Name/Description; Measure Type; Measure of Dispersion; Unit of Measure Baseline Measure Data 24 NPRM: Section IV.C.4

25. Results: Baseline Characteristics 25 ClinicalTrials.gov (current) RemuverolPlaceboTotal Number of Participants 10199200 Age [units: years] Mean ± Standard Deviation 34.78 ± 9.7235.34 ± 10.7134.98 ± 9.89 Gender [units: participants] Female 6063123 Male 413677 Race/Ethnicity, Custom [units: participants] African American 549 Caucasian 90 180 Hispanic 549 Native American 112 Disease duration [units: years] Mean ± Standard Deviation 3.82 ± 3.183.47 ± 2.953.75 ± 3.06 Short Pain Scale (SPS-11) [units: units on a scale Mean ± Standard Deviation 6.48 ± 1.346.57 ± 1.736.52 ± 1.61 Baseline Measures Fictional parallel design study for illustration purposes

26. NPRM: Outcomes Arm/Group Information Analysis Population Information – Number of Participants Analyzed; Number of Units Analyzed (if); Analysis Population Description Outcome Measure Information – Name/description/time point; Measure Type (and measure of dispersion or precision); Unit of Measure Outcome Measure Data 26 NPRM: Section IV.C.4

27. Results: Outcome Measures 27 Measured Values ClinicalTrials.gov (current) Primary Outcome Measure Title Change from Baseline in Pain on the 11-point Short Pain Scale (SPS-11) at Week 24 Measure Description SPS-11 is a validated, self-reported instrument assessing average pain intensity over the past 24 hour period. Possible scores range from 0 (no pain) to 10 (worst possible pain)... Time Frame Baseline to 52 weeks RemuverolPlacebo Number of Participants Analyzed10199 [units: units on scale] Mean + Standard Deviation-3.84 + 0.61-2.08 + 0.51 Fictional parallel design study for illustration purposes Analysis Population Description Intent to treat population (all participants assigned to each intervention group).

28. NPRM: Adverse Events Two tables: (1) all serious adverse events; (2) all adverse events, other than serious, that exceed a frequency of 5% within any arm – Arm/Comparison Group Information – Total Number Participants Affected and at Risk – Total Number Participants Affected and at Risk, by Organ System (NEW) – Adverse Event Information – Term; Organ System – Adverse Event Data – Number participants affected and at risk 28 NPRM: Section IV.C.4

29. Results: Adverse Events 29 RemuverolPlacebo Total # participants affected/at risk4/101 (3.96%)0/99 (0%) Blood and lymphatic system disorders Anemia †1 1/101 (0.99%)0/99 (0%) Idiopathic Thrombocytopenic Purpura †1 1/101(0.99%) 0/99 (0%) Immune system disorders Viral Meningitis †1 1/101 (0.99%) 0/99 (0%) Skin and subcutaneous tissue disorders Psoriasis †1 1/101 (0.99%) 0/99 (0%) Serious Adverse Events ClinicalTrials.gov (current) † Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (12.0)

30. NPRM: Adverse Events (cont.) Additional items considered, seek comment: – Time frame – Collection approach: systematic or non-systematic – Standard vocabulary for adverse event terms – Total number of occurrences of each event – Attribution (to intervention(s) under study) – All-cause mortality table 30 NPRM: Section III.C.15

31. Quality Control Procedures Intended to help ensure posted information is face valid and does not include obvious errors Electronic notification to the RP when issues identified – RP required to correct within 15 days Submitted information posted within 30 days, regardless of whether issues addressed – NCT Number not assigned until issues addressed 31 NPRM: Section III.C.12

32. NPRM: Final Rule Implementation Effective Date – 45 days after the date final rule is published in Federal Register ClinicalTrials.gov modified Responsible Party would have to submit information in manner consistent with final rule Compliance Date – 90 days after the effective date of the final rule 32 NPRM: Section III.D

33. Rulemaking Process – Next Steps Public comment period ends Feb 19, 2015 – Comments welcome on all aspects of proposed rule; NPRM contains explicit requests for comment on certain topics – Submit written comments to Docket No. NIH- 2011-0003 at http://www.regulations.govhttp://www.regulations.gov HHS will review and address all submitted comments Publish Final Rule 33

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35. NIH Resources NIH Draft Policy – Submit comments by Feb 19, 2015 clinicaltrials.disseminationpolicy@mail.nih.gov http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-019.html NIH Definition of Clinical Trial http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html NIH Office of Extramural Research: What NIH Grantees Need to Know About FDAAA http://grants.nih.gov/ClinicalTrials_fdaaa/

36. ClinicalTrials.gov FDAAA Resources History, Policies, and Laws http://clinicaltrials.gov/ct2/about-site/history#NPRM Submit Studies  FDAAA 801 Requirements http://clinicaltrials.gov/ct2/manage-recs/fdaaa#DevelopmentOfRegulations  Support Materials http://clinicaltrials.gov/ct2/manage-recs/resources#FDAAA2007 NIH: Elaboration of Definitions of Responsible Party and Applicable Clinical Trial (Draft, Mar 2009) NIH: What Changes From Current Practice Are Proposed in the NPRM? (Nov 2014) NIH: NPRM at a Glance: Summary of Key Proposals (Nov 2014)

37. ClinicalTrials.gov PRS Resources Protocol Registration and Results System (PRS) General – Data element definitions – Review criteria – Recorded presentations: http://clinicaltrials.gov/ct2/manage-recs/present http://clinicaltrials.gov/ct2/manage-recs/present Results Submission – Simple results templates – Results data preparation checklists – Example records using common study designs (e.g., parallel, cross- over, factorial, dose escalation) Help [PRS Main Menu and data entry screens] PRS staff: register@clinicaltrials.gov Submit Studies > Support Materials: http://www.clinicaltrials.gov/ct2/manage-recs/resourceshttp://www.clinicaltrials.gov/ct2/manage-recs/resources

38. Questions? Contact us at: register@clinicaltrials.gov