ClinicalTrials.gov and FDAAA for NIH Grantees NIH Regional Seminar – October 2015 Rebecca J. Williams, Pharm.D., MPH Assistant Director, ClinicalTrials.gov National Library of Medicine

Overview Introduction to Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) –Rationale –Requirements ClinicalTrials.gov Practical Considerations –FDAAA Next steps –Protocol Registration and Results System (PRS) –Resources NIH Office of Extramural Research (OER) Resources and Tips 2

Rationale for Trial Registration & Summary Results Reporting

Why Conduct Clinical Trials? To obtain new and generalizable knowledge Key component of the body of scientific evidence that is used to inform medical decision making 4

How It’s Supposed to Work 5 Clinical Trials Informed Decisions Health Outcomes Journals FDA Reviews Systematic Reviews Meta-analyses Guidelines

Three Key Issues Not all trials are published Publications do not always include all pre- specified outcome measures Unacknowledged changes are made to the trial protocol that would affect the interpretation of the findings –e.g., changes to the pre-specified outcome measures 6

Kaplan-Meier estimates for ulcer complications according to traditional definition. Results are truncated after 12 months, no ulcer complications occurred after this period. Adapted from Lu Source: Jüni P, Rutjes AW, Dieppe PA. BMJ Jun 1;324(7349):

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Summary of Findings Fewer than half of NIH funded trials registered at ClinicalTrials.gov after September 2005 and completed by December 2008 were published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion After a median of 51 months after study completion, a third of NIH-funded trials in the sample remained unpublished BMJ 2011;344:d7292 doi

Public Benefits of Access to Clinical Trial Data Meet ethical obligation to human subjects (i.e., that results will be used to help others/inform science) Inform future research and research funding decisions Mitigate information bias (e.g., non publication) Evaluate research integrity (e.g.,adherence to protocol) Prevent duplication of trials of unsafe or ineffective interventions Provide access to data to support evidence-based medicine Enhance patient access to enrollment in clinical trials All contribute to increased public trust in clinical research 10

11 Levels of Transparency 11 Zarin DA, Tse T. Science

About ClinicalTrials.gov Clinical studies registry and results database –Over 198,000 studies (trials & observational studies) –Studies with locations in all 50 states and 190 countries –Privately and publicly funded studies involving humans –Study information submitted by sponsors Web Site & registry launched in February 2000 –Results database, in September 2008 –Over 18,000 studies with results Database updated nightly Usage –98 million page views per month –64,000 visitors per day 12

FDAAA and Other Trial Disclosure Policies

Why Register and Report Results? Required by most medical journals (ICMJE*) –Registration for all clinical trials (all interventions) It is Federal law! (FDAAA 801**) –Registration & results submission for “applicable clinical trials” Encouraged for all NIH-supported trials –Registration & results submission, even if not subject to FDAAA –New NIH Policy Proposal to make this *required* * International Committee of Medical Journal Editors ** Section 801 of the Food and Drug Administration Amendments Act of

Other reasons … Center for Medicare and Medicaid Services (CMS) requires NCT Number for coverage of routine costs of qualifying clinical trials U.S. Department of Veterans Affairs (VA) requires registration and results reporting of VA- funded clinical trials U.S. National Cancer Institute (NCI) requires results reporting in a peer-reviewed scientific journal or ClinicalTrials.gov 15

And more reasons… European Union requires registration and results reporting of certain drug and biologic clinical trials Declaration of Helsinki states that all research studies involving human subjects must be registered & researchers have a responsibility to make research results publicly available World Health Organization (WHO) considers registration a “scientific, ethical and moral responsibility” and states that there is an ethical imperative to report results And others!! 16

17 “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.”

NIH Policy Proposal Guide Notice: NOT-OD 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) Includes Phase 1, all intervention types (broader than “ACT”) –Same type of registration and results data and in the same timeframes as the trials subject to FDAAA Comment period closed March NIH Policy Proposal: Revised NIH Definition of “Clinical Trial”:

NCI Clinical Trial Access Policy Guide Notice: NOT-CA Released: January 28, 2015 – Final Trial Results are expected to be reported in a publicly accessible manner (peer-reviewed scientific journal or ClinicalTrials.gov) within twelve (12) months of the Trial’s Primary Completion Date regardless of whether the clinical trial was completed as planned or terminated earlier Will be incorporated as a Term and Condition of the award 19 NCI = U.S. National Institutes of Health, National Cancer Institute

What does FDAAA 801 require? The responsible party for an applicable clinical trial (ACT) subject to FDAAA must : 1. Register the ACT in ClinicalTrials.gov no later than 21 days after enrollment of the first participant; 2. Update the ACT in ClinicalTrials.gov at least once every 12 months (Recruitment Status and Primary Completion Date within 30 days) 3. Submit summary results (including adverse event information) for certain trials not later than 1 year after the trial’s Primary Completion Date. –Delays allowed in some circumstances 20

The Clinical Trial Lifecycle & ClinicalTrials.gov 21

What Studies to Register? All Clinical Trials (ICMJE) “Applicable Clinical Trials - ACTs”* (FDAAA 801) –Interventional study of drug, biologic, or device Exception: Phase 1 drug trials and small feasibility device trials –US FDA jurisdiction (e.g., US site or IND/IDE) –ACTs initiated on or after 9/27/07 or ongoing as of 12/26/07 *Complete definitions at: 22

Where to Register? ClinicalTrials.gov –Protocol Registration and Results System (PRS) –Log-in at: Interactive data entry or XML upload Tool also available for cancer centers submitting protocol information to NCI Clinical Trials Reporting Program (CTRP) Studies conducted outside the U.S. –Be aware of all local requirements! May also be required to register in local trial registry 23

Prior to Trial Initiation Identify roles and responsibilities Responsible Party* (FDAAA 801) –Sponsor IND/IDE holder; if none, then Person or entity who “initiated” the trial –Funding recipient if grant or sponsored research agreement –Funder if procurement funding agreement (contract) –Sponsor may designate the Principal Investigator (PI) as Responsible Party if PI meets certain requirements (e.g., has access to and control over data, right to publish) *Complete definition at IND/IDE= Investigational New Drug Application/Investigational Device Exemption 24

Prior to Trial Initiation (cont.) Register the trial at ClinicalTrials.gov –Before 1 st participant is enrolled (ICMJE) –Within 21 days of 1 st participant enrolled (FDAAA 801) –Tip: Enter NIH Grant number in record (Secondary ID) FDA Informed Consent Regulations (21 CFR§50.25(c)) –A statement must be included in informed consent documents of applicable clinical trials initiated on or after March 7, 2012 regarding availability of information at ClinicalTrials.gov 21 CFR 50.25(c): FDA Guidance: 25

While the Trial is Ongoing Updates to ClinicalTrials.gov –Required at least once every 12 months (FDAAA 801) Update/verify “active” trials once every 6 mo. (ClinicalTrials.gov) Consider any protocol amendments that impact registration –Recruitment status and (primary) completion date must be updated within 30 days of a change (FDAAA 801) 26

Throughout Trial Lifecycle Certification of Compliance to FDA –Form 3674 must accompany human drug, biological, and device product submissions CMS Medicare National Coverage Determination (NCD) for Routine Costs in Clinical Trials* –Must provide NCT Number if submitting claims for routine costs that occur during a clinical trial –Mandatory as of January 1, 2015 Support Materials: 27

Throughout Trial Lifecycle (cont.) Certification of Compliance to NIH –All grants supporting ACTs; whether grantee is RP or not –See: Competing awards (applications): –SF 424: Part II, section 4.1.6SF 424 –PHS 398: Part II, section 4.1.6PHS 398 Non-competing continuation progress reports: –Research Performance Progress Report (RPPR): All SNAP and non-SNAP awards Section 6.7 of RPPR Instruction Guide available at: Unrelated to the FDA certification of compliance 28

NIH Certification of Compliance: Competing applications and PHS 2590 In the “Human Subjects” section: Add a heading entitled “ClinicalTrials.gov” Under the heading, registered trials provide: –NCT number/s –Brief Title/s –ID and contact info for the RP Under the heading, trials not yet registered: –Include a clear statement that the project includes an ACT which will require registration in ClinicalTrials.gov. 29

NIH Certification of Compliance: RPPR Section G. Special Reporting Requirements G.4.c ClinicalTrials.gov Does this project include one or more applicable clinical trials that must be registered in ClinicalTrials.gov under FDAAA? YesNo If yes, provide the ClinicalTrials.gov Identifier, NCT Number (e.g., NCT ) for those trials. 30

After the Trial “Completes” (NIH/FDA Certifications may still apply) Definitions –Primary Completion Date - PCD (FDAAA 801) “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 concluded according to the prespecified protocol or was terminated.” –Study Completion Date (last subject, last visit) Final date on which data were collected –See ClinicalTrials.gov Protocol Data Element Definitions:

After the Trial “Completes” (cont.) Submit Summary Results (FDAAA 801) –Which Trials? ACTs of FDA-approved or -cleared drugs, biologics, & devices; Initiated on or after 9/27/07 or “ongoing” as of 12/26/07 –When to Submit? < 1 year after PCD (or < 30 days of approval or clearance) Delays possible –Seeking approval of a new use (if Sponsor = manufacturer) –Extensions for “good cause” »Pending publication is not considered “good cause” ACT = applicable clinical trial PCD = primary completion date 32

33 After the Trial “Completes” (cont.) Submit Summary Results –Scientific Information (“per arm”)* Participant Flow Baseline Characteristics Primary and Secondary Outcome Measures –Statistical analyses, as appropriate Adverse Events – Serious and “Other” –Administrative Information Results Point of Contact Certain Agreements (related to investigator’s right to publish, if not an employee of sponsor) * ClinicalTrials.gov Results Data Element Definitions at

FDAAA Results Clarifications Summary results at the end of the trial –No interim or “real-time” reporting –No participant-level reporting Summary results submission not required for: –Registered non-ACTs (e.g., observational, Phase 1) –Trials completed by 12/26/07 Relationship to publication (ICMJE) –Submitting summary results to ClinicalTrials.gov will not interfere with publication* –(But, failing to register the trial will!) * 34

FDAAA Enforcement Provisions Notices of non-compliance Civil monetary penalties (up to $10,000/day) Withholding of NIH grant funds 35

Studies Evaluating Rates of Results Reporting Prayle AP et al. BMJ. 2012: Anderson M et al. N Engl J Med Prayle et al. (2012)Anderson et al. (2015)Anderson et al. (2015) – subsample SampleTrials likely to be subject to FDAAA* completed 1/1/2009 – 12/31/2009 (analyzed Jan 2011) Trials likely to be subject to FDAAA* completed 1/1/2008 – 8/31/2012 (analyzed Sep 2013) Main sample + assessment of approval status of product in trial Trials in Sample73813, Study Follow-up after PCD Up to 2 yearsBy 12 months Up to 5 years Overall Rate of Results Reporting All Trials22%13.4%38.3%-- Industry40%17.0%41.5%79 – 80% NIH8%8.1%38.9%49 – 50% Other7%5.7%27.7%42- 45% 36 * Methods for determining “subject to FDAAA” were different in each analysis and both had limitations

Zarin DA et al. N Engl J Med DOI: /NEJMc Trials by 80 Sponsors Estimated to Be Subject to Proposed Results Reporting.

The ClinicalTrials.gov Results Database

Results: NCT Publication: ClinicalTrials.gov:

Results: Participant Flow 40 Placebo + Prednisone Rituximab + Prednisone STARTED88169 COMPLETED64120 NOT COMPLETED2449 Adverse Event1319 Patients’ Decision511 Physicians’ Decision413 Lost to Follow-up23 Death03 Adapted from Merrill JT et al. Arthrit Rheum 2010 and NCT Publication (CONSORT Flow Diagram) ClinicalTrials.gov Patients Randomized 2:1 (n=257) Completed Week 52 (n=64) 73% Rituximab + Prednisone (n=169) Placebo + Prednisone (n=88) Completed Week 52 (n=120) 71% 24 Withdrawals Total 13 Adverse Events 5 Patients’ Decision 4 Physicians’ Decision 2 Lost to Follow-up 0 Death 49 Withdrawals Total 19 Adverse Events 11 Patients’ Decision 13 Physicians’ Decision 2 Lost to Follow-up 0 Death Period 1: 52 Weeks

Results: Baseline Characteristics 41 Placebo + Prednisone Rituximab + Prednisone Total Number of Participants Age [units: years] Mean (Standard Deviation) 40.5 (12.8)40.2 (11.4)40.3 (11.9) Gender [units: participants] Female Male Race [units: participants] White African American Hispanic Asian/Pacific Islander 5611 Other 224 Disease duration [units: years] Mean (Standard Deviation) 8.7 (7.6)8.5 (7.2)8.6 (7.3) Publication (“Table 1”) ClinicalTrials.gov Baseline Measures Adapted from Merrill JT et al. Arthrit Rheum 2010 and NCT

Results: Outcome Measures 42 Measure Title Participants Achieving Either a Major Clinical Response (MCR) or Partial Clinical Response (PCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over the 52-week Treatment Period Measure Description The BILAG Index is used for measuring clinical disease activity in Systemic Lupus … Time Frame Baseline to 52 weeks Placebo + Prednisone Rituximab + Prednisone Number of Participants Analyzed [units: participants] MCR (excluding PCR)1421 PCR1129 Nonclinical Response63119 Publication “At week 52, no difference was noted in major clinical responses or partial clinical responses between the placebo group (15.9% had a major clinical response …) and the rituximab group (12.4% had a major clinical response …)” Figure 2A. Proportion of patients experiencing a major clinical response (MCR) … at 52 weeks Adapted from Merrill JT et al. Arthrit Rheum 2010 and NCT Measured Values ClinicalTrials.gov Primary Outcome

Results: Adverse Events 43 Placebo + Prednisone Rituximab + Prednisone Total # participants affected/at risk 32/88 (36.36%)68/169 (40.24%) Blood and lymphatic disorders Neutropenia0/88 (0.00%)6/169 (3.55%) Pancytopenia 1/88 (1.14%) 1/169 (0.59%) Haemolytic Anaemia 0/88 (0.00%) 1/169 (0.59%) Lymphophenia 0/88 (0.00%) 1/169 (0.59%) Thrombocytopenia 0/88 (0.00%) 1/169 (0.59%) Cardiac disorders Coronary artery disease …. …… Publication Serious Adverse Events ClinicalTrials.gov

General Review Criteria Protocol and results must be clear and informative Review focuses on: –Logic and internal consistency –Apparent validity –Meaningful entries –Formatting 44

Experience with Results Database Entering results is similar to the process of preparing a journal article Data provider must be familiar with the study design and data analysis –Typically, the investigator and/or a statistician will need to be involved 45

ClinicalTrials.gov Practical Considerations

FDAAA - Next Steps HHS published proposed rule for clinical trial registration and results submission under FDAAA. –Public comment period ended March 2015 –Comments now under review. Draft policy requiring all NIH clinical trial grantees to register and report results published in NOT- OD at: 47

Food and Drug Administration Amendments Act of 2007 Announcement in Department’s Unified Agenda of Regulatory Action Agency Develops Draft Notice of Proposed Rulemaking (NPRM) Department and OMB Review NPRM Published in Federal Register Public Comment Period (typically 60 – 90 days) Agency Responds to Comments/ Develops Final Rule Department and OMB Review Final Rule Published in Federal Register 48 Overview of Rulemaking Process

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 N o t C o m b i n a t i o n p r o d u c t 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 49 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 -OR-

Results Submission Additional Issues Addressed in NPRM 50 Topic 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. 50 NPRM: Section III.C.5 to 8.

PRS Entry of NIH Grant Number 51

PRS Tools Protocol Registration and Results System (PRS) – Main Menu – Record List –Column displays if a record has “Problems” –Allows investigators and administrators of organizational accounts to identify potential problems with records, including potential FDAAA issues: Late results - trials with certain characteristics that reached Primary Completion Date more than one year ago and results are not posted on ClinicalTrials.gov Note: Report is for informational purposes only. The Responsible Party must determine if the trial is an “applicable clinical trial” subject to FDAAA requirements. 52

ClinicalTrials.gov PRS Resources Protocol Registration and Results System (PRS) – General –Data element definitions –Review criteria –Recorded presentations: 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: Submit Studies > Support Materials:

* Outcome Measure Type (Circle One) Primary Secondary Other Pre-specified Post- Hoc Safety Issue? (Circle One) Yes No * Outcome Measure Title Outcome Measure Description * Outcome Measure Time Frame * Arm/Group Title Arm/Group Description * Number of Participants Analyzed Analysis Population Description * Measure Type* Measure of Dispersion/Precision (Circle One) Number Mean Median Least Squares Mean Geometric Mean Log Mean (Circle One) Not Applicable Standard Deviation Inter-Quartile Range Full Range Standard Error 95% Confidence Interval 90% Confidence Interval Geometric Coefficient of Variation [*] Category Title * Unit of Measure Simple Results Templates: Basic Information Needed 54

Results Data Preparation Checklists 55

Recorded Presentations 56 Available at: Six presentations with audio and slides General 1.Overview of ClinicalTrials.gov 2.Key FDAAA Issues Results 3. Participant Flow Module 4. Baseline Characteristics Module 5. Outcome Measures and Statistical Analyses Module 6. Adverse Event Module

Contact Us! If submitting results for the first time, we strongly encourage people to contact us before they begin. Our well-trained staff can provide 1-on-1 assistance with any results submission. us at:

NIH OER Resources and Tips

NIH OER Resources “What NIH Grantees Need to Know about FDAAA” Step-by-step guidance Flowcharts for ascertaining ACTs and RP “At-a-glance” requirements FAQs for NIH Grantees 59

Tips: Take a Team Approach Be aware of your Institution’s approach/SOP Work as a team to identify ACTs and RPs –Sponsored research office, PI, Counsel –Work across institutions –Take actions early to clarify roles and responsibilities NIH’s role –Resources –Cannot make determinations or register/report results on behalf of Grantee or RP 60

Tips: Plan Ahead Are the costs (including staff time) of … reporting … in ClinicalTrials.gov allowable charges on an NIH grant? –Given the nature of this requirement and that the project staff will generally be in the best position to submit and maintain these data, the costs of FDAAA compliance will generally be allowable as direct charges to NIH supported grants. While it is expected that these costs will be covered by the funds provided with the grant, administrative supplements could also be considered. 61 NIH Grants FAQs:

Tips: Manage Risk Wisely Grantee Institutions as Sponsors –Do you have standard operating procedures? Including process for when key staff leave the institution –Training –Monitor compliance How will you ensure trials are registered and results reported? (Some institutions require NCT Number for IRB approval) –Use personnel appropriately to fulfill FDAAA Not necessary to have PI designated as RP in order for him/her to enter data Plan for registration and results reporting early in the trial development process –Implement appropriate record retention 62

Tips: Understand FDAAA Responsible Party must register and submit results for applicable clinical trials (ACTs) –Informed Consent –Updates throughout trial lifecycle –Certifications of Compliance Be attentive to rulemaking –Proposed –Draft policy requiring all NIH clinical trial grantees to register and report results published in NOT-OD

Tips: Create culture of disclosure The NIH encourages registration and results reporting for all NIH-supported clinical trials, regardless of whether or not they are subject to FDAAA FDA Compliance Program : Sponsors, Contract Research Organizations, and Monitors* –Instructs FDA staff to identify SOPs and determine if studies were registered on ClinicalTrials.gov appropriately * 64

NIH Grants Contact Information Division of Grants Policy: – –Phone: Division of Grants Compliance & Oversight: – –Phone:

Select Publications 66 Available at: Zarin DA, Tse T, Ross JS. Trial-results reporting and academic medical centers. N Engl J Med May 20. Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov results database – update and key issues. N Engl J Med 2011; Tse T, Williams RJ, Zarin DA. Reporting basic results in ClinicalTrials.gov. Chest 2009;136:

Additional Resources Contact us: ClinicalTrials.gov information (Submit Studies page): Office of Extramural Research (OER) Food and Drug Administration (FDA) ls/FDAsRoleClinicalTrials.govInformation/default.htm 67