ClinicalTrials.gov: Keeping Up with Evolving Clinical Trial Disclosure Requirements Is your Institution Ready?

Transcription

1 ClinicalTrials.gov: Keeping Up with Evolving Clinical Trial Disclosure Requirements Is your Institution Ready? HCCA Conference June 1, 2015 Diane Lehman Wilson, JD, MPP Regulatory Specialist Office of Regulatory Affairs University of Michigan Medical School Emily Ouellette, JD QA/QI Specialist Quality Improvement Program Partners HealthCare 1 World s largest publicly available clinical trials database 2 1

2 Regulatory context Why clinical trial disclosure is important The evolving nature of the requirements Current Requirements Challenges of Implementation at Academic Centers Heads up: Possible Expansion of Requirements Resources 3 How many of you have experience working within the ClinicalTrials.gov database? How many have institutional offices to assist with ClinicalTrials.gov? How many have institutional policies and procedures re: clinical trial registration and results reporting? 3 2

3 2000: ClinicalTrials.gov launched 2007: Congress passes Law (FDAAA)/ expanding requirements (including results reporting) 2008: ClinicalTrials. gov releases Results Database 2014: CMS requires qualified trials to list NCT #s by 1/1/15 for Medicare claims 2015: NCI issues Clinical Trial Access Policy 1997: FDAMA calls for public registry 2005: ICMJE requires registration of trials 2009: NIH holds public meeting re: possible further expansion of requirements 2014: Proposed NPRM & NIH Policy issued for Public Comment CURRENT: Public comments submitted by March 2015 for HHS/NIH Proposals to enhance transparency Adapted and expanded from : 5 NIH Clinicaltrials.gov NIMH data sharing in real time GWAS data and genetic samples sharing NSF Data Sharing plans required Institute of Medicine Report Jan 2015: Moving from a sharing-optional to sharing-required world Europe AllTrials.net: 83,401 people; 550 orgs; Dartmouth is U.S. lead BMJ requirement: individual level data results must be available on request in order to publish EMA Policy on publication of clinical data WHO position statement on Public Disclosure of Clinical Trial Results 3

4 Transparency For honesty For safety For efficiency Identify clinical trials for participants 7 What s the problem? Not all trials are published Publications do not always include all pre-specified outcome measures or reflect the study design Unacknowledged changes are made to protocols that might affect the interpretation of the findings People are unable to find relevant research protocols 8 4

5 2000 JAMA 6 months 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 Juni, P. et al. BMJ 2002;324: All Things Considered Results of Many Clinical Trials Not Being Reported - March 11, 2015 NEJM: Compliance with Results Reporting at ClinicalTrials.gov N Engl J Med 2015; 372: ; March 12, 2015 Anderson et al. 5

6 CMS Updated from D. Zarin, ClinicalTrials.gov, Overview of ClinicalTrials.gov presentation, December 2008, _Handouts.pdf. 11 FDAAA Public notices of noncompliance Withholding of NIH funds FDA sanctions Civil monetary penalties (up to $10,000/day) ICMJE Cannot publish in ICMJE and other select journals CMS Will reject billing claim 12 6

7 ICMJE is rejecting journal articles - both for no registration as well as late registration. FDAAA enforcement has not yet occurred, but it is simmering! CMS will reject billing claim

8 Enacted December 26, 2007 Required for Applicable Clinical Trials : Interventional trials (drugs, biologics, devices) Phase 2 4 (not phase 1 drug; not small feasibility device) US FDA jurisdiction (e.g. IND/IDE or US site) Studies initiated on or after September 27, 2007 or ongoing as of December 26, 2007 When: Within 21 days of enrollment of 1 st subject Update at least every 12 months FDAAA 801 Requirements: For more detailed guidance, see NIH Elaboration Document: 15 NIH s Elaboration Document: 10 pages long!

9 Is it a Clinical Investigation? Defined as any experiment in which a drug is administered or dispensed to one or more human subjects Is the clinical investigation controlled? Is it designed to permit a comparison of a test intervention with a control to provide a quantitative assessment of the drug effect? Concurrent & Non-concurrent controls Is the clinical investigation other than a phase 1 clinical trial? Per FDAAA, Phase 1 includes initial introduction of an investigational drug into humans, metabolism, and pharmacologic actions of a drug, mechanism of action, and early evidence of effectiveness NIH s Elaboration Document: 17 Is it a prospective study of health outcomes? FDAAA defines health outcome where primary purpose is to evaluate a defined clinical outcome directly related to human health Does the study compare an intervention with a device against a control in human subjects? Intervention defined broadly to include various techniques using the device such as (among other things): device regimens and procedures, use of prophylactic, diagnostic, or therapeutic agents Is the clinical study other than: a small clinical trial to determine the feasibility of a device a clinical trial to test prototype devices (primary outcome measure related to feasibility, not to health outcomes) NIH s Elaboration Document:

10 Required for: Applicable Clinical Trial AND Interventional trials (drugs, biologics, devices) Phase 2 4 (not phase 1 drug; not small feasibility device) US FDA jurisdiction (e.g. IND/IDE or US site) Studies initiated on or after September 2007 or ongoing as of December 26, 2007 Study product approved or cleared (for any use) by FDA When: Within 12 months of primary endpoint completion date Delays are possible If you are the manufacturer seeking initial approval or approval for a new use You request an extension for good cause. *Pending publication is not considered good cause* 19 FDA requires that Applicable Clinical Trials include the following informed consent language: A description of this clinical trial will be available on as required by US law. This website will not include information that can identify you. At most, the website will include a summary of the results. You can search this website at any time. Subjects who were consented before March 7, 2012 will NOT have to be re-consented or otherwise sign addendum consent with this language

11 Registration requirements only Limited ICMJE membership, but journals and growing Many non-member journals also adhere to a comparable requirement See ICMJE FAQs: 21 Which studies are required to register? Any human research project that prospectively assigns human subjects or comparison groups to one or more interventions (Any intervention used to modify a biomedical or health related outcome such as drugs, surgical procedures, devices, behavioral treatments, dietary interventions) to study the cause-and-effect relationship between a medical intervention and a health outcome. (Including any biomedical or health-related measure obtained in participants, including pharmacokinetic measures and adverse events.)

12 Currently requires Registration only When: Prior to enrollment of 1 st subject FAQs say: When in doubt, register. The landscape keeps changing: Recently added language encourages results reporting but retains option for publishers to invoke 500 words as prior publication No worries: results reporting doesn t have that much free text available - currently 23 NIH weighs in The NIH encourages registration and results reporting for all NIH supported clinical trials, regardless of whether or not they are subject to FDAAA. New, broader definition of Clinical Trials NB: Case Studies inition%20of%20clinical%20trial% UPDATED_0.pdf 24 12

13 Mandatory reporting of the NCT# on claims for items and services provided in qualified clinical trials for Medicare coverage. Became effective on January 1, Grace period until January 1, 2015 allowing generic # to be used if NCT# not yet obtained. Now you need the actual NCT#! See MLN/MLNMattersArticles/Downloads/SE1344.pdf 25 What is a qualifying trial? * Purpose of trial must be the evaluation of an item/service that falls within Medicare benefit category (e.g. physicians service, durable medical equipment, diagnostic test) Trial must have therapeutic intent Trial must enroll patients with diagnosed disease not only healthy volunteers * This is summary definition. For a complete definition, see Medicare NCD at

14 CMS 2014 FDAAA Results & AE Reporting (2007 proposed expansion 2015) FDAAA & FDAMA Registration (2007) ICMJE Registration (2005 ) NIH encouragement Looking for Participants (2000) or Want to Share Information

15 ICMJE: Anyone can register, but generally the PI FDAAA: The Responsible Party (RP) defined as IND/IDE holder If no IND/IDE: The industry, cooperative group, consortium or other external sponsor that initiated the study If initiated by a Principal Investigator The grantee institution If no external funding, the PI 29 RP can be designated to the PI if PI: Is responsible for conducting the study Has access to and control over the data Has the right to publish the trial results, AND Has the ability to meet the requirements 30 15

16 31 Effectiveness of Bupropion for Treating Nicotine Dependence in Young People Study Design: Multi-center, Randomized, Efficacy Study Interventions: Bupropion, Placebo Primary Outcome: Smoking behavior over 6 months Pharma funded research UT is a site 32 16

17 Effects of Chronic Sleep Restriction in Young and Older People Study Design: Crossover Assignment Interventions: Chronic sleep restriction Primary Outcomes: Changes in sleep and waking EEG measures, frequent measures of performance, attention, alertness Department funded/ PI initiated research 33 Psychiatric study of different groups of people with different trauma backgrounds using an FDA approved drug to produce background anxiety before exposing them to particular (visual or auditory) stimuli to identify differential impacts of trauma that occurred at different ages. NIH funded research UT is the grantee institution 34 17

18 Implantable device designed to relieve the symptoms of heart failure through counterpulsation technology. Intervention IDE Purpose: to test the feasibility of the device 8 people enrolled, 6 month study Device company funded research/ PI at your institution is the IDE holder

19 Expert team Leadership support Effective way to identify clinical trials Education and on-going communication Common sense delegation Support of results and adverse events reporting Auditing to ensure compliance 37 Keeping in mind: Resources Available Size of Institution Investigators strong focus on publication Investigators are agents of the institution With a strong history and culture of autonomy 38 19

20 Full Service Self Service Automated System Incorporate into hybrid system Investigators are mostly on their own This can vary greatly based on available resources and size of institution 39 Founded by Massachusetts General Hospital and Brigham & Women s Hospital Network of 11 hospitals in MA Partners Human Research Affairs oversees IRB and other systems that support regulatory oversight at MGH & BWH Over 7000 ongoing protocols at MGH & BWH 40 20

21 9 IRBs share eresearch applications system Over 5500 studies, more than 25% Social Research Studies Many NOT doing clinical trials. Don t want to make the IRB application too medical-heavy 41 Policy considerations: Obtaining institutional support Determining appropriate scope for the institution Determination of responsible party Identifying who will be the CT.gov expert in-house Process considerations: Identifying studies that need registration Providing education to researchers Identifying who will input the data Designing internal compliance plan 42 21

22 Become a leader; Develop policies; Create structural support Time consuming; New processes; Feels like unfunded mandate Reputation Enforcement 43 Institutional leverage must include federally mandated FDAAA & CMS Will your institution require registration for other requirements? ICMJE? NIH funded? Studies don t always fit nicely into buckets Difficult to get clarification on requirements. Will your institution parse out all the different requirements? 44 22

23 How will you identify that studies need to be registered? Will there be numerous gate keepers? Will your institution require all clinical trials under any definition to register? Does casting a wider net prevent gaps? 45 Who? FTE? Team? Solely dedicated to CT.gov? Or is CT.gov is one more task of many? What is their scope of work? Where do they sit? Will this be a centralized or decentralized process? How do they train and stay current? 46 23

24 Institution vs. Individual (IND/IDE holder or PI) How and where is the RP designation documented Multi-site or Cooperative Groups Investigator-initiated but Pharma sponsored study Best Practice: Get Responsible Party designation in writing 47 Who will input the data? How will the institution provide database mechanics support to those that are inputting data? Mechanics of ClinicalTrials.gov database are not always easy (especially for infrequent users!) Results reporting is where the centralized/decentralized tension becomes a reality Time consuming PI needs to be involved May need biostatistician support 48 24

25 Providing awareness to the research community of requirements and implications. In person trainings More engaging than slide sets; Websites posting policies once they re developed Guidance Tip sheets for mini-issues can help: e.g. How does one even enter the system to post data? 49 At two levels: 1) Is everything registered that needs to be? 2) Are registered records being maintained? Do you have systematic ways to look for problems and fix them? Does your system proactively prevent problems? 50 25

26 1) How does the PI know if Clinicaltrials.gov requirements apply? 2) Who does the input? (PI, Assistant, Centralized?) Does any backup exist? 3) Who, if anyone, checks the input? 4) Who verifies if the system is working? 51 Additional registration data elements If drug in ACT study is available under expanded access, must submit separate expanded access protocol Results reporting for ALL ACTs (currently only those with approved/cleared products are required to post results) Corrections required to record within 15 days of receipt of CT.gov QA Comments 52 26

27 Delayed posting provisions? Extensions to file what is good cause? How does privacy weigh against AE exposure? Speed of system; posting data before QA? Multiple deadlines 892 comments received 53 All NIH funded clinical trials. must register and post results. Revised NIH clinical trial definition: A research study in which one or more human subjects are prospectively assigned 3 to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. NIH Notice of Revised Definition of Clinical Trial

28 National Clinical Trials Registration Taskforce Various academic centers across the country gather for monthly phone conference to: Share tips Develop tools & expertise Discuss evolution of requirements Learn from the experiences of different academic institutions Interested in joining? Contact Sarah White, Taskforce Chair, at 55 28

29 FDAAA FDAAA related information: Office of Extramural Research (OER): ClinicalTrials.gov Database: General information: For specific questions or comments about the ClinicalTrials.gov database: The National Cancer Institute Policy Ensuring Public Availability of Results from NCI-supported Clinical Trials: ICMJE ICMJE Clinical Trial Registration Requirements: 57 Information on NCT# Requirement Learning-Network- MLN/MLNMattersArticles/Downloads/SE1344.pdf CMS: Medicare Coverage Related to Investigational Device Exemption Studies: In December 2013, CMS finalized changes to the IDE regulations (42 CFR 405 Subpart B), effective January 1, CMS added criteria for coverage of IDE studies and changed from local Medicare Administrative Contractor (MAC) review and approval of IDE studies to a centralized review and approval of IDE studies. An approval for a Category A (Experimental) IDE study will allow coverage of routine care items and services furnished in the study, but not of the Category A device, which is statutorily excluded from coverage. An approval for a Category B (Nonexperimental/investigational) IDE study will allow coverage of the Category B device and the routine care items and services in the trial

30 Institute of Medicine Report: Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk; Released 1/14/