clinicaltrials€¦ · fda clinical trial definition: a clinical investigation or a clinical study...

ClinicalTrials.govEriko Iwatate, MPH, CIP

07.21.20

Outline - ClinicalTrials.gov

What? Why? Which When? How? Support?

COVID19 Pandemic

CREDIT PHAREXIA

COVID19 PandemicNoncompliance

CREDIT PHAREXIA


CREDIT PHAREXIA

•2700 (Interventional + observational) trials registered•1500 (Interventional) trials registered•215 trials completed

# of COVID-19 trials on CT.gov

ONLY 1 COVID-19 Trial Reported Results on CT.govAs of July 21, 2020

DOI:https://doi.org/10.1016/S0140-6736(19)33220-9


$12,103

$12,103US government fines

per day, per trial for any non-compliance

Accessed at http://fdaaa.trialstracker.net/sponsor/university-of-texas-southwestern-medical-center/ on July 2nd, 2020

Watchdog

http://fdaaa.trialstracker.net/sponsor/university-of-texas-southwestern-medical-center/

Watchdog

NIH’s Quality Metrics= “%Success”

Analyzed 70 high volume non-industry organizations ● Organizations with >=15 records

during Jan 2019 - May 2020 included● % Success Range: 33.3% to 95.2%● % Success Median: 60.1%

Top

28 U

nive

rsity

Bot

tom

27

Uni

vers

ity

Median=60.1%

“NIH will withhold clinical trial funding to grantee institutions if the agency is unable to verify adequate registration and results reporting from all trials funded at that institution.”

- Francis Collins, NIH Director

Watchdog

● Compare CT.gov trial record and published article

● Find trials with “outcome switching”● Write letters to the Journal publisher for:

○ Article correction○ Article retraction

Why? Which When? How? Support?What?

ClinicalTrials.govThe largest clinical trial registry & results database run by NIH ● >330,000 registrations

○ UTSW: >700 ● >40,000 posted results

○ UTSW: >130

What? Why? Which? When? How? Support?

Public Site

Protocol Registration & Results Systems (PRS)

Purpose: Disclose key information of clinical trial to general public

Basic function:● Registration● Updates● Results reporting

https://clinicaltrials.gov/ct2/home

https://register.clinicaltrials.gov/prs/app/template/Home.vm?uid=U000539J&ts=194&sid=S0005L16&cx=r7pt9g

What? Which When? How? Support?Why?

What? Why? Who? When? How? Support?Which?

Promises to participants

Declaration of Helsinki

Ethical Obligation

Transparency

Scientific Validity

Replicability

Publication bias

EBM for policymakers

Evidence Based

Medicine

FDAAA-801

42 CFR 11

45 CFR 46116(h) (posting of an approved ICF on CT.gov)

21 CFR §50.25(c)(CT.gov statement included in ICF)

Laws

ICMJE policy(registration and data sharing plan)

Publication

Patients

Physicians

Researchers

Granting agencies

Policy Makers

Resource

NIH policyCMS policyNCI policyWHO policy

Funders -Gates foundation-Global Alliance-Wellcome Trust

Reputation(watchdog website FDAAA TrialsTracker)

Other

https://www.govinfo.gov/content/pkg/PLAW-110publ85/pdf/PLAW-110publ85.pdf#page=82

https://www.federalregister.gov/documents/2016/09/21/2016-22129/clinical-trials-registration-and-results-information-submission

https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=83cd09e1c0f5c6937cd9d7513160fc3f&pitd=20180719&n=pt45.1.46&r=PART&ty=HTML#se45.1.46_1116


https://www.govinfo.gov/content/pkg/CFR-2012-title21-vol1/pdf/CFR-2012-title21-vol1-sec50-25.pdf

http://fdaaa.trialstracker.net/


Transparency

Scientific Validity

Replicability

Publication bias


Evidence Based

Medicine



Ethical Obligation

FDAAA-801

42 CFR 11



Laws


Publication

Patients

Physicians

Researchers

Granting agencies

Policy Makers

Resource




Other








FDAAA-801

42 CFR 11



Laws

Transparency

Scientific Validity

Replicability

Publication bias


Evidence Based

Medicine



Ethical Obligation


Publication

Patients

Physicians

Researchers

Granting agencies

Policy Makers

Resource




Other









Publication

Transparency

Scientific Validity

Replicability

Publication bias


Evidence Based

Medicine

FDAAA-801

42 CFR 11



Laws



Ethical Obligation

Patients

Physicians

Researchers

Granting agencies

Policy Makers

Resource




Other








Patients

Physicians

Researchers

Granting agencies

Policy Makers

Resource

Transparency

Scientific Validity

Replicability

Publication bias


Evidence Based

Medicine

FDAAA-801

42 CFR 11



Laws


Publication



Ethical Obligation




Other











Other

Transparency

Scientific Validity

Replicability

Publication bias


Evidence Based

Medicine

FDAAA-801

42 CFR 11



Laws


Publication

Patients

Physicians

Researchers

Granting agencies

Policy Makers

Resource



Ethical Obligation







What? Why? Who? When? How? Support?

Ethical Obligation

Transparency

Scientific Validity

Replicability

Publication bias


Evidence Based

Medicine

FDAAA-801

42 CFR 11



Laws


Publication

Patients

Physicians

Researchers

Granting agencies

Policy Makers

Resource




Other

Which?









What? Why? When? How? Support?Which?

First Things First….. Is the study a clinical trial?NIH clinical trial definition: A research study in which one or more human subjects are prospectively assigned 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

FDA clinical trial definition: A clinical investigation or a clinical study in which human subject(s) are prospectively assigned, according to a protocol, to one or more interventions (or no intervention) to evaluate the effect(s) of the intervention(s) on biomedical or health-related outcomes

ICMJE clinical trial definition: Any research study that prospectively assignshuman participants or groups of humans to one or more health-related interventions (include drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes) to evaluate the effects on health outcome

First Things First….. Is the study a clinical trial?In general*, you answer “Yes” to all questions, then it is a clinical trial

● Does the study involve human participants?

● Are the participants prospectively assigned to an intervention?

● Is the study designed to evaluate the effect of the intervention on the participants?

● Is the effect being evaluated a health-related biomedical or behavioral outcome?

*Pediatric postmarket surveillance of FDA regulated device product (which does not meet the definition of clinical trials) require registration and result reporting

Registration● PI is IND/IDE holder ● FDA Applicable Clinical Trials● Funded by NIH ● Required by funding agency● Required by CMS ● Required by Journal

What? Why? Which? When How? Support?

Which trials need to be registered and results reported?Results posting● PI is IND/IDE holder ● FDA Applicable Clinical Trials● Funded by NIH ● Required by funding agency● Required by CMS ● Required by Journal

https://prsinfo.clinicaltrials.gov/ACT_Checklist.pdf


Registration● PI is IND/IDE holder ● FDA Applicable Clinical Trials● Funded by NIH ● Required by funding agency● Required by CMS ● Required by Journal


Which trials need to be registered and results reported?Results posting● PI is IND/IDE holder ● FDA Applicable Clinical Trials● Funded by NIH ● Required by funding agency● Required by CMS ● Required by Journal

One trial, One CT.gov recordMulti-site trials registered only once, not by individual sites.

Generally, industry sponsored trials do not need to be registered by UTSW PIPI must coordinate with all collaborators before registering trial!




Key clinical trial requirementsRequirement Trial Phase Type Effective on

Registration Results

Applicable Clinical Trials(ACTs)

Not Phase 1 or small feasibility studies

Drugs, biological and devices regulated by the FDA. Results: Only approved, licensed, cleared product

Primary completion date on or after 12/26/2007


Applicable Clinical Trials(ACTs)

Not Phase 1 or small feasibility studies

Drugs, biological and devices regulated by the FDA.Results: Unapproved, approved, licenced, cleared product

Primary completion date on or after 01/18/2017


Clinical trials funded in whole or in part by the NIH

All All interventional trials (e.g., including behavioral intervention)

Activated for accrual on or after 01/18/2017

Results or Journal publication

Covered trial funded in whole or in part by NCI

All All except for observational

RegistrationData sharing plan

Clinical trials to be published in Journal follows ICMJE recommendation

All All July 1st 2005

FDAAA-801

Final Rule42 CFR Part 11

NIH policy

NCI policy

ICMJE policy


https://clinicaltrials.gov/ct2/manage-recs/fdaaa

https://clinicaltrials.gov/ct2/manage-recs/fdaaa

https://grants.nih.gov/policy/clinical-trials/reporting/understanding/nih-policy.htm

https://grants.nih.gov/grants/guide/notice-files/NOT-CA-15-011.html

http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html

What? Why? Which How?When? Support?

Registration

FDAAA-801 & Final Rule Within 21 days of enrollment

NIH Within 21 days of enrollment

NCI Within 21 days of enrollment

CMS NCT number at the time of claim

ICMJE Before enrollment

UTSW At the time of eIRB study submission


When must trial be registered and results submitted?


https://www.federalregister.gov/documents/2016/09/21/2016-22379/nih-policy-on-the-dissemination-of-nih-funded-clinical-trial-information


https://www.cms.gov/Medicare/Coverage/ClinicalTrialPolicies/index?redirect=/ClinicalTrialPolicies


Registration









“Thank you for submitting your manuscript….to the New England Journal of Medicine.

The International Committee of Medical Journal Editors (ICMJE), and therefore our journal, requires that all clinical trials be registered in a publicly searchable registry before submission for publication. As you did not register your study before the first patient was enrolled, or because it was entered into a registry before that registry was publicly searchable, we are returning it to you without further consideration”

From the editors at NEJM in response to a manuscript submission






Registration Results Posting


Within 12 months of primary completion date
















Registration Results Posting Consequences



Civil or criminal judicial actionsCivil penalties ($12,103/day)Loss of HHS funding



Loss of NIH funding



Loss of NCI funding


Claims will not be paid

ICMJE Before enrollment Refusal to publish



Hold Coverage Analysis FinalizationHold Study Activation (Greenlight)

Consequences for noncompliance



https://www.fda.gov/media/113361/download

https://www.fda.gov/media/113361/download





“Registration and results posting are scientific task rather than administrative task.”- Deborah Zarin, MD, Former Director of CT.gov at NIH

Things to remember…& recommendation1



Registration takes up to 10 hours Review cycle up to 7 daysReviewer comments MUST addressed within 15 calendar daysRecommendations: ● Initiate prior to eIRB study submission● PI/Co-I to complete “Outcome Measure Module” and “Arms/Intervention Module ● PI, Co-I, or designated member of the Study Team to do the rest

2



Registration takes up to 10 hours Review cycle up to 7 daysReviewer comments MUST addressed within 15 calendar daysRecommendations: ● Initiate prior to eIRB study submission● PI/Co-I to complete “Outcome Measure Module” and “Arms/Intervention Module ● PI, Co-I, or designated member of the Study Team to do the rest

2

Results posting takes up to 50 hours (depends on the complexity)Review cycle up to 30 daysReviewer comments MUST addressed within 25 calendar daysRecommendations: ● Enter results 3-4 months before due date● PI or Biostatistician to do results posting

2

Results due within 12 months of primary completion date

“Verification”(Continuing Review)

“Updates/Correction”(Modification)

FDAAA-801 Not less than once every 12 months(even no changes)

Within 30 calendar days after changes of:- Overall recruitment status - Actual primary completion date

Final Rule Not less than once every 12 months(even no changes)

Within 15 calendar days after changes of:- Device approval/clearance status- Actual primary completion dateWithin 30 calendar days after changes of:

When must ACTs information be verified or updated?


-primary completion date-study start date-intervention name-availability expanded access-expanded access status/type-individual site status

-IRB status -responsible party and/or contact information-overall recruitment status -Protocol changes that impact registration information



eIRB and CT.gov clinical trial timelineStage of Trial

Bef

ore

Tria

lD

urin

g Tr

ial

Afte

r Tria

leIRB CT.gov

Request access to eResearch

Register trial in Velos

Trial Initiation

Trial CompletionData Analysis

Publication

Protocol Amendments

Trial pushed to eIRB, submit trial in eIRB,

address ER/Board stipulations

Annual record verification● Record verification date● Recruitment status● Completion date

Posting approved unsigned ICF

Results submission● Protocol● Statistical Analysis Plan

Time

Register, release (submit), address PRS reviewer’s comments,obtain NCT#

Modification

Trial approval

Continuing review

Notice of study closure

Obtain PRS account ID

Update Record

Trial approval/public


What? Why? Which When? How? Support?

Trial registration and results system workflowDetermine whether trial requires

registration / result posting

Decide Record Owner &Responsible Party (PI)

Obtain Protocol Registration and Results System (PRS) account

Log in to PRS

Create a new recordEnter study information

PI Approve/Release (submit) record to CT.gov for PRS review

CT.gov PRS review

Address requested changes within 15 calendar days

Record is public

Keep record up to date

Enter results if required PI Approve/Release

to CT.gov for PRS review

CT.gov PRS review

Address requested changeswithin 25 calendar days

Results are public


https://clinicaltrials.gov/ct2/manage-recs/how-apply

https://register.clinicaltrials.gov/prs/app/template/Home.vm?uid=U000539J&ts=194&sid=S0005L16&cx=r7pt9g

https://prsinfo.clinicaltrials.gov/tutorial/content4/index.html#/

UTSW ClinicalTrials.gov Program


Research team-Regulatory guidance-Determination of ACTs

CT.gov processes-PRS Navigation-Registration-Result posting-Updates-ICF posting

ProvideTraining

Assist with user account creation

Assist PRS navigation during registration

Assist with resolving PRS reviewer comments*scientific inquiry must be addressed by investigators

Assist with Registration

Send annual record verification reminders

Assist PRS navigation during record updates

Assist with Updates

Send results reporting reminders

Assist PRS navigation during result reporting

Assist with resolving PRS reviewer comments*scientific inquiry must be addressed by investigators

Assist with Results

Generate monthly compliance metric:# problem records# late results # published# pending PRS reviews

Generate Metric

Develop policy, guidance, checklist(s)

Add CT.gov section in eIRB, develop “Form-CT.gov”

Assist with record transfer

Assist with problem records

One-on-one guidance /office hour

Other

UTSW ClinicalTrials.gov Program (under construction)


Communication ProcessEmail/Phone PI/

Record Owner

Access List Members

Dept Research Manager / Dept. PRS Administrator

HRPP(IRB) Director

Division Director or Department Chair

Vice Provost Dean of Research

Stage #1

Stage #2

Stage #3

Stage #4

Take Home Message and Homework….

● Request a PRS User Account for PI and anyone helping

Send following information to [email protected]

● Name ● Username (UTSW ID that is assigned)● Email address● Department

mailto:[email protected]

● Request a PRS User Account for PI and anyone helping ● Make PI the Responsible Party (for existing study records)● Add research staff in “Access List”● Mark your calendar for results posting and annual update!● Review flow chart● Review selected resources on next slide



● Request a PRS User Account for PI and anyone helping ● Make PI the Responsible Party (for existing study records)● Add research staff in “Access List”

● Add research staff in “Access List”● Mark your calendar for results posting and annual update!● Review flow chart● Review selected resources on next Slide


● Request a PRS User Account for PI and anyone helping ● Make PI the Responsible Party (for existing study records)● Add research staff in “Access List”● Mark your calendar for results

posting and annual update!● Review flow chart● Review selected resources on next slide● Ask if you have questions! [email protected]




posting and annual update!● Review flow chart ● Review selected resources on next slide● Ask if you have questions!



posting and annual update!● Review flow chart ● Review selected resources on next slide● Ask if you have questions! [email protected]


Selected List of Resources● CT.gov Submit Studies Page

○ https://clinicaltrials.gov/ct2/manage-recs/submit-study● PRS User’s Guide

○ https://prsinfo.clinicaltrials.gov/prs-users-guide.html● PRS Guided Tutorials

○ https://prsinfo.clinicaltrials.gov/tutorial/content4/index.html#/● Data Element Definition Documents, Templates and Checklists

○ https://clinicaltrials.gov/ct2/manage-recs/resources#DataElement● Results Quality Control Review Criteria

○ https://prsinfo.clinicaltrials.gov/ResultsDetailedReviewItems.pdf

https://clinicaltrials.gov/ct2/manage-recs/submit-study

https://prsinfo.clinicaltrials.gov/prs-users-guide.html

https://prsinfo.clinicaltrials.gov/tutorial/content4/index.html#/

https://clinicaltrials.gov/ct2/manage-recs/resources#DataElement

https://prsinfo.clinicaltrials.gov/ResultsDetailedReviewItems.pdf

Contact Person for CT.gov Related Issues


Eriko Iwatate [email protected]

Susan Patridge [email protected]

Victoria Brown [email protected]






