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regard to 14, NIH is proceeding towards enforcement action, which could include holds on
current funding or withholding of future funding.

c. How many times has NIH withheld or blocked any funding due to noncompliance
with ClinicalTrials.gov requirements? Please indicate timing, the number of
sponsors and trials, and whether/when compliance was achieved.

Response: As of February 14, 2023, NIH has not withheld or blocked any funding due to
noncompliance with the clinical trials registration and results information submission
requirements.

d. Has NIH pursued any other remedies, e.g., under 45 CFR 75.371, for failure to
comply with any ClinicalTrials.gov requirements? If so, please indicate the nature of
the action, timing, the number of sponsors and trials, and whether/when compliance
was achieved.

Response: NIH has not pursued any other remedies for failure to comply with any
clinical trials registration and/or results submission requirements; however, NIH does
take its responsibilities in facilitating compliance with these requirements seriously and is
working to identify and resolve any instances of noncompliance.

e. What actions has NIH taken, or will it take, in response to the August 2022 HHS
OIG report to improve monitoring of ClinicalTrials.gov compliance, track trial
funding, and increase intramural and extramural clinical trial results reporting?

Response: NIH has worked in close collaboration with partners within the HHS Office of
General Counsel and the Food and Drug Administration to standardize NIH’s approach
across its ICs for verifying extramural grant recipient compliance with both the NIH
Policy and regulatory requirements pursuant to the Food and Drug Administration
Amendments Act (FDAAA) of 2007. The processes and enhancements NIH has
implemented provide a robust and automated system for centralized tracking of
registration and results reporting information, enabling NIH to take action upon the
notification of a potential violation. To support its process, the NIH has enabled new
internal quarterly reporting to NIH ICs of all NIH grant-funded clinical trials that have
not submitted results information to ClinicalTrials.gov by the required deadline. In
addition, FDA refers reports of potentially noncompliant clinical trials with an apparent
association to NIH, so that NIH can verify if the clinical trial has NIH grant-funding to
take further appropriate action.

The Intramural Research Program (IRP) developed and published NIH Policy Manual
Chapter 3007 (MC 3007), “Clinical Trial Registration and Results Information
Reporting.” It establishes responsibilities and procedures for registration and results
information reporting of IRP-conducted or supported clinical trials to ClinicalTrials.gov
and establishes consequences in the event of noncompliance. As of February 14, 2023,
since the implementation of MC 3007 in January 2022, all intramural trials that have
results expected have submitted results information to ClinicalTrials.gov. The IRP’s


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Thank you, again, for contacting us regarding this important matter.

Sincerely,

Orfeo

Andi Lipstein Fristedt

Deputy Commissioner for

Policy, Legislation, and International Affairs
U.S. Food and Drug Administration

Tara A. Schwetz, Ph.D.
Acting Principal Deputy Director
National Institutes of Health


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from ClinicalTrials.gov, providing one tool that Center BIMO staff can use to identify trials
that appear to be subject to clinical trials registration and results information submission
requirements and that may be noncompliant with those requirements. Although this internal
analytics platform has made it easier to identify potential noncompliance, staff still must
review non-public information to verify whether the clinical trials registration and results
information submission requirements apply to each specific trial. This non-public
information may be submitted to FDA in a variety of formats and is not typically readily
accessible as data, thus requiring manual review. To the extent that automation or other IT
solutions could make this information more readily available, it may further streamline
surveillance activities. FDA is exploring such IT enhancements to our internal analytics
platform. However, automation alone may not eliminate the need for manual review and
confirmation.

For NIH-funded trials, what compliance and enforcement actions has NIH taken with
respect to responsible parties that do not comply with ClinicalTrials.gov requirements?

a. What notices or other communications has NIH provided to responsible parties for
noncompliance with ClinicalTrials.gov requirements? How many such
communications has it provided in each year since these requirements have been
effective?

Response: NIH is actively implementing processes to verify compliance with clinical trials
registration and results information submission requirements by NIH grantees, including
additional enhancements in response to an HHS Office of the Inspector General audit.
Driving NIH’s compliance activities is an automated quarterly report which identifies NIH
grant awards registered in NIH’s Human Subjects System (HSS), for which the results
expected date has passed, so that NIH may identify and address potential noncompliance.

As of February 14, 2023, NIH Institutes and Centers (ICs) have sent initial notices of
potential noncompliance letters to recipients for 317 clinical trials. The NIH Office of Policy
for Extramural Research Administration (OPERA) has sent additional notices of potential
noncompliance to recipients for 48 clinical trials where results information was not submitted
in response to the initial NIH IC notice.

b. How many, or what percentage of, recipients of such communications have come
into full compliance after receipt, and in what period of time?

Response: As of February 14, 2023, of the 317 trials for which initial notices of potential
noncompliance were sent to recipients, 267 trials (81.2 percent) were subsequently
determined to be compliant. Specifically, of those, results information was submitted to
ClinicalTrials.gov for 233 trials, and 34 trials were found to be compliant based upon further
review and receipt of additional information from the recipient.

Of the 317 clinical trials referenced above, results information has not been submitted for 50
trials. Of those, 36 are within their allotted timeframe for providing a response, and with


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experience to date with MC 3007 suggests the new policy is an effective tool to facilitate
intramural compliance with reporting requirements.

NIH will continue to assess compliance statistics over time to ensure that responsible
parties of NIH-funded clinical trials comply with requirements under the NIH Policy and
regulations issued pursuant to FDAAA.

3. FDA’s 2020 guidance states it generally intends to identify ClinicalTrials.gov violations
through evidence collected during BIMO inspections or through complaints received by
the agency. Is it necessary to conduct an inspection or receive a complaint to determine
whether a sponsor or trial is subject to and in compliance with ClinicalTrials.gov
requirements, or is FDA able to more efficiently determine this through other means,
such as review of sponsor submissions or communications with sponsors? How does
FDA most commonly assess compliance?

Response: No, it is generally not necessary to conduct an inspection or receive a complaint
to determine whether a sponsor or trial is subject to and in compliance with the clinical trials
registration and results information submission requirements. FDA’s primary means to
identify potential noncompliance is through surveillance, which typically does not involve
inspection. One surveillance approach includes use of an internal analytics platform that
incorporates data from ClinicalTrials.gov and FDA systems to identify potential cases of
noncompliance, which are then further evaluated by staff to confirm applicability of the
requirements and whether potential noncompliance exists, and to prioritize compliance and
enforcement action based on risk criteria.

FDA has, however, integrated ClinicalTrials.gov compliance as a fundamental part of our
BIMO inspection programs (e.g., inspections conducted of sponsors for review of
information submitted to research and marketing applications). We have generally found a
very high-level of compliance during inspections. Similarly, FDA reviews individual
complaints received about potential noncompliance, but those types of complaints are small
and have resulted in only three Pre-Notice Letters being issued.

4. FDA’s 2020 guidance explains that the agency prioritizes enforcement activities based
on product risk, public health need, compliance history, and whether there are
additional violations of clinical investigation requirements. Please explain how FDA’s
compliance and enforcement actions to date have aligned with this prioritization, taking
into account the trials for which FDA has and has not pursued such actions.

Response:

FDA’s risk-based approach to ClinicalTrials.gov compliance has been evolving over the last
several years, and FDA continues to refine its processes for identifying studies for which
ensuring compliance with the clinical trials registration and results submission requirements
may be of greatest public health benefit. Although many of the Pre-Notice Letters and
Notices of Noncompliance issued meet the risk-criteria, we continue to improve the
alignment of our surveillance activities with those criteria.


—_
U.S. FOOD & DRUG INIH)) National Institutes of Health
ie ADMINISTRATION Turning Discovery into Health

April 11, 2023

The Honorable Frank Pallone, Jr.
Ranking Member

U.S. House of Representatives
Washington, DC 20515

Dear Ranking Member Pallone:

Thank you for your letter of January 19, 2023, regarding reporting of certain clinical trial results
information to the ClinicalTrials.gov database. The Food and Drug Administration (FDA) and
the National Institutes of Health (NIH) support and share the goal of increasing transparency of
information about clinical trials through the ClinicalTrials.gov databank, which in turn may
promote more efficient allocation of research funding by identifying gaps and avoiding
duplication of effort. The databank may also help reduce publication and outcome reporting bias.

When considering the summary results information available on ClinicalTrials.gov, it is
important to recognize that the information required to be submitted is not intended to be as
comprehensive as the safety and efficacy data that are submitted to and reviewed by FDA as part
of a medical product marketing application.

Because the information available on ClinicalTrials.gov is only a subset of the information
submitted to FDA in a marketing application, it is generally not possible to draw conclusions
about either the safety or the efficacy of FDA-regulated medical products based solely on the
limited subset of public information that is available on ClinicalTrials.gov for any specific trial.

We offer responses to your specific questions below:
1. How many Pre-Notices and Notices of Noncompliance has FDA sent?

a. How many, or what percentage of, recipients have come into full compliance after
receipt, and in what period of time?

Response:

As of February 14, 2023, FDA has sent a total of 92 Pre-Notice of Noncompliance Letters
(Pre-Notice Letters). Following publication of the Final Rule for Clinical Trials Registration
and Results Information Submission (42 CFR Part 11) in 2016, FDA implemented processes
and procedures for identifying and evaluating potential noncompliance or noncompliance
with the clinical trials registration and results information submission requirements.
Subsequent to the implementation of those processes and procedures, FDA issued 77 Pre-
Notice Letters and four Notices of Noncompliance regarding potential noncompliance and
noncompliance, respectively, with the clinical trials registration and results information
submission requirements. In addition, prior to implementation of the ClinicalTrials.gov Final


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FDA’s current approach to compliance and enforcement of the clinical trials registration and
results information submission requirements is consistent with other FDA compliance
programs, which generally follow a risk-based approach to prioritization of activities.
Examples of risk-based factors that FDA now uses when evaluating potential noncompliance
with the requirements include:

e The vulnerability of the population under study in the clinical trial (for example, pediatric
or cognitively impaired participants);

e The nature of the product involved in the trial (for example, cytotoxic, permanent
implant, new molecular entities, new therapeutic biological products);

e Whether the product involved in the trial is intended to address a significant public health
need (e.g., COVID-19, monkeypox);

e The risks to subjects participating in the trial;

e Whether the product involved is approved or unapproved;

e Whether ClinicalTrials.gov noncompliance exists in conjunction with noncompliance
with other statutory or regulatory requirements pertaining to the conduct of the trial; and

e Trials for which FDA requires submission of an application (e.g., investigational new
drug application (IND) or investigational device exemption (IDE) application), because
these are inherently higher risk studies.

5. Has FDA approved or cleared premarket submissions that do not include the
certification of ClinicalTrials.gov compliance required by section 402(j)(5)(B) of the
Public Health Service Act? If so, what is the basis for taking such action?

Response: FDA would like to clarify that, although section 402(j)(5)(B) of the Public Health
Service (PHS) Act requires that a certification of ClinicalTrials.gov compliance accompany
certain drug, biological product, and device applications and submissions, neither Title VII
of FDAAA, nor section 402(j) of the PHS Act, nor the implementing regulations in 45 C.F.R.
part 11, provide a legal basis for FDA to refuse to approve, license, or clear marketing
applications or submissions based on the absence of the certification, nor does such a legal
basis exist in the Federal Food, Drug, and Cosmetic (FD&C) Act or its implementing
regulations. However, failing to submit or knowingly submitting a false certification to FDA
is a prohibited act under section 301(jj)(1) of the FD&C Act.

Consistent with our approach across compliance programs, FDA utilizes a risk-based
approach to determine whether to take regulatory or enforcement action. For example, when
considering whether to take action, FDA prioritizes failure to submit the certification
required under section 402(j)(5)(B) of the PHS Act in conjunction with noncompliance with
other statutory and/or regulatory violations over failure to submit the certification without
other noncompliance. This risk-based approach helps ensure that any regulatory or
enforcement action is consistent with FDA’s public health mission and how it approaches
other compliance programs when potential or actual non-compliance is identified.


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Rule, FDA issued 15 Pre-Notice Letters for potential noncompliance with the clinical trials
registration or results information submission requirements.

The Pre-Notice Letters have been largely effective. Over 90 percent of Pre-Notice Letter
recipients have submitted the required clinical trial information without the need for further
action by FDA. The median time for responsible parties to submit the required clinical trial
information is 26 days. In the few instances where FDA has issued a Notice of
Noncompliance, the Notices have also been extremely effective. All of the Notice of
Noncompliance recipients subsequently submitted the required clinical trial information.

b. Are there any Pre-Notice recipients that have not come into full compliance that
have not received a Notice of Noncompliance? If so, please explain.

Response:

As of February 14, 2023, all Pre-Notice Letter recipients that FDA subsequently determined
were not in compliance with the clinical trials registration and/or results information
submission requirements have received a Notice of Noncompliance. FDA is currently
reviewing and assessing the clinical trials referenced in six Pre-Notice Letters to determine
whether there has been a violation and if so, FDA will issue a Notice of Noncompliance
Letter to any non-compliant responsible party.

c. For any recipients of a Pre-Notice or Notice of Noncompliance that have not come
into full compliance, has FDA taken any steps toward imposing civil money
penalties or any other penalties? If not, why not? If so, how many sponsors and
what steps has the agency taken?

Response:

To date, Pre-Notice Letters sent to responsible parties have been largely effective in securing
compliance. Four responsible parties who did not come into full compliance following
receipt of a Pre-Notice Letter received Notices of Noncompliance, and all four have
submitted the required clinical trial information. FDA has not pursued civil money penalties
(CMPs) or any other actions against such responsible parties.

d. How many Pre-Notices and Notices of Noncompliance are for trials that have at
least some federal funding from an HHS agency? How many are for trials for which
NIH is the responsible party?

Response:

To the best of our knowledge, FDA has not issued any Pre-Notice Letters or Notices of
Noncompliance to responsible parties with federal funding from an HHS agency or for which
NIH was a responsible party.

e. Given the large number of trials that appear to be noncompliant and the success of
FDA’s Pre-Notices and Notices of Noncompliance, does FDA plan to send these
letters more frequently in the future? If not, why not?


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Response:

When evaluating compliance rates, it is important to recognize that not all clinical trials
registered on ClinicalTrials.gov are applicable clinical trials subject to the clinical trials
registration and results information submission requirements. The databank includes a
substantial number of records to which these requirements do not apply, such as
observational studies, behavioral intervention studies, and phase 1 drug trials, among others.
Indeed, the majority of trials registered on the ClinicalTrials.gov databank are not applicable
clinical trials subject to the clinical trials registration and results information submission
requirements.

For trials subject to the clinical trials registration and results information submission
requirements, issuing Pre-Notice Letters for potential noncompliance and, where a decision
of noncompliance has been made, Notices of Noncompliance, have been largely effective in
securing compliance and improving submission of clinical trial information to
ClinicalTrials.gov more broadly. As noted above, over 90% of Pre-Notice Letter recipients
have submitted clinical trial information without the need for further action by FDA. FDA’s
approach to compliance and enforcement of the clinical trials registration and results
information submission requirements is consistent with other FDA compliance programs,
which generally prioritize activities using a risk-based approach. When deciding where to
focus limited compliance resources, FDA considers which activities are likely to have the
greatest public health impact and balances resource allocation to ClinicalTrials.gov with
resource needs for other compliance programs, such as evaluating inspection reports of
clinical investigators and other establishments to determine whether there appear to be
violations of the law.

FDA continues to develop its ClinicalTrials.gov compliance program and is always looking
at ways to refine its processes for identifying potential noncompliance and issuing Pre-Notice
Letters and Notices of Noncompliance. We have taken several actions to enhance our
compliance and enforcement program since the final ClinicalTrials.gov regulations went into
effect in January 2017, including developing an internal analytics platform that supports
Center surveillance activities related to ClinicalTrials.gov and establishing routine cross-
Center compliance and enforcement policy coordination. These process improvements have
increased program efficiency. However, there are no specific budget resources dedicated
solely to ClinicalTrials.gov enforcement. As a result, Center staff must balance their
ClinicalTrials.gov work with all other components of FDA’s Bioresearch Monitoring
(BIMO) program that may have greater and more direct public health impact.

f. Are there ways FDA may be able to assess violations more efficiently, for example
with the assistance of automated processes? Please explain.

Response:

FDA continues to explore opportunities to assess violations of the clinical trials registration
and results information submission requirements more efficiently, including by enhancing
our internal analytics platform that supports Center surveillance activities related to
ClinicalTrials.gov. This internal analytics platform incorporates data from FDA systems and