Disclosure Requirements for ClinicalTrials.gov: Your FAQs Answered (Part 2)

Barbara Godlew
President, The FAIRE Company, LLC
December 7th, 2012

Disclaimer: This information is intended to provide an overview of the current state of clinical trial registration and results disclosure. Regulatory requirements are paraphrased for clearer communication. Sponsors/institutions should consult their Legal, Regulatory Affairs, and/or Clinical Trials Office departments for institutional practice and policy.*

Barbara Godlew, President of The FAIRE Company, LLC, answers the questions received from attendees of the webinar “Disclosure Requirements for ClinicalTrials.gov: What Institutions Need to Know.” This is the second part in a two-part series of FAQs related to clinical trial disclosure requirements for ClinicalTrials.gov.

Q:  A ClinicalTrials.gov record is flagged since it is time to upload results. However, the PI is still in the process of analyzing the data and writing the manuscript and does not want to publicly publish the results until accepted for publication.  What should be done? Do you have to post anyway? Can you postpone the posting of results until a publication is accepted?

A:  The International Committee of Medical Journal Editors has indicated that they will not consider publishing results to ClinicalTrials.gov as “pre-publication.” Click here to view their FAQs.

One can ask for an extension/delay in disclosing results by contacting the ClinicalTrials.gov staff (register@clinicaltrials.gov), but the request would need to meet their definition of “good cause” and publication issues are generally excluded from that definition.

The data should be reported on ClinicalTrials.gov as soon as possible. Communication with the journal regarding the legal obligatory requirements may also be useful. It’s unlikely that the journal would refuse a manuscript when the institution/investigator is mandated by law to disclose publicly. However, if the trial was not registered according to the journal requirements (generally prior to enrollment of first participant), the journal may take issue with that and reject the manuscript on that basis.

Q:  What is the difference between “Primary Completion Date” and “Study Completion Date.”

A: “Primary Completion Date” is 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. In many oncology trials, this will be different from the “Study Completion Date” because many primary outcome measures have shorter time frames than secondary outcome measures. For example, a primary outcome measure may be tumor progression at 6 months whereas a secondary outcome measure may be survival rates at 5 years.

“Study Completion Date” is the final date on which data was collected. This may coincide with Primary Completion Date, depending upon whether the time frames for the primary outcome measures and the secondary outcome measures were the same or different.  

Q:  You mentioned software that works with the ClinicalTrials.gov database for uploading registries and results. Could you please tell me again what that software is called? 

A: There are  tools that ease the process for registration and results reporting. The first is a clinical trial management system (CTMS), which stores the data in one repository to make the registration of your trial easier. Forte offers OnCore, a comprehensive eClinical solution for this purpose. For more information, you can visit the OnCore home page. There are also software vendors, including Virtify, Inc., that provide a specialized solution for disclosure compliance with ClinicalTrials.gov requirements. Virtify offers the Clinical Trials Registration and Results tool (which integrates with Forte’s OnCore solution, but also acts independently).

Learn more ways a CTMS, like OnCore, can help you maintain compliant regulatory practices. Download the case study.

Q Is reporting of trial data for Phase I in Oncology trials required or does that apply only to phase 1 normal healthy volunteer studies?

A:  At this time, results of Phase I trials are not required to be reported per FDAAA regardless of whether conducted in patients or healthy volunteers. Phase I trials conducted in patients with serious/life-threatening diseases may need to be registered to ClinicalTrials.gov if they meet other criteria in FDAMA.

Q:  Results reporting requirement for approved vs. unapproved drugs. Can you please clarify if both are currently required to report?

A:  FDAAA requires the reporting of summary results information no later than 1 year after the completion date for registered applicable clinical trials involving drugs that are approved under section 505 of the Food, Drug and Cosmetic Act (FDCA) or licensed under section 351 of the PHS Act, biologics, or of devices that are cleared under section 510k of FDCA.  However, NIH encourages results reporting for all NIH-supported clinical trials registered in ClinicalTrials.gov, regardless of whether or not they are required under FDAAA.

Q:  In terms of more detailed advice/training on results entry, especially for oncology trials, is there any one program you would recommend more than another? We have found that the way in which our data have been collected does not necessarily fit with how ClinicalTrials.gov asks for the information?

A:  Currently, I am not aware of any firm that conducts formalized training on entering data into ClinicalTrials.gov other than that offered by the NLM to Clinical and Translational Science Awards recipients. If you are having difficulty resolving errors within a ClinicalTrials.gov record, you may request a teleconference with members of the ClinicalTrials.gov staff for assistance. If you receive an appointment with ClinicalTrials.gov, please ensure that the investigator, trial statistician, and trial manager are on the teleconference to answer questions. As a consultant, I have conducted these full-day workshops in the past, but am not aware of others working with academic centers doing so.  

Q:  Can you explain again how a Phase I study might be an “applicable trial” and in what section of FDAMA this relates to?

A:  FDAMA Section 113 requires registration of clinical trials conducted under an investigational new drug (IND) application for a drug to treat a serious or life-threatening disease or condition if the trial has efficacy endpoints. (Guidance for Industry Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions; Section III A.) Although not all trials carried out under 21 CFR part 312 test effectiveness, FDA considers all phase 2, phase 3, and phase 4 trials with efficacy endpoints as trials to test effectiveness. (Guidance for Industry Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions; Section III E.) Note that FDAMA does not specifically exclude Phase I studies. If a Phase I study has efficacy endpoints (e.g., Phase I trial of a drug [under an IND] to test the effectiveness of Drug A on tumor progression in patients), it could qualify for registration.

Q:  Do the consent form requirements apply to both FDAAA and FDAMA, or FDAAA only (i.e., Phase I trials with efficacy endpoints)?

A: The requirement for this provision was included in FDAAA Section 801. For applicable clinical trials initiated on or after March 7, 2012, informed consent documents must be in compliance with the new requirement in 21 CFR § 50.25(c) and include a specific statement that refers to the trial’s description on www.ClinicalTrials.gov. If, however, the informed consent is used for non-applicable clinical trials, you may be required to post information to ClinicalTrials.gov according to the new informed consent language.

Q:  Are interventional studies with approved meds, used for approved label uses, have the same scrutiny that IND and NDE studies, as far as registration and results reporting goes?

A:  It is my understanding that all applicable clinical trials receive the same level of review from the ClinicalTrials.gov staff.

Q:  I understand that there are requirements for reporting results of trials that involve drugs or devices, but what about radiation? Where does that fit in (because that is all we do)? 

A:  If the radiation is an intervention in an applicable clinical trial, it would require registration and results reporting. If the radiation involves an applicable device trial, (see the definition of applicable device trial in the Elaboration of Definitions of Responsible Party and Applicable Clinical Trial document), it may be eligible for delayed registration and results reporting. For additional clarification, please contact ClinicalTrials.gov at register@clinicaltrials.gov or Jarilyn Dupont (jarilyn.dupont@fda.hhs.gov) at the FDA. The ICMJE policy may differ from Federal regulation. Click here to view ICMJE requirements.

Q:  Do lab draws that don’t change the plan of care (only for data collection) need to be reported? 

A:  Unless the method for drawing the specimen includes an applicable clinical device trial in human subjects, the Elaboration of Definitions of Responsible Party and Applicable Clinical Trial document suggests for purposes only of the requirements under 402(j) of the PHS Act, the definition of human subject does not apply to de‐identified human specimens. For additional clarification, please contact ClinicalTrials.gov at register@clinicaltrials.gov or Jarilyn Dupont (jarilyn.dupont@fda.hhs.gov) at the FDA.  The ICMJE policy may differ from Federal regulation. Click here to view ICMJE requirements.

Q: Is there additional training available for navigating Clinicaltrials.gov? 

A:  Currently, I am not aware of any firm that conducts formalized training on entering data into ClinicalTrials.gov other than that offered by the NLM to Clinical and Translational Science Awards recipients. If you are having difficulty resolving errors within a ClinicalTrials.gov record, you may request a teleconference with members of the ClinicalTrials.gov staff for assistance. If you receive an appointment with ClinicalTrials.gov, please ensure that the investigator, trial statistician, and trial manager are on the teleconference to answer questions. As a consultant, I have conducted these full-day workshops in the past, but am not aware of others working with academic centers or research organizations doing so.

Q:  We are starting a small industry sponsored phase 1 safety/feasibility clinical trial (20 patients) using an FDA-approved device for an on-label indication in cancer patients. Sounds like we need to register based on FDAMA, but not by FDAAA. Can you clarify if we need to register and/or report on ClinicalTrials.gov? 

A:  Based on the question, I am making the assumption that you are starting a study of a drug using an FDA-approved device. FDAMA does not address device studies. However, if the device has a drug imbedded within it (ie, drug-eluding stents) or a drug is being delivered via the device, it may be required to be registered according to FDAMA if the trial has efficacy endpoints and meets the other requirements of FDAMA. Phase 1 trials do not need results reported on ClinicalTrials.gov at this time.

Q:  I was under the impression that only primary outcome measures had to be included on the registry.  But as it was presented today it sounds like any secondary outcome measures in the protocol must be included in the registry as well, correct? 

A:  FDAAA requires the registration and reporting of all primary and secondary outcome measures.

Q:  Regarding “Primary Completion Date,” I am confused as to what date to put for that field. 

A:  “Primary Completion Date” is 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. In many oncology trials, this will be different from the “Study Completion Date” because many primary outcome measures have shorter time frames than secondary outcome measures. “Study Completion Date” is the final date on which data was collected. This may coincide with Primary Completion Date, depending upon whether the timeframes for the primary outcome measures and the secondary outcome measures were the same or different.

Q:  If a community hospital is performing an interventional trial using dietary supplements would that require registration?   

A: If the dietary supplement falls under FDA jurisdiction and meets the other requirement of an applicable clinical trial, it will require registration and possibly results reporting.

Discover more free regulatory & compliance resources on the Forte Clinical Research Blog.

Q:  Please go over the results reporting timeline (12 months after primary outcome). 

A:  Results of applicable clinical trials must be reported within 12 months following the primary completion date. Primary Completion Date is 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 pre-specified protocol or was terminated. “Study Completion Date” is the final date on which data was collected. This may coincide with Primary Completion Date, depending upon whether the timeframes for the primary outcome measures and the secondary outcome measures were the same or different.

Q:  If a non-ACT is posted onto ClinicalTrials.gov, is the new consent language required? 

A:  Non-applicable clinical trials are not subject to the new consent language. If, however, the informed consent is used for non-applicable clinical trials, you may be required to post information to ClinicalTrials.gov according to the new informed consent language.

Q:  Can you go over the requirement of registration for phase I trials for serious illnesses? Can you give an example of such a trial?

A:  FDAMA Section 113 requires registration of clinical trials conducted under an investigational new drug (IND) application for a drug to treat a serious or life-threatening disease or condition and also tests effectiveness. (Guidance for Industry Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions; Section III A.) Although not all trials carried out under 21 CFR part 312 test effectiveness, FDA considers all phase 2, phase 3, and phase 4 trials with efficacy endpoints as trials to test effectiveness. (Guidance for Industry Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions; Section III E.) Note that FDAMA does not specifically exclude Phase I studies. If a Phase I study has efficacy endpoints (eg, Phase I trial of a drug [under an IND] to test the effectiveness of Drug A on tumor progression in patients), it could qualify for registration.

NCT01060514 appears to be a possible example of this type of trial, although I cannot determine from the public view of ClinicalTrials.gov if it meets all requirements of FDAMA (e.g., was if filed under an IND?).

Q:  Do Phase II-IV trials of drugs, biologics, or devices not approved by FDA need to be registered?  

A:  Any Phase II-IV drug/biologic trial that is a controlled clinical investigation that investigates a drug that falls under FDA jurisdiction (ie, applicable clinical trial) must be registered whether for an approved or unapproved product/use/indication. Device studies that are prospective clinical studies of health outcomes AND compares an intervention with a device against a control in human subjects AND is subject to Section 510(k), 515, 520(m) of the FDC Act AND is NOT a small device feasibility study or clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not health outcomes must be registered.

Q:  Regarding results reporting, what about an oncology trial where the primary endpoint is “time to local recurrence?” 

A:  The primary outcome measure should have an estimated time frame.

Q:  Are you saying that trial results should be posted online at ClinicalTrials.gov before the manuscript is accepted by the journal? 

A:  Trial results of applicable clinical trials must be posted within 12 months of the primary completion date regardless of publication status. If publication occurs outside of this time frame and the results of the applicable clinical trial are not posted, the institution is at risk for noncompliance penalties.

Q:  Regarding registering a trial on ClinicalTrials.gov, in a multicenter trial, is the PI at the lead site responsible, or the sponsor? 

A:  In a multicenter trial in which the Sponsor initiates the trial and its employees conduct the trial, the Sponsor generally registers the trial. The Sponsor, however, may designate the PI to be the Responsible Party and to be responsible for registering the trial. NIH/FDA considers holders of an IND or IDE the Responsible Party.

Q:  We were told NOT to use the new ICF language for non-ACTs. Is there anything wrong with using the new ICF language even if it is not an ACT? 

A:  The requirement for this provision was included in FDAAA Section 801. For applicable clinical trials initiated on or after March 7, 2012, informed consent documents must be in compliance with the new requirement in 21 CFR § 50.25(c) and include a specific statement that refers to the trial’s description on www.ClinicalTrials.gov. If, however, the informed consent is used for non-applicable clinical trials, you may be required to post information to ClinicalTrials.gov according to the new informed consent language.

Q:  I have an additional question regarding H.R. 6272 TEST Act.  You mentioned, I believe, that this act is scheduled to go into effect sometime in 2013, correct? Is that when compliance will start being enforced with it or will there be a grace period?  I pulled up the act and read it this morning. If I read correctly, investigators will also have to start uploading their consent documents, protocol and protocol revisions/amendments? 

A: The TEST Act is currently only in bill form and is not a law. It has been prioritized by Rep. Markey for 2013, which means it will probably be brought into Committee early in 2013 for changes, votes, etc.

Q:  Who is responsible for registering trials on ClinicalTrials.gov – the Sponsor or the Principle Investigator on a multi-site trial? Or satellite Principle Investigators? If trials are NOT registered, who will be held liable? Is it the Institution’s IRB or Site Principle Investigator or Sponsor or The Principle Investigator listed on the Study Protocol?  

A:  The responsibility for registering trials to ClinicalTrials.gov depends upon a number of things. The Sponsor (usually the pharma/biotech/medical device company) that initiates the trial and its employees conducting the trial is the entity that registers the trial. For multicenter trials, it is often the Sponsor, but could also be someone who initiates the trial and has someone else (ie, CRO) conduct the trial. The Sponsor, however, may also designate the PI to be the Responsible Party and to be responsible for registering the trial. NIH/FDA considers holders of an IND or IDE the sponsor/responsible party (i.e., sponsor-investigator).

If your institution is only one of many taking part in a multicenter trial in which the Sponsor is a pharmaceutical company, it is most often the pharmaceutical company that will hold the IND/IDE and will register the trial. However, each academic medical center/academic research organization should verify that this is the case as stipulated in their contract with the company.

In terms of who is held responsible, FDAAA does not have a provision for this and that responsibility will most likely (or should) be determined in agreements between investigators, IRBs, academic medical institutions/academic research organizations, and sponsors, etc.

Q: The International Committee of Medical Journal Editors has indicated that they will not consider publishing to ClinicalTrials.gov as “pre-publication.”

A:  Click here to view their FAQs. One can ask for an extension/delay in disclosing results by contacting the ClinicalTrials.gov staff (register@clinicaltrials.gov), but the request would need to meet their definition of “good cause” and publication issues are generally excluded from that definition. The data should be reported on ClinicalTrials.gov as soon as possible. Communication with the journal regarding the legal obligatory requirements may also be useful. It’s unlikely that the journal would refuse a manuscript when the institution/investigator is mandated by law to disclose publicly. However, if the trial was not registered according to the journal requirements (generally prior to enrollment of first participant), the journal may take issue with that and reject the manuscript on that basis.

Q:  I recently had an email about whether or not our university is auditing ClinicalTrials.gov submissions. The person said she had been trying to research this and was finding that not many people actually audited submissions. I was wondering if you had any further information on this? 

A:  I’m not entirely sure about the email regarding auditing ClinicalTrials.gov submissions. I have participated with the DIA and others to construct a survey that deals with disclosure operations and policies for both industry and academia. Perhaps this is what you mean? In my experience, I have found that academic medical institutions/academic research organizations lag substantially behind in terms of preparing protocol registrations/results records and generally have not constructed institutional disclosure policies and compliance tracking to minimize risk to the organization. This is the type of work I do (although I choose the term “assess” rather than audit because I am not an accountant and do not do financial risk audits) and I am currently working with both industry and academia to assist them with their disclosure efforts.

Q Our university has all of the PIs that register studies in ClinicalTrials.gov put the University down as the sponsor in order for us to maintain control and be able to remind the PIs when studies come up needing attention. The definition says that the Responsible Party (RP) should be whoever has access to the results. The only time we have ever had difficulty is when a PI leaves the university unexpectedly. I was wondering what were your thoughts on the PI being the RP versus the institution being the RP. Our thought was since the University was the RP by virtue of being the IND/IDE [holder], we would make them all be the University as the RP so that we would know when studies needed attention and when they were updated.  

A: Some institutions function in the manner you describe (ie, University as Responsible Party) regarding who retains responsibility for registering the trial and reporting the results and it seems to work well in some cases. However, if your institution is conducting a large number of trials, this method may be overwhelming to the person managing notifications from ClinicalTrials.gov about individual clinical trials.

For clinical trials conducted under an IND:

According to the Elaboration of Definitions of Responsible Party and Applicable Clinical Trial document, a Sponsor is an entity that initiates a clinical investigation, but does not actually conduct the investigation. Examples of Sponsors could include individuals, corporations, academic medical centers, grantee contractors, awardees, and so on. If the entity holds the IND and is something other than an individual (e.g., academic medical center) and uses its own employee(s) to conduct a clinical investigation, that entity is considered to be a Sponsor (not a Sponsor-Investigator), and the employees are considered investigators. Sponsors may delegate authority to Principal Investigators to be the Responsible Party.

Additionally, Sponsors may choose to retain the role of Responsible Party if the Principal Investigator cannot be designated as the Responsible Party (e.g., cannot or does not have access to and control over the data, does not have the right to publish the results of the trial, or cannot meet all of the requirements for the submission of clinical trial information).

A Sponsor-Investigator is an individual who both initiates and actually conducts, alone or with others, a clinical investigation. Sponsor-Investigators who hold INDs are considered the Responsible Party.

For clinical trials NOT conducted under an IND:

The Sponsor is the person/entity that initiated the trial. If the person/entity received research assistance funding such as a grant or sponsored research agreement, the funding recipient generally will be considered the Sponsor. The Sponsor is the Responsible Party unless it delegates that role to the Principal Investigator. If the clinical trial is conducted by an entity under a procurement funding agreement (e.g., a contract), the funder is generally considered the Sponsor. The Sponsor is the Responsible Party unless it delegates that role to the Principal Investigator.

If no funding agreement supports the clinical trial, the person/entity who initiates the trial (i.e., prepared and/or planned the trial) and has appropriate authority/control over the trial to carry out the responsibilities under FDAAA, that person/entity is the Sponsor and the Responsible Party. The Sponsor may delegate the Principal Investigator to be the Responsible Party.

QI also would like to have more information on the www.diahome.org organization. Currently, funding is an issue, so the more information that I can provide on how this team/organization will be of benefit to the University [will enable me] to justify the $175.00 fee.    

A:  Regarding the Drug Information Association’s Clinical Trial Disclosure Special Interest Area Community (SIAC): This link will take you to the public face of our organization within DI. DIA is a neutral global nonprofit association that provides knowledge resources across the full spectrum of medical product development. As a SIAC, we have grown from 7 members in 2005 to more than 250 members from many areas of clinical research. Within the SIAC, we have industry representatives (with regulatory, clinical, clinical operations, medical writing, and statistical backgrounds), journal representation, academic medical institution clinical trial managers and leadership from Clinical Trial Offices, ClinicalTrials.gov staff as well as other US and ex-US regulatory authority representatives.

ClinicalTrials.gov staff attends our meetings, which occur monthly, and have a standing agenda item for updates as well as clarifying questions from our members. Many people have indicated that they use our meetings as their primary source of information for clinical trial disclosure information. We also have guest speakers, often from ex-US health authorities, and do our best to keep our constituents up to date on the latest legislative developments worldwide. We are actively trying to grow the academic sector membership because we recognize a real need here. We have minutes to meetings dating back to 2005 as well as copies of legislation, analyses, presentations, etc. We also generally have presentations at our annual meeting as well as publications in the Drug Information Journal. This link will take you to a page that provides information on other SIACs with which we network and interact frequently.

*Disclaimer: This presentation is the intellectual property of Barbara Godlew owner of The FAIRE Company, LLC and protected under the copyright laws of the United States of America and other countries. Use by permission. All rights reserved.

This information is intended to provide an overview of the current state of clinical trial registration and results disclosure. Regulatory requirements are paraphrased for clearer communication.

Sponsors/institutions should consult their Legal, Regulatory Affairs, and/or Clinical Trials Office departments for institutional practice and policy.

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Learn how a CTMS, like OnCore Enterprise Research, can help your organization maintain compliant regulatory practices, including improving your budgeting and billing compliance processes.

3 Comments

3 thoughts on “Disclosure Requirements for ClinicalTrials.gov: Your FAQs Answered (Part 2)

  1. What are the non-compliance penalties? Who enforces them.? The 2007 FDAAA had an explicit section, that
    “The law also included penalties for noncompliance, such as the withholding of NIH grant funding and civil monetary penalties of up to $10,000 a day.” Has that ever been enforced? If not, why not? Is it still part of current law?
    Thank you.
    Donald F Klein MD DSc

  2. what was that date that NCI sponsored trials were required to be listed in clinicaltrials.gov,

    Could the trial be open before listing the trial with clinicaltrials.gov?

  3. A sponsor who holds the IND for a study being conducted at our AMC has asked that the PI be the RP and register the study in CT.gov. The statute defines the term as follows:
    “(1) the sponsor of the clinical trial (as defined in section 50.3 of title 21, Code of Federal
    Regulations (or any successor regulation); or
    (2) the principal investigator of such clinical trial if so designated by a sponsor, grantee,
    contractor, or awardee, so long as the principal investigator is responsible for conducting the
    trial, has access to and control over the data from the clinical trial, has the right to publish the
    results of the trial, and has the ability to meet all of the requirements under this subsection for
    the submission of clinical trial information.”

    My question is, how do we document that the Sponsor (RP) has designated these responsibilities to the PI consistent with the conditions described in the statutory definition? In our case, the protocol includes an investigator confidentiality statement that says: “The confidential and proprietary information in this document is owned by XYZ, Inc and provided to you as an Investigator, potential Investigator, or consultant, for review by you, your staff, and applicable institutional review board(s). The information cannot be used, or divulged to any third party or published without the written consent of XYZ, Inc. except to the extent necessary to obtain informed consent from those persons to whom study medication may be administered. Any misappropriation of this information is prohibited by law”. Doesn’t this statement negate the statutory conditions, because the PI cannot publish? Do other institutions allow a Sponsor (entity) that holds the IND to designate the PI the RP and if yes, how do they demonstrate that the statutory conditions are met? Thank you.

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