By James E. Valentine* & Anne Marie Murphy –
As we previously reported, last month the National Institutes of Health (“NIH”) published a Notice of Proposed Rulemaking on clinical trials registration and results submission (“NPRM”), and is requesting public comment by February 19, 2015. The NPRM generally applies to “responsible parties” for “applicable clinical trials.” In our previous post we took a first look at some of the key areas of expansion that are being considered as part of the rulemaking process, which includes NIH’s proposal to require disclosure of results information for trials of products that are not approved and limit the delay for disclosure of those results. In addition to these high profile issues, there are a wide range of other clarifications and changes proposed in the 116-page NPRM.
Applicable Clinical Trials
The registration and results reporting requirements apply to all “applicable clinical trials.” Section 801 of the Food and Drug Administration Amendments Act of 2007 (“FDAAA 801”) defined an “applicable clinical trial” as either an applicable device clinical trial or an applicable drug clinical trial. An applicable drug clinical trial is defined as a controlled clinical investigation, other than a phase 1 clinical investigation of a drug subject to [the New Drug Application (“NDA”) or Biologics License Application (“BLA”) sections of the Federal Food, Drug, and Cosmetic Act (“FD&C Act”). An applicable device clinical trial is defined as either (1) a prospective clinical study of health outcomes comparing an intervention with a device subject to the 510(k), Premarket Approval (“PMA”), or Humanitarian Device Exemption (“HDE”) sections of the FD&C Act against a control in human subjects except for feasibility studies or (2) a pediatric postmarket surveillance as required under section 522 of the FD&C Act.
A key consideration in determining if a study meets the definition of an applicable clinical trial is if it is “controlled.” The NPRM proposes to include both concurrent controls and non-concurrent controls, such as historical controls or comparisons to baseline data. For single-arm trials, the NPRM would require that the control be specified in the protocol or statistical analysis plan, and for this to be identified as part of registration. NIH invites comments specifically on this approach for identifying controlled single-arm trials.
Another key consideration is whether the drug is subject to U.S. Food and Drug Administration (“FDA”) regulation (as opposed to studies conducted entirely outside of the U.S.). In general, studies are considered subject to FDA regulation if they meet one of the following criteria:
- include one or more clinical study sites in the United States;
- study a drug that is manufactured in the United States or its territories and is exported for use in a clinical trial outside the United States; or,
- conducted under an Investigational New Drug (“IND”).
Rather than continuing to have registrants indicate whether their trial is an applicable clinical trial, NIH proposes using a limited set of registration data elements on ClinicalTrials.gov to simplify the determination of whether a particular study meets the definition of an applicable clinical trial.
While not new information, the NPRM reiterates FDAAA 801’s definition for a “responsible party” with respect to a clinical trial of a drug or device as either (1) the sponsor of the clinical trial, or (2) the principal investigator of such clinical trial if designated by a sponsor, so long as the principal investigator is responsible for conducting the trial, has access to and control over the data from the trial, has the right to publish the results of the trial, and has the ability to meet all of the registration and reporting requirements. If the trial is conducted under an IND or IDE, the IND/IDE holder is the sponsor; otherwise the sponsor is the person or entity who initiates the trial, by preparing and/or planning the trial, and who has authority and control over the trial. For a pediatric postmarket surveillance of a device that is not a clinical trial, the responsible party is the entity whom FDA directs to conduct the surveillance of the device.
In the NPRM also reiterates FDAAA 801’s general registration requirement: a responsible party must register an applicable clinical trial at ClinicalTrials.gov not later than 21 calendar days after enrolling the first participant. The NPRM specifies requirements for registration, which include establishing structured data elements within four categories:
- descriptive information (e.g., title, brief summary, primary purpose, study design, study phase, study type, primary disease or condition being studied, intervention name, study start date, completion date, enrollment);
- recruitment information (e.g., eligibility criteria, gender, age limits, overall recruitment status, actual enrollment, individual site status);
- location and contact information (e.g., name of sponsor, responsible party, facility information); and,
- administrative information (e.g., unique protocol identification number, FDA IND number, human subjects protection review board status, record verification date, responsible party contact information).
Many of the registration data elements outlined in the NPRM are not required in the PHS Act but have been proposed by NIH under their statutory authority to modify requirements, mostly to aid in the determination of whether or not a clinical trial is an applicable clinical trial (some of these data elements have already been implemented, either prior to the enactment of FDAAA or as part of NIH’s implementation since 2007):
- Single Arm Controlled? – a sub-element of Study Design that would enable the NIH to determine whether a registered clinical trial is an applicable clinical trial when such a determination cannot be made based on other submitted registration data elements.
- Whether Study is a Pediatric Postmarket Surveillance of a Device – indicates if the study is a pediatric postmarket surveillance of a device to confirm that the study is an applicable device clinical trial.
- Other Intervention Name(s) – a requirement if the sponsor has used more than one name publicly to identify the intervention under study in the clinical trial.
- Intervention Description – to be submitted as clinical trial information to help distinguish between similar interventions.
- Studies an FDA-regulated Device/Drug – to indicate whether or not a clinical trial studies an FDA-regulated device or drug to assist in determining whether or not a clinical trial is an applicable device or drug clinical trial.
- U.S. FDA Approval, Licensure, or Clearance Status – to indicate whether any intervention regulated by FDA and studied in the clinical trial has been approved to help in assuring the data bank operates in compliance with statutory requirements (e.g., determining when clinical trial registration information submitted for an applicable device clinical trial may be posted publicly).
- Product Manufactured in the U.S. – to assist determining whether a registered clinical trial is an applicable clinical trial.
- Why Study Stopped? – when a trial is suspended, terminated, or withdrawn prior to its completion as anticipated by the protocol, in addition to updating the Overall Recruitment Status, a brief explanation of why the clinical trial was stopped (e.g., because of safety concerns, difficulties in recruitment, or for financial reasons) is required.
- Actual Enrollment – submission of the actual enrollment figure after enrollment is closed (i.e., when overall recruitment status is updated to “active, not recruiting” or “terminated”) to aid in tracking the subsequent progress of clinical trials.
- Human Subjects Protection Review Board Status – to indicate whether a clinical trial registered is undergoing or has undergone human subjects protection review board review or is exempt from approval “to enhance patient enrollment.” This data element is consistent with prior Agency practice of requiring this information.
Also, Section 402(j)(2)(A)(ii)(II)(gg) of the PHS Act specifies that for an applicable clinical trial of a drug that is not approved, the responsible party must specify whether or not there is expanded access for those who do not qualify for enrollment in the clinical trial and, if so, how to obtain information on such access. In furtherance of making this information readily available, the NPRM proposes to create an Expanded Access record with its own NCT number. This record would consist of additional data elements describing the expanded access, including eligibility criteria for participation.
NIH invites comments on its proposed modifications and additions to the data elements of clinical trial registration information, including the benefits and burdens associated with structuring of certain registration data elements.
Posting of Registration Information – Drugs vs. Devices
Registration information for applicable drug clinical trials must be publicly posted by NIH no later than 30 calendar days after it is submitted. The NPRM proposes to not make publicly available certain administration information, including the IND number and responsible party contact information.
By comparison, public posting of registration information for applicable device clinical trials is not so straightforward. For trials of devices that were previously approved or cleared for any indication, registration information must be posted by NIH no later than 30 days after results information is required to be posted. The NPRM proposes that, in practice, this registration information will be posted as soon as practicable after submission, but not later than 30 days after clinical trial results information is required to be posted.
Meanwhile, the NPRM lays out the original statutory scheme to delay posting of registration information for applicable device clinical trials that have not previously been approved or cleared. Registration information for these trials must be posted publicly no earlier than the date of approval or clearance of the device and no later than 30 days after such date. NIH anticipates there will be a number of situations in which those who conduct this category of device clinical trials may prefer to make the registration information publicly available prior to this statutory mandated time frame (e.g., to meet ICMJE policy, assist in recruitment efforts). The NPRM seeks input on potential mechanisms for addressing these situations.
FDAAA 801 requires the submission of results information for each applicable drug clinical trial for a drug that is approved or licensed and each applicable device clinical trial for a device that is cleared or approved. Following initial approval, clinical trial results information must be submitted no later than one year after the completion date or 30 calendar days after FDA approves the product, whichever is sooner.
By contrast, for applicable clinical trials of drugs or devices that are not approved, licensed, or cleared, whether or not approval was sought, the statute provides that NIH determine through regulation whether results information must be submitted and, if they are, the date which such information shall be required to be submitted. Pursuant to this authority, NIH proposes to require submission of results information for applicable clinical trials that are not approved by FDA and to limit the delay for disclosure of those results.
Generally, these results submissions for applicable clinical trials involving unapproved products are required no later than one year after the completion date of the clinical trial. The exception to this proposed rule is that if initial approval is being sought, or may at a future date be sought, then the responsible party may delay submission by providing a certification prior to that deadline. The allowable delay period for results information is now proposed in the NPRM to be limited to two years after the submission of a certification, and only one certification may be submitted for each clinical trial. Therefore, the total delay in disclosure of results would be up to three years after the completion date of the trial.
If, instead, the sponsor of the applicable clinical trial is seeking approval of a new use for a previously approved drug or device, and has filed, or plans to file, with FDA within one year, the responsible party may submit a certification for delayed submission of results information. This will delay the deadline for results submission to 30 calendar days after the earliest of the following events:
- FDA approves the product for the use studied in the applicable clinical trial;
- FDA issues a letter that ends the regulatory review cycle for the application, but does not approve the product for the use studied in the applicable clinical trial; or,
- the application seeking approval of the new use is withdrawn without resubmission for not less than 210 calendar days.
Notwithstanding these deadlines, the responsible party must submit complete results no later than two years after the date that the certification was submitted, except in situations where the required clinical trial results information has not been collected.
The NPRM also proposes to allow submission of partial results where results for a secondary outcome measure have not been collected by the completion date, as well as extensions of results reporting for “good-cause.”
As proposed in the NPRM, drug clinical trial results information will be submitted through structured data entry, in an effort to ensure all required data elements are provided and to optimize the presentation of the submitted data. The pre-specified fields for results reporting are proposed to consist of:
- information documenting the progress of human subjects through the clinical trial by arm;
- information on demographic and baseline measures and data collected by arm or comparison group and for the entire study population;
- data for each primary and secondary outcome measure by arm or comparison group, including the results of scientifically appropriate statistical analysis performed on that data;
- summarized adverse event information grouped, including (a) serious adverse events grouped by organ system and (b) all adverse events, other than serious adverse events, that exceed a frequency of five-percent within any arm of the clinical trial, grouped by organ system; and
- certain administrative information (e.g., results point of contact).
At this time, NIH has not proposed requiring submission of either non-technical or technical summaries of trial results, or submission of the full protocol, but is considering whether to do so as part of the rulemaking. To this end, NIH invites comments on methods to help determine if either type of summary or the full protocol should be required.
NIH is required to publicly post this required results information no later than 30 calendar days after it is submitted.
In general, the NPRM provides that updates of clinical trial information must be provided every 12 months, unless there are no changes in that time frame. A responsible party would have to submit updates until the final results information has been submitted for all primary and secondary outcome measures and all adverse events collected in accordance with the protocol.
However, the NPRM identifies several data elements that would be required to be updated more quickly:
- No later than 30 days after the change occurs: study start date, intervention name(s), availability of expanded access, overall recruitment status, individual site status, human subjects protection review board status, completion date, responsible party, responsible party contact information, and if the protocol is amended in a manner that changes are communicated to human subjects.
- No later than 15 days after the change occurs: U.S. FDA approval, licensure, or clearance status.
Comments can be submitted no later than February 19, 2015 to docket number NIH-2011-0003 at Regulations.gov. NIH also announced, in conjunction with the NPRM, a draft policy that would extend similar registration and reporting requirements to all clinical trials funded by NIH, regardless of whether they are subject to FDAAA.
*Not admitted to practice law. Working under the supervision of the Firm’s attorneys.