[Federal Register Volume 79, Number 135 (Tuesday, July 15, 2014)]
[Proposed Rules]
[Pages 41149-41152]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-16374]



Food and Drug Administration

21 CFR Part 15

[Docket No. FDA-2014-N-0824]

Confidentiality of Interim Results in Cardiovascular Outcome 
Safety Trials; Public Hearing; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notification of public hearing; request for comments.


SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
hearing that will provide a forum to discuss confidentiality of interim 
results for certain cardiovascular outcomes trials (CVOTs) submitted to 
the Agency while the trials are still ongoing. The purpose of the 
public hearing is to initiate constructive discussion among regulators, 
researchers, health care providers, representatives from the 
pharmaceutical industry and health care organizations, and the general 
public, about appropriate handling of interim analysis results of these 
ongoing CVOTs. FDA is also opening a public docket to receive comments 
on this topic.

DATES: The public hearing will be held on August 11, 2014, from 8 a.m. 
to 5 p.m. Individuals who wish to present at the public hearing must 
register by July 28, 2014. Section IV provides attendance and 
registration information. To ensure consideration, submit comments by 
July 28, 2014. Electronic or written comments will be accepted after 
the public hearing until October 10, 2014.

ADDRESSES: The public hearing will be held at the FDA White Oak Campus, 
10903 New Hampshire Ave., Bldg. 31 Conference Center, the Great Room 
(rm. 1503), Silver Spring, MD 20993-0002. Entrance for the public 
hearing participants (non-FDA employees) is through Building 1 where 
routine security check procedures will be performed. For parking and 
security information, please refer to http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.
    Submit electronic comments to http://www.regulations.gov. Submit 
written comments to the Division of Dockets Management (HFA-305), Food 
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 
20852. Identify comments with the docket number found in brackets in 
the heading of this document.

Administration, Center for Drug Evaluation and Research, 10903 New 
Hampshire Ave., Bldg. 21, rm. 4508, Silver Spring, MD 20993, 301-796-
9686, FAX: 301-796-9907, email: indira.hills@fda.hhs.gov.


I. Background

A. The Requirement for Postmarketing Studies To Assess the Risk of a 
New Drug

    In some cases, studies submitted to FDA as part of a new drug 
application or biologics license application will demonstrate that a 
drug is safe and effective for its intended use (i.e., that its 
benefits outweigh its identified risks), but the Agency will 
nevertheless require a sponsor to conduct additional postmarketing 
studies or trials under section 505(o)(3) of the Federal Food, Drug, 
and Cosmetic Act (the FD&C Act)

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(21 U.S.C. 355(o)(3)) for the following reasons: To assess a known 
serious risk related to use of the drug, to assess signals of a serious 
risk related to use of the drug, or to identify an unexpected risk when 
available data indicate the potential for a serious risk.

B. FDA's Approach to the Approval of Drugs To Treat Type II Diabetes

    For most drugs, clinical trials of reasonable size can establish a 
favorable relationship of benefit to relatively common risks, but they 
are not large enough to assess the risk of rare serious events such as 
heart attacks, strokes, or death. Where there is concern about these 
risks (e.g., concern about drugs to treat Type II diabetes mellitus 
(T2DM) or to promote weight loss), development programs include CVOTs 
to help assess the risk to meet the requirements for drug approval. In 
some cases, applicants have conducted a metaanalysis of cardiovascular 
(CV) risk from Phase 2/3 trials to help establish the safety of a drug 
and a separate larger CVOT as a postmarketing requirement under section 
505(o)(3) of the FD&C Act. In other cases, analyses of interim data 
from a single CVOT will demonstrate that a drug is safe with regard to 
CV risk for its intended use, and, if the overall risk-benefit analysis 
supports approval, the applicant will further assess the CV risks by 
continuing the trial as a postmarketing requirement.
    The Agency has described its expectations for CV outcome data for 
drugs to treat T2DM in the guidance for industry ``Diabetes Mellitus 
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat 
Type 2'' (available at Diabetes'' (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071627.pdf), which 
was issued based on the discussion at an advisory committee meeting,\1\ 
as well as in other available data and information. The guidance makes 
recommendations about how to demonstrate that a new therapy to treat 
T2DM is not associated with an unacceptable increase in CV risk.

    \1\ On July 1 and 2, 2008, the Endocrinologic and Metabolic Drug 
Advisory Committee met to discuss the role of CV assessment in the 
premarketing and postmarketing settings (http://www.fda.gov/ohrms/dockets/ac/cder08.html#endocrinologicmetabolic).

    The guidance states that before submission of a new drug 
application (NDA) or biologics license application, the premarketing CV 
outcome data should show that the incidence of important CV events 
occurring with the investigational agent is not more than 80 percent 
increase compared to the control group (i.e., that the upper bound of 
the 2-sided 95 percent confidence interval for the estimated risk ratio 
for CV events is less than 1.8). The guidance also states that if the 
risk ratio is between 1.3 and 1.8 and the overall risk-benefit analysis 
supports approval, a postmarketing trial will generally be necessary to 
show that the upper bound of the 2-sided 95 percent confidence interval 
for the estimated risk ratio is less than 1.3. This showing can be 
achieved by conducting an adequately powered new postmarketing trial, 
by combining results of separate premarketing and postmarketing trials, 
or by continuing a large CVOT in which a planned interim analysis is 
the basis for concluding that the risk ratio is less than 1.8. If the 
risk ratio of 1.3 is ruled out based on premarket data, then a 
postmarketing requirement may not be necessary.

C. Interim Analyses, the Importance of Their Confidentiality, and the 
Role of the Data Monitoring Committee

    Interim analyses are analyses of study data conducted partway 
through an ongoing clinical trial. They can play an integral role in 
clinical trials by allowing for the safety of enrolled patients to be 
monitored at various intervals in the study and also by allowing for 
the possibility of stopping the trial early for safety concerns, for 
futility, or for early evidence of efficacy that would make it 
unethical for the trial to proceed. Confidentiality of interim data is 
a paramount concern: The 1998 International Conference on Harmonization 
(ICH) guidance for industry ``E9 Statistical Principles for Clinical 
Trials'' (ICH E9 guidance) (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073137.pdf) 
reflects a collective view across regulatory agencies in the European 
Union, Japan, and the United States when it states that ``All staff 
involved in the conduct of the trial should remain blind to the results 
of such analyses, because of the possibility that their attitudes to 
the trial will be modified and cause changes in the characteristics of 
patients to be recruited or biases in treatment comparisons.''
    An independent Data Monitoring Committee (DMC) is usually 
established to review the interim analysis results and make 
recommendations to the sponsor about any action needed based on those 
results, allowing the sponsor and other personnel associated with the 
trial to remain masked to interim results. In 2006, FDA issued the 
guidance for clinical trial sponsors ``Establishment and Operation of 
Clinical Trial Data Monitoring Committees'' (DMC guidance) (available 
at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf) that reiterated many of the best practices for interim 
analyses and DMCs outlined in the ICH E9 guidance. Specifically, the 
guidance states that ``[p]rocedures should be established to safeguard 
confidential interim data from the project team, investigators, sponsor 
representatives, or anyone else outside the DMC and the statistician(s) 
performing the interim analyses (see 21 CFR 314.126(b)(5) (drugs) and 
21 CFR 860.7(f)(1) (devices)).'' An exception is made in considering 
the need to disseminate safety data to allow for appropriate monitoring 
of patients' safety.

D. Potential Adverse Consequences of Disclosure of Interim Results

    The concern with widespread disclosure of interim results in an 
ongoing trial, as described in the DMC guidance, stems from the 
potential of the disclosure to negatively affect the conduct of the 
remaining portion of the trial. The impact could include unanticipated 
changes in recruitment, treatment administration, or other aspects of 
trial conduct, as well as loss of objectivity in safety event 
reporting. Sponsors and other interested parties with access to interim 
data may have difficulty managing the remainder of the trial in an 
objective manner, particularly if changes to the trial protocol are 
needed for other reasons. Knowledge of interim data may influence 
decisions about the trial going forward, and it is nearly impossible to 
assess the impact of that influence on the trial's final results. To 
ensure the integrity of the trial and the validity of its findings, the 
DMC guidance strongly recommends maintaining the confidentiality of 
interim data until the trial completion.

E. Partial Disclosure of Interim Trial Results by FDA and the Purpose 
of This Hearing

    Once FDA sends an approval letter for a new drug, the FD&C Act and 
FDA regulations require that a summary or summaries of the safety and 
effectiveness data and information submitted with or incorporated by 
reference in the application be made available immediately for public 
disclosure, with certain limited redactions. FDA's analyses of the 
safety and effectiveness data and information from clinical studies 
that support the approval of a new drug are typically disclosed with 
little or no redaction. However, data relied on to make approval 
decisions are ordinarily

[[Page 41151]]

derived from fully completed clinical trials. In the case of T2DM 
therapies where a single, large CVOT to rule out CV risk was designed 
to meet both the requirement for approval and the postmarketing 
requirements, approval would indicate that the study had indeed ruled 
out the risk ratio of 1.8, so this aspect of the interim results would 
be known. But that fact would not reveal the detailed result, e.g., a 
finding that CV events were actually reduced by the drug in the interim 
analysis. Disclosure of detailed and more extensive information or 
analyses from an ongoing trial, that is, the results of an interim 
analysis, could undermine the integrity of the trial and jeopardize its 
continuation, which could delay or even prevent obtaining the safety 
data about serious risks that were required to be assessed at the time 
of approval.
    For example, in connection with a recent approval decision of a 
drug to treat T2DM (see MEMORANDA: Disclosure of Interim Cardiovascular 
Risk Study Data, NDA 22271, Nesina (alogliptin) tablets, and Its Fixed-
Dose Combination Product NDAs 22426 and 203414, dated March 12, 2013, 
and Disclosure of Interim Cardiovascular Risk Study Data and 
Information Relied on to Approve, NDA 22271, Nesina (alogliptin) 
tablets, and Its Fixed-Dose Combination Product NDAs 22426 and 203414, 
dated March 12, 2013, available at http://www.fda.gov/Drugs/NewsEvents/ucm398454.htm), FDA released information at the time of approval that 
was considered not likely to undermine the integrity of the ongoing 
trial, including (1) general background and study information; (2) 
high-level summary conclusions that the trial ruled out the 
prespecified risk margin recommended by FDA guidance; and (3) other 
data and information from the trial unrelated to CV risk. FDA decided, 
however, to delay disclosure of other information that it determined 
could jeopardize successful completion of the trial, specifically point 
estimates of hazard ratios and associated confidence intervals for CV 
risk and detailed data on CV events and rates. Based on the 
circumstances of this case, FDA determined that delaying disclosure of 
these data was appropriate for a limited time. This information would 
become available when FDA completed its review of the final CV risk 
study report and had taken any related regulatory action based on the 
final results.
    The Agency is holding this hearing to solicit input from 
stakeholders on the effects of disclosing information or analyses, at 
various levels of detail, from an ongoing trial, and whether general 
information about the trial can be disclosed without significant risk 
to the integrity of the trial or its completion. Making a determination 
about the effect of disclosure on a particular trial requires 
consideration of the details of that trial and relevant context.

II. Scope of Public Input Requested

    FDA is seeking input from the various stakeholders on the following 

 When a trial to evaluate CV safety of a new treatment is 
ongoing at the time a drug is approved, do stakeholders agree that 
disclosure of detailed analyses (such as point estimates of hazard 
ratios and the associated confidence intervals) could undermine the 
integrity of an ongoing trial and jeopardize its continuation, 
potentially eliminating or substantially delaying the Agency's ability 
to obtain needed long-term safety information?
    [cir] What interim findings, if disclosed, would represent the 
greatest risk to trial integrity or jeopardize trial continuation?
    [cir] Can partial disclosure of interim findings at the time of 
approval, essentially disclosing only that the standard for approval 
has been met, offer protection of trial integrity and also provide 
health care practitioners with the essential scientific information 
needed to inform their use of the drug?
    [cir] If the detailed interim results were disclosed at the time of 
approval, and the ongoing study was discontinued at that time, would it 
be feasible to conduct a new large trial as a postmarketing requirement 
that would fulfill the original study objective?
 Are there other, alternative trial designs that would allow 
for disclosure of interim results on safety risks at the time of 
product approval while also allowing for further information to be 
obtained postmarket?

III. Notice of Hearing Under 21 CFR Part 15

    The Commissioner of Food and Drugs is announcing that the public 
hearing will be held in accordance with part 15 (21 CFR part 15). The 
hearing will be conducted by a presiding officer, who will be 
accompanied by FDA senior management from the Office of the 
Commissioner and the Center for Drug Evaluation and Research.
    Under Sec.  15.30(f), the hearing is informal and the rules of 
evidence do not apply. No participant may interrupt the presentation of 
another participant. Only the presiding officer and panel members may 
question any person during or at the conclusion of each presentation.
    Public hearings under part 15 are subject to FDA's policy and 
procedures for electronic media coverage of FDA's public administrative 
proceedings (part 10, subpart C (21 CFR part 10, subpart C)). Under 
Sec.  10.205, representatives of the electronic media may be permitted, 
subject to certain limitations, to videotape, film, or otherwise record 
FDA's public administrative proceedings, including presentations by 
participants. The hearing will be transcribed as stipulated in Sec.  
15.30(b) (see section VI for more details). To the extent that the 
conditions for the hearing, as described in this notice, conflict with 
any provisions set out in part 15, this notice acts as a waiver of 
those provisions as specified in Sec.  15.30(h).

IV. Attendance and Registration

    The FDA Conference Center at the White Oak location is a Federal 
facility with security procedures and limited seating. Individuals who 
wish to attend the public hearing must register on or before July 28, 
2014, by visiting https://www.surveymonkey.com/s/7L8Z66Q and contacting 
Indira Hills (see FOR FURTHER INFORMATION CONTACT). Early registration 
is recommended. Registration is free and will be on a first-come, 
first-served basis. However, FDA may limit the number of participants 
from each organization based on space limitations. Onsite registration 
on the day of the hearing will be based on space availability.
    FDA will provide additional background information at the time the 
Federal Register notice is published and an agenda approximately 2 
weeks before the hearing at FDA Meeting Information page, which is 
available online at http://www.fda.gov/Drugs/NewsEvents/ucm398454.htm.
    Time will be reserved during the hearing for planned presentations 
from the audience. If you would like to present at the hearing, please 
indicate this in your hearing registration. Time for audience 
presentations is limited and will be assigned on a first-come, first-
served basis. Note also that time will be designated throughout the day 
for general comments and questions from the audience following the 
panel discussions.
    In this Federal Register notice, FDA has included specific issues 
that will be addressed by the panel. If you wish to address one or more 
of these issues in your presentation, please indicate this at the time 
you register so that FDA can consider that in organizing the

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presentations. FDA will do its best to accommodate requests to speak, 
and will determine the amount of time allotted to each presenter and 
the approximate time that each oral presentation is scheduled to begin.
    If you need special accommodations because of disability, please 
contact Indira Hills (see FOR FURTHER INFORMATION CONTACT) at least 7 
days before the hearing.
    A live webcast of this hearing will be viewable at https://collaboration.fda.gov/dmcidcvtpart15/ on the day of the hearing. A 
video record of the hearing will be available at the same Web address 
for 1 year.

V. Comments

    Regardless of attendance at the public hearing, interested persons 
may submit either electronic comments regarding this document to http://www.regulations.gov or written comments to the Division of Dockets 
Management (see ADDRESSES). It is only necessary to send one set of 
comments. Identify comments with the docket number found in brackets in 
the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at http://www.regulations.gov.

VI. Transcripts

    As soon as a transcript is available, it will be accessible at 
http://www.regulations.gov. It may be viewed at the Division of Dockets 
Management (see ADDRESSES). A transcript will also be available in 
either hard copy or on CD-ROM, after submission of a Freedom of 
Information request. Written requests are to be sent to Division of 
Freedom of Information (ELEM-1029), Food and Drug Administration, 12420 
Parklawn Dr., Element Bldg., Rockville, MD 20857.

    Dated: July 8, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-16374 Filed 7-14-14; 8:45 am]