Medical device companies developing a product that poses
significant risks to patients must obtain an Investigational Device
Exemption (IDE) from the FDA before they conduct clinical trials in
humans to assess the feasibility of the device or to obtain data to
support a Pre-Market Approval (PMA) application to the FDA to
market the device in the U.S. On Nov. 10, 2011, the FDA issued two
related draft guidance documents, one designed to foster
early-stage development of medical devices and one to promote the
initiation of clinical trials of medical devices by clarifying the
FDA's approval process.
The first draft Guidance, titled "Investigational Device
Exemptions for Early Feasibility Medical Device Clinical Studies,
Including Certain First in Human (FIH) Studies," seeks to
promote early state development. The draft Guidance begins by
distinguishing among several types of clinical trials, including
"early feasibility," "first in human,"
"traditional feasibility," and "pivotal"
studies. The draft Guidance is focused on early feasibility
studies, which it defines as "a limited clinical investigation
of a device early in development, typically before the device
design has been finalized, for a specific indication (e.g.,
innovative device for a new or established intended use, marketed
device for a novel clinical application)." According to the
draft Guidance, an early feasibility study may "evaluate the
device design concept with respect to basic safety and device
functionality in a small number of subjects (generally fewer than
10 initial subjects) when this information cannot be readily
provided through additional nonclinical assessments or appropriate
nonclinical tests are unavailable." The draft Guidance relates
to first in human studies only to the extent they also meet the
definition of an early feasibility study.
Significantly, the draft Guidance describes new FDA policies
concerning the application for and approval of IDEs for early
feasibility studies. First, the new policy allows for FDA approval
of IDEs for early feasibility studies with less nonclinical data
than required for a traditional feasibility or pivotal study. Given
that early feasibility studies, by definition, are only appropriate
when additional nonclinical data are not available or are not
adequate to advance development of the product, the new policy
allows an IDE for such a study to be approved with less evidence.
Second, the new policy allows for "timely device and clinical
protocol modifications during an early feasibility study"
through new approaches such as (1) allowing more types of
modifications to be made under a five day notification to FDA and
without actual prior FDA approval, (2) permitting changes without
FDA approval contingent upon acceptable nonclinical test results,
and (3) interactive review of IDE supplements.
The second draft Guidance, titled "FDA Decisions for
Investigational Device Exemption (IDE) Clinical
Investigations," summarizes the FDA's IDE approval process
and describes the different types of decisions FDA makes and the
common reasons behind them. As noted above, the goal is to clarify
FDA's decision process and thereby promote the initiation of
clinical trials for medical devices. Some of the decisions that FDA
makes during the approval of an IDE for a particular product are
designed to allow clinical investigations to begin, even though
there may be issues with the IDE application, while still
protecting the patients.
This Guidance identifies and describes several FDA responses to an
IDE application: (1) Approval, (2) Approval with Conditions, (3)
Staged Approval or Staged Approval with Conditions, and, (4) Future
Considerations in Approval, Approval with Conditions, or
Disapproval. Approval is just what it states and allows the IDE
applicant (or sponsor) to "begin subject enrollment in
accordance with the limits described in FDA's decision letter,
including the maximum number of subjects and investigational
centers." Approval is automatic if FDA does not respond to an
IDE application within thirty days of its receipt. FDA will approve
an IDE application when it contains adequate data and an
appropriate plan for the clinical trial.
The draft Guidance states that upon Approval with Conditions, and
upon approval by the relevant Institutional Review Board (IRB), the
sponsor may begin enrolling subjects in the trial "on the
condition that, within 45 days from the date of FDA's decision
letter, the sponsor submits information addressing the issues
identified in FDA's [conditional approval] letter." The
common reason for this type of decision is that, although there may
be some outstanding issues with the IDE application, "the
information provided is sufficient to justify human clinical
evaluation of the device, and that the proposed study design is
generally acceptable."
The draft Guidance describes Staged Approval or Staged Approval
with Conditions as a decision that allows enrollment in a clinical
trial to begin, limited to a certain number of patients in the
first stage, while certain outstanding questions are answered at
the same time. The sponsor can expand enrollment after submitting
an IDE supplement that answers the outstanding questions. The draft
Guidance states that Staged Approval is used most often with
pivotal studies, defined as "studies that are designed to
provide the primary clinical evidence to support a marketing
application" (PMA).
Finally, the draft Guidance notes that any type of FDA decision on
an IDE application, including a disapproval, may refer to future
considerations "intended to provide helpful advice to sponsors
regarding important elements of the future application that the IDE
may not specifically address." Several examples are given,
including the FDA may remind the sponsor that in light of exclusion
criteria from a clinical trial, the device may not be approved for
certain patient populations. The FDA may alert the sponsor to
certain analyses that it expects to see in a final PMA, such as
"analyses demonstrating that [any] US and non-US data can be
pooled." If the FDA wants to see additional non-clinical data
as part of the final PMA, the decision letter (again of any type)
may so advise the sponsor.
As always, it is important to remember that "FDA's
guidance documents ... do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's
current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory
requirements are cited." Further, the documents described
above are drafts, not final guidances.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.