Comments regarding In Vitro Diagnostic Multivariate Index Assays (IVDMIAs)

BIO appreciates the opportunity to comment on the Food and Drug Administration&rsquo;s (FDA&rsquo;s, the Agency&rsquo;s) Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays.</p>

Re: Docket No. 2006D-0347, Federal Register: July 26, 2007 (Volume 72, Pages 41081-

Dear Sir/Madam,

The following comments are provided by the Biotechnology Industry Organization (BIO). BIO represents more than 1,100 biotechnology companies, academic institutions,
state biotechnology centers and related organizations across the United States and 31
other nations. BIO members are involved in the research and development of healthcare,
agricultural, industrial and environmental biotechnology products. BIO also produces the
annual BIO International Convention, the global event for biotechnology. BIO
appreciates the opportunity to comment on the Food and Drug Administration’s (FDA’s,
the Agency’s) Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In
Vitro Diagnostic Multivariate Index Assays.

BIO appreciates the additional clarification provided by the FDA in the revised draft
Guidance. We specifically note the revised definition of In Vitro Diagnostic Multivariate
Index Assays (IVDMIAs) and the identification of a transition period in which
enforcement discretion will be exercised. We respectfully submit the following
comments on the July 26, 2007 draft Guidance.

General Comments:

IVDMIA regulation in the broad context of genetic testing and personalized

BIO believes there is an interdependency between the draft IVDMIA guidance and other related regulatory documents that are currently being considered and developed.
Specifically, we note the intersection of: (1) the draft IVDMIA Guidance; (2) Draft
Guidance for Industry and FDA Staff, Commercially Distributed Analyte Specific
Reagents (ASRs): Frequently Asked Questions; and (3) the pending guidance to assist
laboratories that manufacture IVDMIAs in complying with Quality System (QS)
regulations, including how Clinical Laboratory Improvement Amendments (CLIA)
requirements may partially fulfill QS requirements. For many companies, a
comprehensive understanding of the regulatory environment created by these documents
is necessary to efficiently and responsibly plan for and incorporate regulatory
expectations into manufacturing and other business practices. This is needed to foster an
environment in which technologies can be supplied in a compliant manner with minimal
interruption to patient populations. It is important to note that there are patient
populations dependent upon many products currently marketed that will be affected by
changes to the regulatory environment contemplated by these draft and pending

Recommendation: We encourage the agency to consider this interdependency as it
develops final guidance and implements its policies. At a minimum, we encourage open,
in-depth, public forums with stakeholders during the implementation period. We
recommend that FDA continue to engage stakeholders in a formal, deliberative and
interactive process to enhance understanding and transparency of the broad regulatory
environment for genetic tests. We recommend that a formalized structure and rationale
be developed for the classification and regulation of specific subsets of in vitro
diagnostics, including all genetic tests and molecular diagnostics. We expect that it
would benefit this process to be informed by other expert assessments and advisory
reports to be released in the near future.

Ongoing Industry–Stakeholder–FDA Dialogue

In addition to initiating the regulatory discussion recommended above, FDA should
continue to interact directly with stakeholders, including industry, in an organized forum
to publicly examine the impact of and to address ongoing questions surrounding the
implementation of the IVDMIA Guidance. This will be highly instrumental in
identifying the least burdensome approach to compliance for the newly regulated

Recommendation: BIO proposes the FDA partner with industry to coordinate an
outreach and educational program to bring industry and the broader community of
stakeholders – including patients, physicians, and payers – to a clearer understanding of
the changes proposed and the requirements to achieve compliance in an orderly manner.
BIO Comments to Docket No. 2006D-0347

Specific Comments:

Definition and Regulatory Status of IVDMIAs

The draft Guidance states that an IVDMIA “[p]rovides a result whose derivation is nontransparent and cannot be independently derived or verified by the end user” and
describes several types of devices that would meet this definition. Some ambiguity
remains as to the examples provided and the threshold of “transparency” required for a
test to be exempt from regulation under the guidance or to remain clear of regulatory
enforcement action.

Recommendation: BIO proposes that FDA provide a rationale narrative or logic map to
make apparent the FDA’s method of IVDMIA assessment and classification, to give
industry the ability to independently evaluate regulatory requirements for future product
planning. We request further clarity as to what extent an interpretation function would
need to be available, published, and/or disclosed in order to be sufficiently transparent
under the definition used in the guidance such that a test may not be considered an
IVDMIA. Please provide additional specific examples of the types of tests that qualify as
IVDMIAs, if possible.

Premarket and Postmarket Requirements for IVDMIAs

We believe the draft guidance should be more explicit regarding FDA’s specific
expectations for laboratories to comply with other requirements that currently apply to
medical device manufacturers, such as medical device reporting (MDR), registration and
listing, and labeling. For example, would a laboratory that offers an IVDMIA have to
register and list all tests offered, or only the IVDMIA? We also think there are significant
questions remaining in translating the FDA QS regulations and CLIA quality practice
requirements that could already be captured under current best practices in CLIA
regulation. As noted above, quality practices and other regulatory requirements for
IVDMIAs are highly interdependent. Sufficiently analyzing the impact on manufacturing
practices will require a comprehensive understanding of the regulatory environment.
Recommendation: BIO proposes that FDA provide further clarity on the specific
requirements for laboratories regarding MDR and provide a comparative matrix for QS
regulations and operational requirements for dually regulated IVDMIAs under FDA and

Timeline for Submitting IVDMIAs for FDA Review

We appreciate that FDA has recognized the need for a transition period for laboratories to
come into compliance with the substantial new regulatory requirements under the
BIO Comments to Docket No. 2006D-0347,
Guidance. BIO encourages FDA to fully consider the large impact of this change in the
regulatory paradigm, and the capacity of companies, including emerging diagnostics
companies, to gain sufficient understanding and clarity with respect to FDA requirements
and processes in order to integrate the new requirements into their business practices and
clinical research programs. The proposed transition times may not be adequate to achieve
these goals.

We are also concerned about the potential disruptive impact on patient care in cases
where the timeline provided is insufficient for FDA to complete its review of a currently
marketed product. For example, if a manufacturer submits a 510(k) or PMA within the
initial 12 month transition period, but the review time exceeds 6 months, an IVDMIA that
is currently well-established in clinical practice and reimbursed by third-party payers
could suddenly be categorized as “investigational” pending clearance or approval,
resulting in denial of coverage and limiting access for patients. This issue is even more
likely to occur for IVDMIAs that require PMA submissions, since the average FDA
review time for PMAs approaches 12 months.

Recommendation: BIO proposes that active dialogue be commenced between the
Agency and industry to adequately assess the impact of this change in the regulatory
paradigm and the transition period that will be appropriate to ensure that manufacturers
can adequately plan for and incorporate changes to ensure there is no disruption in the
availability of these important products. In addition, we recommend that FDA review
time after submission of a 510(k) or PMA not be included in the transition period.

Least Burdensome Approach and Impact on Innovation and Availability

The draft Guidance represents a significant extension of the regulatory paradigm by
extending medical device regulations to IVDMIAs. This shift from the current regulation
under CLIA will have an impact on the cost of development and ongoing compliance,
and could result in the delay of market introduction of these assays. For some test
developers and small business entities, the increased costs and delay in market
introduction may make commercialization of the test cost-prohibitive. A direct
discussion between industry and FDA about the challenges of adapting to regulatory
changes in an emerging marketplace would ensure that these issues are fully considered
and help to provide a clear pathway for the least burdensome approach.

Recommendation: BIO proposes that FDA partner with industry to coordinate a
workshop on the development and commercialization environment of IVDMIAs in order
to identify a least burdensome regulatory approach. Such a forum could highlight the
value of innovation in diagnostics and identify policies that support continued innovation
and continued availability of safe and effective products.
BIO Comments to Docket No. 2006D-0347,
Respectfully submitted,

Chris Colwell
Director, Healthcare Regulatory Affairs
The Biotechnology Industry Organization (BIO)
BIO Comments to Docket No. 2006D-0347,

BIO's letter to the FDA