Recently, the U.S. Food and Drug Administration, or FDA, issued a draft guidance¹(the guidance) outlining considerations for the development and labeling of in vitro companion diagnostics to support indicated uses for multiple drug or biologic oncology products.

Companion diagnostics are in vitro diagnostic devices that provide information which is considered essential for the safe and effective use of a corresponding therapeutic product. Companion diagnostics are a key component of precision medicine, which aims to treat only patients who will likely benefit from a therapeutic, thereby maximizing therapeutic benefits and minimizing associated risks.

The FDA requires that use of a companion diagnostic and its associated therapeutic be stipulated in the instructions for use in the labeling of both the therapeutic and the associated companion diagnostic. However, in oncology, many companion diagnostics are paired with a single therapeutic, or at most two or three therapeutics.

The FDA notes that this limited pairing many not be "optimal for patient care because a clinician may need to order a different companion diagnostic (i.e., one that includes other therapeutic products on its label), obtain additional biopsy(ies), or both, to have additional therapy treatment options."²

As an example, the guidance provides a table that contains five FDA-approved therapeutic products (all of which are tyrosine kinase inhibitors) for the treatment of patients with non-small cell lung cancer (NSCLC), and whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.³The table shows, however, that each of the four FDA-approved companion diagnostics is suboptimally approved for only a subset of the five FDA-approved therapeutic products:

FDA Approved Companion Diagnostics	Therapeutic Products
Afatinib	Gefitinib	Erlotinib	Osimertinib	Dacomitinib
Therascreen EGFR RGQ PCR Kit	X	X	-	-	X
Cobas EGFR Mutation Test V2	-	X	X	X	-
Oncomine Dx Target Test	-	X	-	-	-
Foundation One CDx	X	X	X	-	-

The FDA notes that the oncology community would be better served by a companion diagnostic labeled or "indicated" for "identifying patients with NSCLS whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations and are suitable for treatment with a tyrosine kinase inhibitor approved by FDA for that indication."⁴

In wording similar to the expanded indication for the companion diagnostic, the FDA also suggests that for therapeutics, "the therapeutic product labeling should specify use of an FDA-approved or cleared IVD companion diagnostic device, rather than a particular manufacturer's IVD companion diagnostic device."⁵

The guidance also provides five considerations⁶regarding the expanded labeling for companion diagnostics, including whether:

1. A specific group or class of oncology therapeutic products can be defined for which the companion diagnostic will identify an appropriate patient population that may benefit from treatment;
2. There is a detailed understanding of a. the mechanism of action of the specific group or class of oncology therapeutic products and b. the interactions between the therapeutic products and the biomarker(s), at the mutation level, detected by the companion diagnostic;
3. There is sufficient clinical experience with at least two therapeutic products for the same biomarker indications;
4. Analytical validity of the companion diagnostic has been demonstrated across the range of biomarkers that inform the indication; and
5. Clinical validity of the companion diagnostic has been demonstrated with therapeutic products in the disease of interest.

Importantly, for device manufacturers, the guidance notes that companion diagnostics with expanded indications need not be developed de novo, but can be expanded versions of previously approved or cleared companion diagnostic tests for which the test's sponsor "submits a premarket approval, or PMA, supplement or a new 510(k) application, as appropriate, to expand the labeling to broaden the indication for use with a specific group or class of oncology products in the same disease…"⁷

The guidance encourages sponsors considering development of a companion diagnostic for broader labeling to meet with the FDA early in the development process.

Precision medicine has increased the importance of companion diagnostics in many fields of medicine, including oncology. Companion diagnostics that have broad labeling can be more valuable to physicians, patients, sponsors, and payors. But substantial work can be required to justify the broad labeling, and a sponsor contemplating broad labeling should meet with the FDA early in the development process. Also, the labeling for a companion diagnostic and its associated therapeutic(s) can have important implications for: promotion and marketing, patenting, Orange Book listings, patent term extension, maximizing drug and device revenue through life cycle management, reimbursement, company valuation, licensing, and infringement determinations. Finally, sponsors contemplating diagnostic patent claims should carefully consider ongoing patent subject matter eligibility developments in the U.S.

For questions regarding companion diagnostics, therapeutics, their combined use, or any FDA- or patent-related matter, please contact Vern Norviel or David Hoffmeister, or any member of the patents and innovations or FDA regulatory groups.

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