On April 13, 2020, the U.S. Food and Drug Administration (FDA) issued a guidance outlining considerations for the development and labeling of in vitro companion diagnostics to support indicated use with oncology drug groups. Companion diagnostic (CDx) tests are in vitro diagnostic tests which provide information that is essential for the safe and effective use of a corresponding drug or biological product. Historically, many FDA approved or cleared CDx tests have been indicated for use with one, or at most, a few specific drugs. This can create uncertainty for healthcare providers and, in some instances, require otherwise unnecessary additional patient biopsies.

The guidance provides the following illustrative example:

There are five FDA-approved drugs indicated for the treatment of patients with non-small cell lung cancer (NSCLC). The five drugs (afatinib, gefitinib, erlotinib, osimertinib, and dacomitinib) are all indicated for treatment of patients with NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutions as detected by an FDA-approved test. EFGR missense mutations, deletions, and insertions have been documented in a variety of cancers including glioblastoma and lung cancer. However, as shown in the following guidance table, each FDA-approved CDx test is only indicated for a subset (one, three, or four) of the five FDA-approved drugs:

FDA-Approved Companion Diagnostics	FDA-Approved 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	-	-	-
FoundationOne CDx	X	X	X	X	-

The guidance notes that it could be possible for CDxs that are "adequately validated to detect biomarker(s) of interest and to identify appropriate patients for treatment" to be "indicated more broadly" for use with a "specific group of oncology therapeutic products." The agency notes, however, that broader use is "not as simple as just matching diagnostic targets with therapeutic targets." Because different diagnostics for the same target(s) may utilize "different cut-offs, filters, or other design feature[s]," any differences "should be evaluated to ensure it is clinically appropriate to take a broader labeling approach."

Development and Labeling

The guidance provides five considerations that CDx test developers should evaluate when determining whether their test could be developed, or whether their approved CDx labeling could be revised through submission of a supplement, to support "a broader labeling claim such as use with a specific group of oncology therapeutics (rather than listing an individual therapeutic product)." The five considerations are:

1. Ability to group drugs;
2. Detailed understanding of drug mechanism of action and interaction with CDx biomarker(s);
3. Clinical experience with the drugs;
4. Analytical validity of the CDx; and
5. Clinical validity of the CDx.

We provide more detail for each consideration below.

Consideration 1: Whether a specific group of oncology therapeutic products can be defined for which a companion diagnostic will identify an appropriate patient population for potential treatment.

For guidance purposes, the FDA defines a specific group of oncology therapeutic products as "those approved for the same indications, including the same molecular alteration(s), such as mutation(s), amplification(s), and fusion(s) for which clinical evidence has been developed with at least one device for the same specimen type for each therapeutic product."

Consideration 2: Whether there is a detailed understanding of a) the mechanism of action of the specific group of oncology therapeutic products being considered for use with the companion diagnostic and b) the interaction between the therapeutic products and the biomarker(s), at the molecular alteration level, detected by the companion diagnostic.

The guidance notes that having a "detailed understanding of the mechanism of action for the therapeutic is critical to support broader labeling …"; and that a "detailed understanding of the interaction between the therapeutics and the biomarker could be achieved through clinical studies, retrospective analyses of clinical data, or both, supported or extended by nonclinical information …"

Consideration 3: Whether there is sufficient clinical experience with at least two therapeutic products for the same biomarker-informed indications.

Sponsors, the guidance notes, could "utilize currently available information, such as that published in peer-reviewed literature," or "perform new clinical studies … to show that there is sufficient and consistent clinical experience with the group of oncology therapeutic products for the same biomarker indications."

Consideration 4: Whether analytical validity of the companion diagnostic has been demonstrated across the range of biomarkers that inform the indication.

Analytical validity is the "ability of a companion diagnostic to perform as intended in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol." The agency notes that using a validated test to detect specific analytes of interest is "critical to ensuring that false negative or false positive results are not driving clinical decisions or therapeutic choices."

Consideration 5: Whether clinical validity of the companion diagnostic has been demonstrated with the therapeutic products in the disease of interest.

The guidance notes that approved or cleared CDxs "can generally leverage the information in their already cleared or approved submission to demonstrate clinical validity of the companion diagnostic with the other therapeutic products in the disease of interest." Future sponsors for non-approved or non-cleared CDxs "could perform, for example, [a clinical study], or concordance studies with a previously approved companion diagnostic for that indication to demonstrate high agreement, or prospectively-defined retrospective sample analyses to demonstrate comparable clinical performance."

Conclusion

Where appropriate, having a CDx approved or cleared for a group of oncology drugs can provide significant advantages for the test developer, test provider, patients, and healthcare providers. The guidance encourages sponsors considering development of a CDx for broader labeling to meet with CBER, CDRH, or CDER, in coordination with the Oncology Center of Excellence (OCE), as appropriate, early in development, to discuss. We strongly support that recommendation.

For questions about CDx test development, clearance, or approval, or for any FDA related test, please contact Vern Norviel or any member of Wilson Sonsini's FDA Regulatory, Healthcare and Consumer Products practice.