FDA released long-awaited draft guidance on the development of drugs with companion diagnostics July 12, but the 12-page document’s concise nature left some in the industry longing for more insight.

With the release, FDA delivered on a promise to industry to outline publicly how it will address the development and simultaneous approval of drugs and diagnostics. Its approach appears to be deliberately vague, however, avoiding clarification of what industry perceives as some of the regulatory uncertainties that are hampering development (Also see "Companion Diagnostics Move Toward Mainstream Drug Development" - In Vivo, 1 March, 2010.).

The agency strayed from a more ambitious concept paper on the prospective development of drugs and diagnostics released in 2005, a document that ran 37 pages. Likely, it is looking to maintain a flexible pathway for the approval of such products as it gains more experience in cross-divisional regulation.

The draft guidance provides a straightforward explanation of how FDA defines an in vitro companion diagnostic device, its expectations for the simultaneous development of such products and therapeutic drugs, and subsequent simultaneous regulatory review by the relevant centers at FDA, with collaboration across divisions.

The draft document’s ability to speed the process of simultaneous development, however, seems unlikely. Thus far, the agency has been working with sponsors on a case-by-case basis, and based on the initial guidance document, it appears likely to continue to do so.

The Good And Bad Of Loopholes

"There are a lot of gaps in this document," said Eric Lawson, chairman of the Companion Diagnostic Working Group of the Association of Medical Diagnostics Manufacturers and VP Medical Affairs and Compliance at Metamark Genetics, Inc., a diagnostic test developer working in the field of cancer. “We wanted some tools we could use to aid industry, to aid FDA's collaboration and communication with industry," he said, noting the current document doesn't provide those specifics.

Personalized Medicine Coalition Public Policy Director Amy Miller agreed that FDA should provide more details to assist industry. "I was pleased to see the focus on collaborative review between the drug center and the device center; that collaboration is absolutely necessary to move personalized medicine forward, but I had a lot of questions," she said. For example, the agency routinely evaluates risk when it reviews drugs, but the document does not discuss how reviewers will incorporate risk into their assessment of a diagnostic linked to a drug, nor does the draft outline the process by which various centers will collaborate, she said.

While the document is thin on details, the agency was smart to leave the door open to a more flexible approach, some argue.

"The guidance is a good start, laying out some needed definitions and clarifications on what FDA is considering a true companion diagnostic," said Kristin Pothier, a partner at the health care consulting firm Health Advances. "FDA also makes several references to the potential for exceptions for use of a therapeutic with an unapproved diagnostic."

The case of KRAS is a good example. Although KRAS is a widely known biomarker in oncology, the discovery that only non-mutant KRAS tumors respond to EGFR inhibitors like Amgen Inc.'s Vectibix (panitumumab) and Eli Lilly & Co./ Bristol-Myers Squibb Co.’s Erbitux (cetuximab) came out well after those drugs had reached the market. KRAS testing is widely used today based on non-FDA approved laboratory-developed tests, but FDA has yet to OK a companion diagnostic.

An FDA green light is necessary for the test information to be included in the drug label, which, in turn, enables manufacturers to discuss the test publicly; currently, for example, the Erbitux label only states: “Erbitux is not recommended for the treatment of patients whose colorectal cancer tumors have mutations of the KRAS gene,” limiting Bristol’s leeway in messaging.

FDA Calls For Simultaneous Review

The guidance clearly states that drugs and companion diagnostics should be developed contemporaneously and, when possible, will be reviewed simultaneously.

Applications for companion diagnostics will be reviewed by the relevant device authorities, namely the Center for Devices and Radiological Health, while the drug application would be reviewed by the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research.

"FDA review of the test/therapeutic product pair will be carried out collaboratively among relevant FDA offices," the guidance says. The document doesn’t offer clear-cut language detailing the process, however.

"People are going to be curious about how it is actually going to work….how easy is this collaboration going to be, how easily is it going to be instantiated into practice, into product review," said PMC's Miller.

FDA defines a companion diagnostic as an "in vitro diagnostic device that provides information that is essential to the safe and effective use of a corresponding therapeutic product."

Leaving The LDT Door Open

When a device is "essential" to the safe and effective use of a drug, FDA does not expect to approve the drug application unless the device is also approved, according to the document. That provides some validation to the device industry. But FDA could waive the stipulation in two scenarios: if the drug addresses a life-threatening condition for which no other treatment exists and the benefits of the drug outweigh the risk, or in the case that a safety issue emerges with an existing drug and labeling is updated to mention use of a test that is not yet approved.

That language leaves open the door to the use in some instances of an LDT, Lawson said. FDA has historically not enforced oversight of LDTs, diagnostic tests that the agency doesn’t approve because laboratories develop and use them in-house only, but last year it announced plans to establish a new regulatory framework for such tests that would broaden its enforcement oversight (Also see "FDA: Draft Guidance For Laboratory-Developed Test Regs Taking Extra Time" - Medtech Insight, 25 April, 2011.).

Information about the use of a diagnostic will be included in the corresponding drug's labeling, FDA says in the guidance. It should identify a type of diagnostic test, i.e. "the intended use," rather than referencing a specific manufacturer's test, the agency adds. The diagnostic labeling must specify the therapeutic products for which it has been cleared. In some cases, that could include an entire class of drugs, in which case the class of drugs would be specified, not the products.

A device and drug can be studied in the same trial as long as the study meets both the requirements of FDA's IDE regulations for devices and IND regulations for drugs. Information about a device should be included in the IND to inform FDA about how it will be used to enroll patients in a trial and how it will be validated. CBER or CDER will reach out to the appropriate diagnostic review center, CDRH or CBER, and joint advice will be provided to the sponsor, the guidance says.

"FDA strongly encourages sponsors considering developing either of the products discussed in this guidance to request a meeting with both relevant device and therapeutic product review divisions as early in development as possible," the document concludes.

Both in terms of how the elements will be split for review between centers and in the suggestion for consultation with both teams early in development, FDA is not departing from its ad hoc practices. And by leaving the language vague, FDA avoids laying out a rigid process it may later have trouble orchestrating.

"If these draft guidelines become a reality, the FDA will need to immediately build up its infrastructure and expertise across two divisions," said Pothier. "This is a tall order."

Many in the industry have long questioned whether FDA has the scientific expertise, the funding and human resources to stay apace with advances in personalized medicine.

While the industry has buzzed about personalized medicine, biomarkers and the promise of companion diagnostics to target drugs to the right patients, few examples of such products exist in the market, and there are even fewer examples of a drug and diagnostic developed together. Roche Holding AG's Genentech unit's Herceptin (trastuzumab), approved for use in breast cancer patients with HER2-positive tumors in 1998, is the earliest and still the most clear-cut example. Other drug/diagnostic examples exist, but more often a biomarker has been identified and a test developed after a drug has been on the market (for example, warfarin or the EGFR inhibitors).

And biomarkers that offer explicit information doctors can tie to therapeutic decision making are still rare. But industry has made strides recently in developing drugs based on biomarkers, and developing tests, either internally or through partnerships with diagnostic manufacturers, to screen patients. As a result, the agency will be tasked with addressing these considerably more complex applications.

In an interview late last year, FDA's Vicki Seyfert-Margolis, PhD., senior advisor for science innovation and policy for the office of the commissioner and one of the regulators who worked on the draft guidelines, admitted that the many complexities around the topic, both procedural cross-center issues and scientific hurdles, made developing the guidance challenging (Also see "FDA's Seyfert-Margolis On Companion Diagnostics Guidance" - Pink Sheet, 8 November, 2010.).

Two drug/diagnostic combinations currently pending at FDA, both with priority reviews, are serving as test cases for how the agency will handle the approval of such products in the new decade. Pfizer Inc. and Roche submitted applications for targeted cancer therapeutics just weeks apart: the ALK inhibitor crizotinib for non-small cell lung cancer and the BRAF inhibitor vemurafenib for melanoma.

Pfizer's crizotinib filing coincided with a submission from Abbott Laboratories' molecular diagnostics unit for an ALK FISH assay to identify the 3%-5% of NSCLC patients with the rare genetic rearrangement (Also see "Abbott Follows Pfizer To FDA With Co-Developed Lung Cancer Diagnostic" - Medtech Insight, 30 May, 2011.).

Roche simultaneously filed an application for the Cobas 4800 BRAF V600 Mutation test as a companion to vemurafenib (Also see "Roche's Vemurafenib Filed With Companion Diagnostic In Tow" - Pink Sheet, 11 May, 2011.).

FDA is soliciting comment on the draft guidance for 60 days from its publication in the Federal Register July 14.

By Jessica Merrill

FDA Releases Companion Dx Guidance Broad In Scope, Limited In Detail

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