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PMC Asks FDA to Issue New Guidance Reflecting Rapidly Evolving Rx/Dx Co-development Landscape

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By Turna Ray

Drug/diagnostic co-development is not the ideal scenario presented by the US Food and Drug Administration's 2005 concept paper, which describes regulatory and evidentiary guidelines for the simultaneous development of a single test in conjunction with a single drug, a white paper issued by the Personalized Medicine Coalition this week asserts.

The reality of developing personalized therapeutics -- involving a genetic test to determine dosing, predict response, or gauge adverse reactions -- is often confounded by varying evidentiary criteria for drugs and diagnostics; differing development timelines for tests and therapeutics; and divergent business motivations of pharmaceutical and diagnostic firms. As a result, PMC argues in its white paper, any forthcoming FDA guidelines on drug/diagnostic co-development must delineate areas of regulatory flexibility and address alternative development models to account for the realities of this strategy.

Rx/Dx co-development is considered the linchpin of personalized medicine. But since issuing a concept paper more than four years ago, the FDA has not put forth more definitive guidance explaining how sponsors should develop combination products or how the agency plans to coordinate its drug and diagnostic divisions to review such products.

Meanwhile, genomic advances have marched on, bringing to market hundreds of new genetic tests and several new genetically targeted drugs. Even the FDA has updated labeling for several drugs to recommend or require genetic testing prior to administration. This rapidly evolving area of pharmacogenomically guided medicine requires the FDA to revisit its now outdated concept paper on Rx/Dx co-development, which is something the agency has realized.

PMC's white paper, written at the suggestion of the FDA, comes at a time when the agency is going back to the drawing board on crafting regulatory policy for genomic medicine. Recognizing that the field of pharmacogenomics has rapidly advanced since 2005, the agency is planning to hold public hearings and issue a series of white papers outlining the most up-to-date knowledge on the issue [see PGx Reporter 04-22-2009].

"The concept paper, as currently drafted, comprehends only a narrow slice of innovative diagnostic development," the PMC noted in the white paper. "Overall, the concept paper implies that the diagnostic and the drug are manufactured either by the same company or by two companies with common interests. This is often not the case.

"Given the different timelines associated with the development of drugs versus diagnostics, many requirements contemplated in the concept paper could add significantly to the time required for commercialization of products (both drugs and diagnostics) and hamper the ability of independent diagnostic companies to innovate," the PMC stated.

In addition to issuing the white paper, PMC has also proposed a list of topics for FDA public workshops or white papers on drug/diagnostic co-development. The topics include: regulatory process for companion diagnostic approval and drug labeling updates; evidence requirements for combination products; pre-clinical pilot feasibility studies; adaptive trial designs; FDA interagency coordination in reviewing drug/diagnostic combination products; as well as issues beyond the stated scope of FDA's concept paper.

Non-Ideal as the Norm

Over the four-year period since FDA first issued its concept paper, the agency has updated several drug labels with genetic information, and a number of drug and diagnostic firms have gained experience with launching combination products. One thing that has become clear is that although FDA might prefer the simultaneous development of a drug/diagnostic product, the reality doesn't always play out in such an idyllic fashion.

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Certainly, there are examples of the perfect scenario, such as the case of Pfizer's HIV drug Selzentry and Monogram Biosciences' Trofile test. The companion test was developed alongside Pfizer's drug early in its development, and data on the clinical and analytical validity of Trofile was submitted to the FDA as part of the drug's master file.

This scenario was certainly facilitated by the fact that Pfizer invested in Monogram and paid for a bulk sum of the test's development and global marketing alongside the drug [see PGx Reporter 05-10-2006].

But not all diagnostic developers are as lucky as Monogram in enticing deep-pocketed big pharma to court them through companion diagnostic development. As such, companion diagnostic development is undertaken at varying stages in the drug development cycle, contingent on regulatory action, the state of the science, and pharma's business strategy for its drug. And as such, the non-ideal Rx/Dx co-development strategy has emerged as the norm.

"In many cases diagnostic test development cannot begin until a biomarker has been qualified and validated. This can occur at various points along the drug development and regulatory approval continuum, but [FDA's] concept paper does not address this reality and therefore is not representative of most drug development strategies," the PMC pointed out in its white paper.

Pharmacogenetic testing for the anticoagulant warfarin, a drug for which the FDA updated the label to include genetic risk data in 2007, more than 50 years after the drug's approval, is a non-ideal example of a combination product development. The adoption of genetic testing for warfarin has been hampered by the lack of clinical utility data on PGx-based dosing and the fact that doctors are very used to dosing the drug through frequent blood testing to monitor the international normalized ratio [see PGx Reporter 05-06-2009].

Companion tests are emerging through other pathways. For example, a companion test has been validated for use alongside marketed drugs based on research with archival biological samples from previously conducted drug trials. Additionally, marketed genetic tests are being used to hone in on subpopulations for investigational drugs in clinical trials.

Earlier this year, FDA accepted retrospective genomic analysis from Amgen and Bristol-Myers Squibb/ImClone in updating labeling for a class of EGFR-inhibiting monoclonal antibodies for colorectal cancer. KRAS testing was available in Europe for commercial use and in the US for research use before the FDA recommended that patients with certain KRAS mutations should not receive Amgen's Vectibix and BMS/ImClone's Erbitux. However, the update to the labels of the drugs presented an alternative to the gold-standard clinical study design -- the prospective randomized-controlled trial [see PGx Reporter 10-07-2009].

PMC points out that the varying development scenarios -- for example when a biomarker has not been developed at the time of drug approval, when a test already exists, and when a test is available but for a different indication -- require regulatory flexibility from the agency, and the FDA should identify alternative evidentiary requirements and clinical trials designs accommodating these scenarios.

Dx Developer Is Not Rx Maker

Industry observers feel that pressure from payors is pushing drug developers to embark on companion test development when deciding on a drug's reimbursement. Michael Swanick, global pharmaceutical and life sciences tax leader at PricewaterhouseCoopers, recently told Pharmacogenomics Reporter he "anticipates that alliances and collaborations [with regard to Rx/Dx codevelopment] will be inevitable as the market need expands."

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But increasing collaborations and the recent flurry of M&A activity in the healthcare industry puts into focus that often the drug developer is not the diagnostics maker. As a result, timelines and development strategies interests of multiple industry players have to be aligned, the PMC notes in its white paper. The scenario that one diagnostic company will deal with one drug company when embarking on an Rx/Dx collaboration, as described in the FDA concept paper, is not possible given the number of players involved for such a deal to come to fruition.

For example, Monogram, the maker of the Trofile assay accompanying Pfizer's HIV drug, was acquired this year by Laboratory Corporation of America. While acquisition by a large reference laboratory, such as LabCorp, means more marketing muscle and development dollars for a comparatively smaller diagnostics firm, it also means that there will be more players and divergent business interests at the negotiating table with when it comes time for drug/diagnostic co-development deals.

In the same vein, Pfizer and GlaxoSmithKline this year spun off their HIV/AIDS drugs franchise into a separate firm, called ViiV Healthcare, which will now house Selzentry and another personalized GSK drug, Epizicom, which combines lamivudine and the genetically targeted abacavir [see PGx Reporter 11-11-2009].

The FDA last year updated the labeling for abacavir to include information about the increased risk of fatal hypersensitivity reaction in HIV patients who have the HLA-B*5701 allele [see PGx Reporter 07-30-2008]. LabCorp also markets an HLA-B*5701 test for hypersensitivity reaction.

According to CEO Dominique Limet, ViiV Healthcare's unique structure has the potential to "re-energize" the pharmaceutical industry's involvement in driving HIV treatment innovation and improving access. However, under ViiV, it is currently unclear how the drug/diagnostic co-marketing arrangements will be handled for these pharmacogenetically guided drugs.

Reflecting on increasingly complex business structures within the healthcare industry, PMC suggested that the agency needs to "address how it proposes to deal with [the] challenge" when "the diagnostic developer is not the drug developer."

PMC asks the agency to specifically address the challenges "related to diagnostic approval timelines versus drug approval timelines.

"Drug approval times can be very lengthy and during that time a diagnostic may change substantially (e.g., there may be technological improvements in the assay platform or there may be updates to algorithms used to assess outcomes) as new data are incorporated into the test process," the PMC notes.

Defining Evidence and Regulation

In its white paper, PMC asked the FDA to further detail alternative clinical trial designs investigating the analytical and clinical validity, and clinical utility of the companion test.

For example, the agency should delineate when it is acceptable to use archival samples in the development of companion tests, as was done in the labeling updates for Vectibix and Erbitux.

"Identify requirements for assay validation through the lifecycle of drug development, specifically the more common scenarios of biomarker discovery late in the drug approval process or after the drug has been approved for commercialization, including markers developed for uses or combinations of therapies that are common in clinical practice but not included in FDA-approved labeling for the therapeutic product," PMC advised.

Furthermore, the FDA should "clarify that randomized-controlled trials, although the 'gold standard,' may not be necessary or [ethically] appropriate in many cases," the PMC pointed out.

Also, while conducting genetically enriched trials to exclude non-responders and those at risk of adverse reactions is ethically sound, the FDA has often required inclusion of "negative" subgroups for drug approvals. The agency should provide further guidance in this regard, PMC noted.

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The agency should also provide additional clarity on the varying regulatory criteria for those devices regulated by the FDA and those overseen by the Centers for Medicare & Medicaid Services, PMC held.

The FDA has said it intends to regulate a subset of more complex laboratory-developed tests, called in vitro diagnostic multivariate index assays, that were previously regulated by CMS under the Clinical Laboratory Improvement Amendment. The FDA has yet to finalize its guidance on IVDMIAs, which has been a source of controversy and confusion for test developers [see PGx Reporter 08-12-2009].

While PMC doesn't take issue with the agency regulatory authority over this subset of LDTs, the white paper does urge the agency to lay out the divergent regulatory situation for tests overseen by FDA and those under CLIA through a transparent rulemaking process.

"For example, labeling is provided with IVDs to explain to the laboratory how to run the test as well as to identify intended use claims that have been established by the kit manufacturer and cleared or approved by the FDA," PMC noted in the white paper. "With LDTs, the laboratory does not need labeling to tell it how to run the test.

"Further, under CLIA, the laboratory must interact directly with the treating physician and provide the physician certain information about the test, whether it is labeled or not," PMC pointed out. "This is consistent with the practice of medicine, in that FDA-regulated products may be lawfully used in a manner other than the FDA-approved use in the treatment of patients by a physician."

Regulatory Coordination

In its 2005 concept paper, the FDA advises sponsors to use the Voluntary Exploratory Data Submission program, which allows companies to discuss genomic analysis on subpopulations for drugs without the fear of regulatory action.

According to Issam Zineh, associate director for genomics at the Office of Clinical Pharmacology at FDA's Center for Drug Evaluation and Research, since 2008 submissions to the VXDS program have grown 250 percent. While participation in the VXDS program imparts no regulatory action on specific investigational and new drug applications, increasing discussions between the FDA and sponsors through this program are certainly giving both parties a better idea of the level of evidence necessary for the regulatory approval of genomically guided personalized medicine products.

The agency notes in that initial paper that sponsors should discuss regulatory submissions for companion tests early in the development cycle of the drug and diagnostic.

However, real-world Rx/Dx deals show that risk-averse pharma companies are more comfortable inking Rx/Dx deals after a test has garnered significant clinical and market experience. For instance, DxS' KRAS mutation test was available in Europe and US before Amgen and BMS inked development deals for companion tests for Vectibix and Erbitux.

Inside the FDA, the structure of how the agency is reviewing combination products is also changing.

The agency this year created a new personalized medicine group within the Office of In Vitro Diagnostics in FDA's Center for Devices and Radiological Health to help increase genomic knowledge within the device group and to coordinate reviews of combination products between the drug and device divisions [see PGx Reporter 11-11-2009]. Elizabeth Mansfield, director of personalized medicine at OIVD, stepped into this newly created role this year as the head of the personalized medicine group.

Given these changes, the PMC advised the agency to outline how its separate drug and diagnostic divisions plan to work together to facilitate review and approval of Rx/Dx combination products.

Specifically, the FDA needs to "clarify which ... center/division/office will lead joint meetings for co-developed diagnostics, how meetings will proceed and be managed throughout the co-development process, and the level of involvement of the Office of Combination Products," PMC said in the white paper.

According to Zineh, FDA's drug division plans to advance several new guidance documents, including regulations for adaptive design and enrichment, premarket application of pharmacogenetics research methodologies, and a biomarker qualifications process guidance that "hopefully will be up for clearance by the end of the year." All these efforts stand to further inform Rx/Dx co-development.

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