NEW YORK (GenomeWeb News) – The Personalized Medicine Coalition today released a white paper outlining areas requiring more clarity from the US Food and Drug Administration on facilitating the development and regulatory review of drugs and companion tests to determine dosing, predict benefit, or gauge adverse reactions.
"Although genomic science and technology continue to advance rapidly, innovative companies cannot realize their full potential to co-develop, validate and commercialize drugs and diagnostics to benefit patients without greater regulatory clarity," the PMC said in the white paper. "In particular, greater clarity is needed with respect to the standards of evidence necessary to validate co-developed and independently developed diagnostics to support a specific reference to or requirement for such testing in therapeutic labeling, as well as the process developers should take to develop such evidence."
In order to craft the white paper, PMC convened 40 PMC members from various healthcare stakeholders, including laboratories, diagnostic manufacturers, and pharmaceutical firms. The final version of the document was voted on and approved by all PMC members, spanning government, industry, and non-profit sectors.
PMC's white paper comes at a time when the FDA has decided to go back to the drawing board on crafting regulatory policies for genomic medicine. Recognizing that the field of pharmacogenomics has rapidly advanced since the FDA's 2005 concept paper on drug/diagnostic co-development — a strategy considered critical to the advancement of personalized medicine — the agency is planning to hold several public hearings and issue a series of white papers outlining the most up-to-date knowledge on the issue.
While FDA's original concept paper focuses mainly on the simultaneous development of a therapeutic and a companion test, this "ideal" development scenario doesn't reflect the challenges of bringing genomically targeted medicines to market, the PMC said.
The PMC requests FDA to outline areas where regulatory flexibility and alternative clinical trial models are needed to accommodate for the variety of drug/diagnostic development scenarios that can emerge, 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.
"The concept Paper, as currently drafted, comprehends only a narrow slice of innovative diagnostic development," the PMC noted. "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.
There are certainly examples of FDA's ideal Rx/Dx co-development scenario, in which the diagnostic is developed alongside the drug and the combination product is simultaneously launched. This was the case for Pfizer's HIV drug Selzentry and Monogram Biosciences' Trofile test.
However, in recent years, alternative development strategies have emerged where a companion diagnostic test has been developed for a drug that has been commercially available for many years; a companion test has been validated for use based on research with archival biological samples from previously conducted drug trials; and a marketed genetic test is being considered for companion testing for several drugs not yet launched by pharmaceutical firms.
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 and the fact that doctors are used to dosing the drug through frequent blood testing to monitor the international normalized ratio.
Any FDA guidance of Rx/Dx co-development should address these types scenarios, the PMC pointed out.
Specifically, the FDA should "identify, describe and/or distinguish specifically the diagnostic assays that have been developed as companions to drugs already approved for clinical use, as well as those that have been developed for use with a particular drug before FDA has approved the drug as safe and effective for clinical use," the PMC white paper noted. "In addition, FDA should describe how the agency will treat these varying scenarios as compared to the 'ideal' co-development pathway envisioned by the concept Paper, in particular with respect to acceptable methods of validation."
Another alternative model of drug/diagnostic product development emerged this year after 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 the US 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 prosepective randomized-controlled trial.
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 address these situations.
In its white paper, PMC advises the FDA to further clarify alternative clinical trial designs for Rx/Dx combination products. For example, the agency should delineate when it is acceptable to use archival samples in the development of companion tests. 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 points out.
For example, 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 notes.
Finally, the agency needs to outline how its separate drug and diagnostic divisions plan to work together to facilitate review and approval of Rx/Dx combination products. 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.
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 with FDA's Center for Drug Evaluation and Research.
At the suggestion of the FDA, PMC has also proposed a list of topics for FDA public workshop 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.
A more detailed version of this article will appear in this week's issue of Pharmacogenomics Reporter.