<figcaption> Credit: © Steve Allen/Getty Images</figcaption>
Credit: © Steve Allen/Getty Images

In medicine, it is obvious that good diagnostics go hand-in-hand with proper treatment. The business world as well as Food and Drug Administration regulators are increasingly building this understanding into product development by supporting codevelopment of new drugs with diagnostics.

?As therapies become more receptor- or pathway-­specific, the more important it becomes to demonstrate that the intended patient will be effectively and safely treated,? says Russ Bell, executive vice president of Fullerton, Calif.-based Beckman Coulter, a clinical diagnostics company.

Just over a year ago, Beckman Coulter announced the signing of an exclusive licensing agreement with Critical Therapeutics, a biopharmaceutical company based in Lexington, Mass., for intellectual property and patent rights to its High Mobility Group Box Protein 1 (HMGB1) technology. Critical Therapeutics is looking at HMGB1, a pro-inflammatory cytokine, as a potential therapeutic target for health issues that include sepsis. It licensed the technology to...

?Critical Therapeutics recognized that their research and development programs would benefit from having a companion diagnostic, so they sought out potential partners,? explains Bell. ?It is a chance to bring in a novel marker that may have broad applicability in a very underserved disease: sepsis. Right now, there is a significant diagnostic gap in diagnosing and treating this disease.?

Other companies are also following this approach, with some seeking external partners to coordinate the development of drugs with diagnostic or delivery devices and others turning to divisions within their own corporations to spur codevelopment. The goal isn?t only to match the proper diagnosis with the right treatment, but also to predict which drug and dosage will work best for each patient. And the industry is getting encouragement from the FDA.

The market is changing with the heightened awareness that drugs are effective in only about half of patients who take them, says Felix Frueh, associate director of genomics at the FDA?s Center for Drug Evaluation and Research in Rockville, Md. ?What happens next is a trial-and-error situation where you lower or raise the dose if it doesn?t work, or you change the drug.?

Bell agrees, pointing out that 7% of US drug expenditures are spent on treatments that trigger adverse responses, leading to more than $50 billion in additional expenses. Another third of the drug budget, he says, is spent on drugs that do not have the desired response.

Both Bell and Frueh see diagnostic codevelopment as a way to reduce this problem. A move to codevelopment is also being fueled, in part, by discoveries in the fields of pharmacogenomics and biomarker identification.

?The realization that genomics could be the critical factor in how people react to drugs is here, and I think that we?re at the brink of this knowledge being used in drug development for a variety of reasons, including that you want your efficacy signal to be bigger and you want to avoid toxicity,? says Frueh. Although scientists have been aware of the links between a patient?s genes and response to a drug for quite some time, it has only been with the advent of technologies such as high-density arrays, haplotype maps, and high-sensitivity biomarker analysis that they have been able to begin to act on this knowledge.

Frueh and his colleagues at the FDA published the ?Drug-Diagnostic Co-Development Concept Paper?1 in April 2005 in order to start a more formal conversation between government and industry. As Frueh explains, the goal of codevelopment is finding the best possible strategy to have a diagnostic tool ready for approval when the FDA is evaluating a related new drug, so that delays in the application of either drug can be avoided.

?The focus of the codevelopment concept paper really is not products such as the Roche AmpliChip, because these are really add-on products that are not specifically tied to a drug,? Frueh says. ?What we?re really talking about are projects ? and we are short of really good examples ? where drugs and tests are codeveloped and where a test is required for the use of the drug.? An example he offers is the cancer drug Herceptin and the codevelopment of the immunoassay that identifies the HER2 biomarker in patients with breast cancer.

Competitive advantage

From the corporate perspective, companies are starting to see the codevelopment strategy as a way to bolster flagging drug sales. In late October, Merck CEO Richard Clark told analysts that his company was considering entering the device and diagnostics market. According to JP Morgan analyst Chris Shibutani, who attended the meeting, the company was considering a future where it would move beyond pure pharmaceuticals to include implantable devices and diagnostics, either through company acquisitions or partnerships.

Similarly, Vancouver-based Angiotech Pharmaceuticals, which specializes in drug-drug and drug-device combinations, is bringing codevelopment in-house through efforts such as its recent acquisition of Edwards Lifesciences? Lifespan vascular graft business. ?The purpose of this acquisition is to serve as a significant stepping stone to Angiotech?s commercial initiatives,? explains company CEO William Hunter. ?With ownership of the entire process and combination product, Angiotech will be able to better economically capture the full value of the combination product ? both device and drug.?

It would seem that large pharmaceutical firms with expansive technical and financial resources will have a market advantage over smaller firms in this respect. The reality, however, may be just the opposite.

?Surprisingly, there have been few if any examples? of success in which the diagnostics unit codeveloped a product with the pharmaceuticals unit within the same company, says Bell. But going outside, he adds, may not be an option for large pharmaceutical companies reluctant to share proprietary information. One company, though, has appeared to make it work: the diagnostics division of Roche Molecular Systems.

?Roche Molecular Systems has always worked closely with the pharma industry and developed diagnostic products that would benefit patients? treatment,? says Karen Long, vice president of regulatory affairs at Roche Molecular Diagnostics, citing its HIV-1 Monitor product, which uses in vitro nucleic acid amplification to determine viral load.

Overcoming challenges

The process of developing a device or diagnostic in step with a related drug has its unique challenges. One is coordinating the asynchronous timelines of drug development and diagnostic/device development.

?Someone once told me that the half-life of a device before it becomes updated and improved is 18 months,? says Frueh. ?Naturally, that poses a challenge on the strategy of codevelopment. I feel it?s very likely that you?re actually going to see improvements over the period of time that the drug is being developed for the test and very likely after the drug is on the market. We?ve seen that with Herceptin, and I?m sure that we?re going to be seeing that a lot more.?

Another issue is that different FDA departments review devices and diagnostics, so there is a concern that a complex approval process will become even more complicated. ?I think it gets easier simply because one thing you have to demonstrate when you apply for market approval for a device is clinical utility,? argues Frueh. ?Well, if you use the device in a clinical setting such as a clinical trial, you?re done. Vice versa, I think if the device works well, you?re probably going to be able to generate better clinical data that is going to help you get the drug approved.?

Some evidence bears this out. Gary Ingenito, Angiotech senior vice president of clinical and regulatory affairs, says that their experience with the FDA has been very positive. ?The FDA Office of Combination Products functions well to designate combination products as drugs or devices, and the interagency agreements allow good collaboration.?

Beckman Coulter?s Bell agrees, though with some reservation. ?Coordination across various agencies is always a thorny issue, especially for pioneer products,? he says. ?That doesn?t mean we should shy away from these opportunities. The companies that conquer this new process first will have a decided advantage over those that don?t.? n



1. Drug-Diagnostic Co-Development Concept Paper, Draft, Department of Health and Human Services, Food and Drug Administration, April 2005.?www.fda.gov/cder/genomics/pharmacoconceptfn.pdf

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