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Stakeholders Consider If FDA's IVDMIA Draft Guidance Can Inspire Rx/Dx Codevelopment

It’s no secret that the divergent development timelines for therapeutics and diagnostics are a major roadblock to Rx/Dx co-development deals. However, drug and diagnostics developers have had difficulty formulating strategies to align their divergent timeframes in a way that is mutually beneficial.
However, some industry players believe that the FDA’s draft guidance on in vitro diagnostic multivariate index assays may help meet those goals because it would require certain tests to be approved by the FDA, therefore reducing some of the added risk that would ordinarily discourage pharmas from working with diagnostic shops hand in hand.
Caroline Popper, regulatory affairs senior advisor at Exagen, said that while the guidance doesn’t have provisions for aligning timelines, FDA oversight of IVDMIAs may spur Rx/Dx codevelopment by giving pharmaceutical companies more confidence in the diagnostics they use to narrow their clinical trial population. 
Essentially [the IVDMIA draft guidance] aligns diagnostic and drug development, but I don't believe it aligns timelines,” Popper told Pharmacogenomics Reporter during the Experimental Biology annual meeting, held in Washington, DC, earlier this month. “My interpretation is what is happening is IVDMIAs are useful in segmenting the patient population for clinical trials because they define patients with specific attributes in the drug development process.
“Then, when all is said and done, those same IVDMIAs may continue to be useful in selecting patients who would benefit most from those particular compounds once they are approved,” she said.
Exagen recently submitted its breast cancer recurrence test, eXagenBC, to the FDA for clearance [see PGx Reporter 04-11-2007]. If approved, it will be the second FDA-cleared test for breast cancer recurrence after Agendia’s MammaPrint test.
Others in the industry agree. “When you look at it from a co-development perspective, it is really out of sync with diagnostics development,” Scott Fogerty, manager of clinical market development at Affymetrix, said at a recent conference. “I will say that [with] the recent revelations from the IVDMIA emerging guidance, there may be a way to put this back on track.”
Fogerty did not elaborate, and Affymetrix did not respond to requests for comment.
Is IVDMIA Draft the Answer?
To be sure, Popper said she believes that the development of therapeutics and diagnostics are so fundamentally different that they perhaps cannot be merged.
“I think you can go a long way to aligning the drug and the diagnostic, but there would still be the fundamental difference between drug development and diagnostic development,” she said.
It can take as much as 15 years to bring a drug to market, while it takes only a few years for a diagnostic company to launch a new test. Additionally, pharmaceutical companies that use diagnostics in their drug-development strategies typically wait until late-stage studies.
While the draft IVDMIA guidance may not specifically speak to aligning timelines, the FDA did issue a concept paper on drug/diagnostic codevelopment in April 2005. The agency is slated to issue a draft guidance on the subject this year.
In the concept paper, the FDA notes that “the optimal time to perform studies of a new biomarker as potential diagnostic tests to be used in informing the use of a new drug or to obtain samples for a future biomarker diagnostic test study (if a new biomarker diagnostic test has not yet been developed and clinically validated) is at the time of conducting adequate and well-controlled clinical trials for that drug in phase 3 of drug development.”
According to the FDA, this timing “offers a unique opportunity to study a population that represents the intended use population in a controlled manner (e.g., with assignment to drug and placebo, and results of the diagnostic test blinded).”
Affy’s Fogerty pointed out that by working with diagnostic companies to enrich their clinical trials, drug developers are essentially taking on more risk, since the platform may also fail along with the drug in late-stage research.
“What they are doing is taking a risky developing program, in terms of drug development of more than $1 billion, and now you’re actually adding on increased risk with a companion diagnostic,” Fogerty said. “If it doesn’t make it, then now [drug makers] have an issue with getting [their] drug approved and [the diagnostic developer is] slowing down that process. That’s a real challenge for pharmaceutical executives.”
Ultimately, Fogerty noted, “it really doesn’t matter what the ‘omics’ is – whether its proteomics, genomics, or metabolomics. What really matters the most are the economics.”

At the end of the day, Fogerty noted, “it really doesn’t matter what the ‘omics’ is – whether its proteomics, genomics, or metabolomics – what really matters the most are the econ-omics.”

One area in which diagnostics shops and pharmaceutical companies see eye to eye is in picking the right patients for the right drug. This is one area where the IVDMIA guidance, by requiring FDA clearance for such tests, can bolster pharmaceutical executives’ confidence to use diagnostics to narrow their patient population for a trial.
Although drug and diagnostic development have different concerns, “patient stratification is important in diagnostics and is important in the development of drugs,” Popper said. “[B]oth are focused on taking advantage of our more complex understanding of biology, which is essentially an acknowledgement of category subjects.”
“Essentially IVDMIAs are looking at [a] more sophisticated segmentation of a patient population,” she added. “There are ways to shorten the drug-development timeline, [but] I don't think you're going to be able to cram a drug-development timeline into a diagnostic development timeline. Still, understanding biology like we do now, and the segmentation, will facilitate both.”
Probably Not
Paul Radensky, a health law attorney with McDermott, Will, & Emery, does not believe that the IVDMIA draft guidance will encourage Rx/Dx codevelopment.
Radensky told Pharmacogenomics Reporter in an e-mail earlier this month that Rx/Dx codevelopment is most expeditious if information about the diagnostic is included in the drug label.  
“Under such circumstances, the diagnostic will likely be subject to FDA review and the clearance/approval of the diagnostic and therapeutic will likely be linked in time,” he said. “This will certainly be the case if the diagnostic/therapeutic is considered a combination product, but is also likely to be the case when the diagnostic and therapeutic are co-developed but not designated as a combination product.”
Radensky noted that if the IVDMIA guidance is finalized, it would not necessarily allow for timely entry of companion diagnostics to the market.
“The IVDMIA guidance, if finalized, would not serve to align timelines between Rx and Dx approvals,” he wrote in his e-mail. “What the IVDMIA guidance would do is require [a lab-developed test] to follow an IVD pathway. It would not offer any opportunity for more timely clearance of an LDT than is currently available for an IVD test kit that already falls under FDA jurisdiction.”  
By contrast, Radensky wrote that “under current policy where LDTs are not subject to FDA clearance, a laboratory can establish the performance specifications for the assay as required by CLIA (and state licensure laws) on its own schedule consistent with what the science would require so that the lab can be ready to offer the test clinically/commercially at the time the therapeutic is approved. This current process is clearly more flexible than an FDA-clearance/approval pathway as would be required under the IVDMIA guidance.”
Radensky’s sentiments were echoed by many laboratory-test developers at FDA’s IVDMIA public hearing in February. At the meeting, many device manufacturers criticized draft guidelines discussing the regulation of such products, claiming that FDA oversight would be too cumbersome for companies, stifle innovation, and hinder patients’ access to such products [see PGx Reporter 02-14-07].
At the same time, pharma has often criticized device manufactures for not adequately establishing the clinical validity of their tests. This one aspect, pharma officials say, is a major barrier to advancing personalized medicine [see PGx Reporter 05-02-2007].
Device manufacturers like Exagen and Agendia who have put in the time and money to pursue FDA clearance for their tests are hoping that their investment will pay off in the marketplace.
“I could imagine as we go forward [that] therapeutics companies will be very interested in our cleared IVDMIAs to select patient subsets for their trials,” Exagen’s Popper said. “Having IVDMIAs that are cleared provides confidence and I guess [suggests] quality control for drug developers, [and] that the parameters they are using to select their patients have met the standards of the FDA.”

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