Originally published Nov. 16.
BOSTON – Although Qiagen is now a key diagnostic development partner for pharma companies looking to advance personalized treatments, the firm's road to launching its first companion test earlier this year wasn't without its perils. In light of this, Qiagen's experience commercializing the diagnostic, a KRAS test to identify best responders to the colorectal cancer drug Erbitux, offers valuable lessons for future personalized medicine collaborations between drug and diagnostic firms, according to a company official.
Although Qiagen subsidiary DxS was offering a laboratory-developed KRAS test as early as 2004, it was only in July this year that Qiagen received approval from the US Food and Drug Administration for the test as a companion diagnostic to gauge whether colorectal cancer patients being considered for treatment with Erbitux have KRAS mutations and therefore shouldn't receive the drug.
"In many respects [for] the KRAS program, the title of that talk should be 'How Not to Do a Companion Diagnostic Program,'" Paul Ravetto, associate director of program management at Qiagen, said during a presentation at the World CDx conference in Boston this week. "Now, we're on the other side of it. … We have that experience and we know actually how to overcome these hurdles."
Today, the conventional wisdom is that pharmaceutical firms should identify whether a drug needs a companion test as early as possible in its development cycle and, if it's necessary, waste no time in identifying a diagnostic partner to start developing the test. However, just a few years ago, most drug developers didn't have processes in place for systematically evaluating whether the success of their treatments could depend on a diagnostic. This led to some missed opportunities.
In the case of Bristol-Myers Squibb/Eli Lilly's Erbitux, the association between KRAS mutations and drug response was identified after the colorectal cancer treatment had already been on the market for several years. The FDA approved Erbitux for advanced colorectal cancer in 2004, but it wasn't until 2009 that the agency updated the drug's label with the advice that patients with KRAS mutations shouldn't receive it (PGx Reporter 7/22/2009).
In order to issue the class labeling update, the FDA reviewed retrospective analysis from previously conducted prospective studies showing that patients with mutations in KRAS codons 12 or 13 did not benefit from EGFR inhibitors such as Erbitux and Amgen's Vectibix. The agency generally considers prospective randomized-controlled studies to be the gold standard for evaluating whether a drug is safe and effective in a patient population. However, it made an exception in updating the labels of Erbitux and Vectibix, since these drugs were already on the market and the genetic association with nonresponse was already known in the literature. A prospective study in which colorectal cancer patients harboring KRAS mutations received the drugs would have been unethical and difficult to recruit.
"The analysis was basically a prospective-retrospective analysis, in order to backfill the need for a companion diagnostic," Ravetto said.
When BMS and Lilly realized they would need a companion diagnostic for Erbitux, they initially decided to partner with privately held DxS. Soon after establishing this collaboration in 2009, DxS was acquired by Qiagen, which was trying to expand its presence in the personalized medicine space (PGx Reporter 9/23/2009).
Being under Qiagen helped DxS gain the "pedigree" and the global reach that big pharma was looking for in a companion diagnostic partner, Ravetto said. Still, in pursuing regulatory approval for the KRAS companion test for Erbitux, Qiagen was among the first diagnostic shops to navigate uncharted territory.
Ravetto's presentation made it clear that Qiagen wasn't working under an ideal Rx/Dx codevelopment scenario. Not only did the firm have to deal with the challenge of developing a companion test for an already marketed drug at a time when the regulatory framework for companion diagnostics was still in flux, but it had to submit additional studies to the FDA after it filed its premarket approval application last year. This put immense pressure on the test-development team to scale up regulatory commitments in line with Erbitux's review time frame.
Despite these setbacks, Qiagen was ultimately successful. The FDA earlier this year simultaneously approved a new, first-line indication for Erbitux in combination with the chemotherapy FOLFIRI in KRAS mutation-negative, metastastic colorectal cancer patients alongside Qiagen's Therascreen KRAS RGQ PCR Kit. The process was a learning experience for Qiagen, Ravetto said, adding that the company now is in a better position to smoothly take its other companion diagnostic projects through regulatory approval.
Navigating Uncharted Territory
By 2010, Qiagen settled on using the Rotor-Gene Q platform for the KRAS companion test and that's when the development program started taking shape, Ravetto said. Qiagen decided to pursue a modular premarket approval application, under which instead of filing all the evidentiary information at once, the company can submit data packages addressing different aspects of the test over a period of time.
Ideally, the agency prefers that certain aspects of the test's performance, such as its analytical validity, are established before it goes into human clinical trials, giving diagnostic firms more time to get the test ready for clinical use.
"It seems for companion diagnostics, the agency is moving toward recommending modular PMAs," Ravetto said. Under this framework, the FDA encourages companies to first submit modules on the instrument, software, inspections, manufacturing, and clinical performance. "So, all you're really waiting for is that clinical data, that validation from the actual pivotal trial."
Although Qiagen used the modular PMA path, the company hit a snag after it filed its application in July 2011. According to Ravetto, the FDA issued a "deficiency letter" a few months later, asking Qiagen to perform additional studies. As a result the company had to "procure significantly more samples" and conduct additional statistical analysis.
Because the development paradigms for a drug and diagnostic are markedly different, it is already a challenge for commercial partners to advance a combination product in parallel. On top of this, incongruent regulatory timeframes for therapeutics and tests add another layer of stress for developers.
When a drug maker files a new drug application or a biological license application, it is on either a six- or 10-month review clock. For a diagnostic PMA, however, the 180-day review clock stops if the company is required to submit additional data and resumes again when the required information is submitted.
While Qiagen was working to provide the data FDA had asked for, in the fall of 2011, BMS/Lilly submitted its supplemental BLA for Erbitux as a first-line metastatic colorectal cancer treatment for KRAS-mutation negative patients. Since the FDA was on a 10-month review time clock for the Erbitux sBLA, based on BMS/Lilly's filing date, a regulatory decision could be expected in July 2012.
If the agency had not asked for more information, Qiagen would likely have received a regulatory decision on the companion test by January 2012. Regardless, a Qiagen spokesperson noted that the FDA's request for additional data did not delay the approval of the test. "The test was always scheduled to be approved together with the drug."
Qiagen didn't announce it had received a deficiency letter from the FDA, keeping its pharma partners' interest in mind, the spokesperson added. "We always said that our submission continued to be under review."
However, since Erbitux is dependent on the KRAS companion test to pick out which colorectal cancer patients should receive it, the FDA would likely deem the drug application "not approvable" if Qiagen failed to resubmit its PMA for the diagnostic ahead of the agency's review deadline for the sBLA. This put a hard deadline on Qiagen for fulfilling its additional requirements for the companion test.
"So, you can imagine the stress and pressure that was going on both internally and externally during this time," Ravetto said.
Ultimately, Qiagen submitted everything it needed to complete its PMA for the KRAS test by March of this year. A few months later, in July, the FDA approved the new indication for Erbitux for KRAS mutation-negative colorectal cancer. On the same day, the agency also approved Qiagen's Therascreen KRAS RGQ PCR Kit.
Benefit of Experience
Qiagen steered through the regulatory system to garner approval for its companion diagnostic during a time when there was little formal guidance as to the types of validation studies FDA wanted to see. Agency officials have acknowledged that it has been a steep learning curve for them as well, working out the regulatory requirements for drug/test combination products with early players in personalized medicine.
"What was interesting in 2008 and in 2009 [when] we had interactions with the FDA on the pre-IDE, [was that] at the time there was no guidance. There was nothing saying, 'This is the roadmap for developing your CDx … these are the verification studies you have to do, these are the validation studies you have to do,'" Ravetto said. "It would be fair to say [that] at the time, this was [also] new to the agency."
The FDA issued a draft guidance on companion diagnostics development last year in which it stated its preference that a drug and the accompanying test be developed at the same time. The agency emphasized that a treatment that depends on the use of a diagnostic should be a 510(k) cleared or premarket-approved test available for use once the drug is green lighted. Moreover, the FDA advised drug and diagnostic companies to meet with the agency early and often to figure out the clinical validation requirements they need to fulfill for the development of a companion test (PGx Reporter 7/13/2012).
"It would be fair to say [that] a lot of what's gotten into this document has probably been the result of our interactions over the last three or four years," Ravetto noted.
Last year was a big year for the FDA in terms of drug/test combination product approvals. Soon after the agency issued its draft guidance, it approved Pfizer's ALK inhibitor Xalkori for non-small cell lung cancer and Roche/Plexxikon's BRAF inhibitor Zelboraf for melanoma, both with companion tests to pick out best responders to the drugs. The experience of approving these drug/test combinations likely also helped the agency, pharma, and diagnostics firms hone in on specific development and regulatory challenges of Rx/Dx codevelopment (PGx Reporter 2/29/2012).
Of course, counter to Qiagen's experience commercializing the KRAS test for Erbitux, the FDA approved Xalkori and Zelboraf with their accompanying diagnostics in record time. At the meeting in Boston, a Pfizer official discussing the development program for Xalkori highlighted that the ALK fusion marker's association in NSCLC was identified in 2007, and Xalkori and Abbott Molecular's ALK companion test were approved four years later. FDA reviewed the marketing applications for the drug and test in under five months.
Erling Thor Donnelly, Pfizer's director of worldwide regulatory strategy, attributed the success of the development program to "a little luck" in already having an investigational ALK inhibitor in its pipeline when the gene-disease association was identified. Additionally, "blunt feedback from the FDA" in 2010 impressed upon Pfizer that its drug would not be approved without a companion test and this spurred the company to engage Abbott in an Rx/Dx partnership early on. Despite Pfizer's relatively positive experience bringing its personalized NSCLC treatment to market, Donnelly acknowledged that the ideal Rx/Dx scenario "doesn't often occur."
Qiagen's own efforts shepherding the PMA for its KRAS companion test through regulatory approval has allowed it to build a strong foundation for additional Rx/Dx collaborations. "Moving on from 2007 and 2008, we [have a] much more proactive and forward-thinking attitude in terms of these programs," Ravetto noted. "We see pharma coming to us earlier and earlier and saying, 'Okay, we've got a Phase III trial starting in 2015 or 2016,' and we're able to develop a timeline appropriately."
Qiagen has around 15 partnerships with pharma companies for companion diagnostics. In addition to the test for Erbitux, the firm has also submitted a PMA for a companion KRAS test for the colorectal cancer drug Vectibix. By year end, Qiagen is hoping to submit an application with the FDA for its Therascreen EGFR test, which assesses best responders to Boehringer Ingelheim's investigational NSCLC drug afatinib.
For the third quarter of this year, the company reported that its personalized healthcare products grew at a double-digit clip over the prior-year period, driven mainly by increased demand for the Erbitux KRAS companion test following its approval. Qiagen said that revenues from co-development projects with pharma rose over the year-ago period, but did not provide further details on that business.