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Companion diagnostics has been on the rise for a few years now, with summer 2011 proving something of a landmark period: the US Food and Drug Administration (FDA) posted draft guidance on companion diagnostics in July of that year (1), before approving two cancer drugs and their accompanying tests the following month. Zelboraf® and the BRAF mutation test for patients with metastatic melanoma were approved on 17th August 2011. Xalkori® and the corresponding Vysis ALK Break Apart FISH Probe Kit, which detects gene rearrangements, were approved just nine days later.

Close Collaboration

Such simultaneous approval of drug and companion diagnostics is the very approach recommended in the FDA guidance. Yet achieving this synchronicity is a major challenge, particularly because few, if any, companies are equipped to handle development of a drug and diagnostic on their own.

In the case of Xalkori, it took close collaboration between three pharma partners. The companion diagnostic was created by Pfizer and Abbott, with the companies jointly meeting the FDA in July 2009. Just over two years later, the drug and companion diagnostic were approved. Accelerated approval was gained based on Phase 2 data. Phase 3 and other post-market studies are ongoing.

Validation and global testing to support the regulatory submission for the assay was subsequently provided by LabCorp, which also, following approval, immediately made the test commercially available nationwide. It played a similar role in the approval and roll-out of Roche’s Zelboraf, the other targeted drug and companion diagnostic approved in August 2011.

Since 1998, when Genentech gained approval for Herceptin®, the industry has struggled to live up to the lofty goals set for targeted drugs and companion diagnostics. However, the breakthroughs of summer 2011 heralded a real change, and there are now increasing collaborations across different industry sectors, with the expectation that more companion diagnostics will be approved. The stage is now set for pharma to fulfil the promise of personalised medicine through this field.

Alternative Model

In the past, the route to approval for a companion diagnostic was for an in vitro diagnostics (IVD) company to submit data in a pre-market approval application to the FDA. Under this model, a third-party laboratory often generates data and then becomes one of several sites offering the test. It is a model that works very well for some companies, notably Pfizer and Roche in the August 2011 approvals, and one LabCorp continues to support through its testing labs. The use of laboratory-based assays has provided another route for approval and commercialisation.

The FDA opened the door to the alternative model by rethinking its oversight of laboratory-developed tests (LDTs). Historically, the FDA took a hands-off approach to LDTs, but signalled a change in 2010 when it called a public meeting to begin a dialogue. The shift was prompted by the growing complexity of LDTs and their emerging role in personalised medicines.

Using the LDT approach enables the development and validation of assays on established IVDs. FDA investigational device exemption is sought for clinical trials in which the result of the companion test is used as part of the inclusion criteria for patient enrolment in the study.

All this can be done using a centralised approach, with one service provider handling test development, regulatory submissions and eventual commercial launch. Alternatively, if volumes or prescribing preferences call for a decentralised model, IVD partners can come on board for kit development when needed.

Faster and Less Risky

For pharma companies – and particularly small biotechs – the model offers several advantages. By running the tests in one or more labs, the upfront financial and time costs of kit manufacturing may be reduced. Taking this approach also standardises operating practices by restricting use of the assay to a network of laboratories managed by one organisation.

Reliance on the existing standards used by the central lab network helps testing achieve a greater assurance of quality and consistency of results – especially in those circumstances in which the expected test volumes are low – because the same reagents, procedures and laboratory equipment are used.

Many of these advantages mean FDA-approved LDTs are particularly well-suited to orphan indications, or occasions when time or money are constrained. Yet any drug developer, big or small, can benefit from the shortened development timelines.

Time can be saved by the streamlining of various development steps which are managed in line with existing laboratory guidelines – for example, clinical laboratory improvement amendments and clinical assessment protocols. Reducing the need for large-scale kit production lowers upfront investment, while running the tests in labs gives greater control. The use of a single laboratory to validate and test clinical trial specimens is likely to be supported by the FDA and the European Medicines Agency.

Keys to Success

While LDTs ease development in some cases, many of the challenges for simultaneous drug and companion diagnostic FDA approval remain. To complicate matters further, drug and diagnostic developers are two distinct sectors with different business models. As Andrew Pollack wrote in a 2011 New York Times article, alliances between the two are “a dance between a giant and a pixie, locked in an embrace but with a tendency to move in opposite directions” (2).

Companion diagnostic projects are inherently complicated. Timing it so a companion diagnostic receives approval at the same time is challenging, but this process has been supported, as outlined in an FDA concept paper in 2005 (3).

Choosing the right companion diagnostic partner can minimise these potential problems. In both the IVD and LDT models, in-depth experience in test development, regulatory submissions and commercialisation is vital. In the case of FDA-approved LDTs, excellent links to IVD companies are also needed to ease the potential switch to a decentralised model, if necessary.

Both partners must show a degree of fiscal flexibility. In some cases, a fee-for-service model might make the most sense. On other occasions, the two partners might agree to each shoulder some of the development costs.

Working Alliances

There are numerous considerations, many of which are new to drugmakers. Going forward, successful drug development programmes will need collaborations with diagnostic companies, so the pressure is on to make these alliances work. Given that approval of a targeted therapy is tied to the success of its companion diagnostic, the collaborator selection process is particularly important and, if done properly, can only enhance the chances of success.

1. Guidance for Industry and Food and Drug Administration Staff – In vitro companion diagnostic devices, FDA, July 2011
2. Pollack A, A push to tie new drugs to testing, New York Times, 26th December 2011
3. Draft Drug-Diagnostic Co-development Concept Paper, FDA, April 2005

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Alan Wookey is Associate Vice President and Executive Director of Companion Diagnostics at LabCorp Clinical Trials. He works across the industry to develop biomarker programmes with pharma and biotech, from analytical and clinical validation through to regulatory approval and commercialisation. Prior to joining LabCorp, Alan held leadership positions in oncology clinical development at AstraZeneca. He earned his degrees in Microbiology from the University of Liverpool, and has been focused in pharmacogenetics and personalised medicine for more than 10 years.
Alan Wookey
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