Jane Papadaki Markley of Asuragen explains why she believes the current Rx/Dx partnering model is at best no longer fit for purpose and, at worst, broken.
The CDx partnership heralds a new era in bringing drugs to market with matching diagnostics, providing enormous potential to advance personalized medicine. Although pharma and Dx manufacturers have warmly embraced the concept of a CDx partnership, the benefits of which have been discussed elsewhere, closer examination reveals that this is far from a balanced union. With CDx development, validation and regulatory submission all linked to the drug clinical trials and regulatory activities, everything must be well synchronized for a successful combined launch in the global marketplace.
Essentially, three years of CDx development and commercialization must overlay and intertwine the approximate four to five years of drug development and commercialization post-phase II. Thus, simultaneous worldwide commercialization for Dx and Rx poses a significant challenge with varying levels of risk as both partners juggle to keep such a complex project within scope, on schedule and close to budget. To mitigate risk, a CDx manufacturer will want to enter the schedule later or require funds to offset costs related to CDx development, validation and registration to fully absorb costs related to prelaunch activities, sales training and collateral development so these are not jeopardized.
For pharma, the investment in the CDx partnership in terms of dollars and effort is a fraction (ranging from $3 million to $30 million) of their Rx development budgets (ranging from $500 million to $1 billion). By contrast, for a small or mid-size Dx company, there is considerable investment to develop and commercialize a Dx (ranging from $10 million to $106 million). For both partners the risks are high. One is ensuring synchrony of the drug/Dx development programs to converge towards corresponding approval for both products with no delays due to asynchrony. If the CDx fails as a consequence of drug trials, with unsatisfactory outcome or insurmountable registration blocks, then pharma may shelve the project resulting in a huge loss for the Dx company not covered by the initial pharma/CDx investment. Even if the Rx/Dx partnership survives and a new CDx is brought to market, the revenues realized can fall far short of expectations. Two recently launched CDxs in the US have met with such challenges, compromising the forecast sales revenues for these CDx manufacturers.
One aspect of the CDx arrangement somewhat overlooked is the requirement for the CDx format to be locked down early in the development phase and then pass through validation in clinical trials and ultimately registration with this format. In the field of oncology, where the role of new mutations is constantly evolving, this can mean that when the product finally reaches the market it can already be eclipsed by newer formats that are not only in greater demand but actually incorporated into country specific guidelines. The KRAS kit from DxS (now Qiagen), Therascreen, was developed and clinically validated in a series of clinical trials with Vectibix, sponsored by Amgen. This generated data for CE marking in Europe and a PMA for IVD use in the US. However, although the assay format includes seven of the most common KRAS mutations on codons 12 and 13, labs, physicians and some guidelines (UK) now demand an assay with more mutations, up to 12, and also mutations found on codon 61, 46 and 149. This results in much fiercer competition for Therascreen and the reluctance to switch from LDTs or other commercial KRAS kits which entered the market without pharma/CDx partnerships or full regulatory approvals.
Greater consideration also needs to be given to CDx platforms since they are the bottleneck for true global adoption of personalized medicine and, in some cases, the brake on otherwise successful CDx partnerships. Take, for example, the Roche BRAF V600 CDx assay for Zelboraf, a highly effective therapy for melanoma. During clinical trials, many labs were provided with the Roche z480 platform to generate data for necessary CDx registrations. Such labs were thus content to use the Roche BRAF assay in this setting, but post-FDA market clearance, labs across the US were not universally adopting the assay because they didn’t have the platform and didn’t have capital equipment budgets to purchase it either. Moreover, it becomes difficult to justify the purchase of a platform dedicated to a single FDA-cleared BRAF assay when BRAF testing is already being performed in the lab using an LDT for larger volume colon cancer or thyroid testing. So, while the FDA mandates that Rx decisions about prescribing Zelboraf use exclusively the Roche V600 BRAF assay, in reality most labs remain with their LDTs or run the assay ‘off label’ on a non-validated platform with consequent risks, i.e., potential inferior performance, denied coverage, etc.
In summary, while it is clear that there are risks and rewards for both parties, CDx manufacturers enter this partnership with far greater risk than the pharma partners. So if we expect Beauty to fall in love with the Beast and live happily ever after then we need to consider the provision of incentives, such as tax incentives for CDx manufacturers, reduced filing costs for registration, multi-platform approvals or other creative measures. Certainly, FDA fast-tracking efforts have shown success in two CDx partnerships, namely Zelboraf and BRAF and Xalkori and ALK4, so wishes can come true.