The evening before the WCIO Annual Scientific Meeting, the leadership gathers with senior executives from our corporate sponsors and exhibitors to provide an update on WCIO and solicit feedback and advice. This turns into a free-wheeling discussion, at times brutally frank, and is very valuable as we strategize ways to enhance IO as the fourth pillar of cancer care.
At this year’s session, one of the corporate representatives asked what WCIO was doing about research, stating that research is something that “IR’s are historically not very good at.” I had to struggle to keep a straight face, since he works for a company that did not do a clinical trial to get FDA approval for their own product, but rather inserted it into the US market through one of the back-door mechanisms. This practice is the rule rather than the exception in the device industry.
So why don’t we have more good IO research? There are lots of reasons.
- IO trials are very difficult to design. Systemic therapy trials treat all tumors in the body at the same time, definitions of response and progression are standardized, and progression anywhere defines failure of therapy. In contrast, image-guided therapies treat tumors piecemeal. Since not all tumors are treated at the same time, time-dependent outcomes such as time to progression (TTP) and progression-free survival (PFS) are hard to define. RECIST criteria do not work for image-guided therapies, and alternative imaging measures of response such as necrosis and functional imaging have not been validated. Progression does not define failure of therapy, since embolization and ablation can be repeated multiple times. Given the lack of standard definitions for response, progression, and treatment failure, designing these trials is a nightmare! Putting together the ECOG Phase 3 trial of chemoembolization +/- sorafenib took about two years. much of it struggling to define meaningful endpoints.
- They are difficult to accrue. To show survival benefit requires a randomized controlled trial. Trials typically have very strict inclusion and exclusion criteria, which exclude the majority of patients with the disease. Making matters even more challenging, the control arm for most IO trials is either a systemic therapy or supportive care. Given a choice between standard-of-care only versus adding a cutting-edge image-guided therapy which already exists, patients want what they perceive is in their best interests, which is to add the image-guided therapy. Since these treatments are available to them off trial, patients do not want to enroll in studies and take the risk of being randomized to the control arm. Hence, only a small percentage of potential patients are both eligible and willing to enroll.
- Pivotal studies are expensive, lengthy, and do not fit the business plan for devices. The FDA has raised the bar considerably, requiring long-term clinical endpoints such as progression-free or overall survival. These studies take several years and cost tens of millions of dollars. Even if successful, it takes additional years for FDA approval, development of CPT codes and RVU valuations for a novel device. Pharmaceutical companies can invest billions in a new drug, expecting many years of patent protection, and do not require a CPT code. The lifespan of medical devices is shorter than the cycle of clinical trial and approval; by the time a device company completes a study, competitors have built a better mousetrap and jumped into the market with a 510k approval based on the lead companies’ device. This regulatory environment is hostile to proper device development and testing, resulting in the plethora of ablation devices and novel embolics entering the market on generic approvals and marketed for off-label use.
So are IR’s bad at research? None of the barriers described above have anything to do with us. It is not difficult to accrue patients to Phase 1 and 2 studies, where everyone gets the new therapy. For common diseases, trials that do not have prohibitive exclusion criteria usually accrue within a year. I finished the first multi-center Phase 2 study of Therasphere for HCC in 9 months! In the face of the multiple challenges and barriers to definitive Phase 3 trials, it is noteworthy that some of WCIO’s corporate partners have stepped up to the plate and are doing things the right way. Sirtex and Nordion are both running randomized controlled trials of radioembolization, and Merit/Biosphere is doing an RCT for their drug-eluting embolic. Next time you see your rep from these companies, give him a pat on the back and a big thank you for their support of IO clinical research. Now we have to step up to the plate and accrue patients to these studies. Maybe at next year’s corporate advisory dinner, we won’t have the pot calling the kettle black.