Innovation and the Role of Alternative Markers of Efficacy

There is no arguing that early diagnosis and improved treatment measures have had a positive impact on cancer survival. While personalized medicine has helped identify the right patient population and target a regimen using biomarkers, immuno-oncology (I-O) has revolutionized the treatment approach in advance solid tumors, boosting the body’s immune system to mobilize a more resilient response. However, as drug development is a lengthy process, in 1992, the FDA instituted the Accelerated Approval Program to enable the quicker approval of drugs that treat serious conditions and that fill an unmet medical need, based on a surrogate end point.1

A payer and an oncologist deliberated the role of these surrogate markers that are commonly finding their way into clinical trials, and their influence on innovation in drug development, during a Peer Exchange convened by The American Journal of Managed Care in November 2014. The panel discussion, which was a part of the Oncology Stakeholders Summit, saw participation by Ira M. Klein, MD, MBA, FACP, national medical director, Clinical Thought Leadership, Office of the Chief Medical Officer, Aetna Inc; and Richard W. Joseph, MD, assistant professor, Division of Medical Oncology, Mayo Clinic. The session was moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University and associate director of surgical intensive care at NewYork-Presbyterian Hospital.

Dr Salgo began the discussion by asking the panel’s opinion on how different stakeholders—providers, the FDA, payers, and the pharmaceutical industry—would define the value of such innovative approaches in oncology. Dr Klein was of the opinion that while each entity has a mission of improving patient outcomes, each must balance this with a business mission. As an entity, patients are “all in,” he said; they understand the value of cancer care because they are paying the initial costs. The FDA understands the value, as it encourages the science to move forward and accept breakthrough therapies, even though regulators primarily approve drugs based on efficacy and safety. The payer, on the other hand, is invested in understanding value deployed through integrated delivery systems. Payers, Klein said, are framing models that measure value. Dr Joseph presented the example of pembrolizumab, which was recently approved for advanced melanoma. The trial, he said, was part of the expanded access program, which allows patients free access to the drug, adding that while the trial started in April 2014, the drug was approved in September 2014. During that time period, the trial participants did not have to worry about co-payments. However, following the approval, questions remain on treatment duration and the ultimate decision rests with the patients: some patients might improve on the drug and want to continue the regimen, while others might feel great but opt out once they have to share the cost through a co-pay, Joseph pointed out. Therefore, he believes that multistakeholder decisions would contribute to a more valuebased system.

Salgo asked the panel whether conducting clinical trials in cancer patients who have the worst prognosis and have failed other therapies can impact the value of a treatment. Not really, said Joseph, because patients willing to participate in the trials have failed standard therapy and are willing to try an experimental drug. He went on to say that these patients are among the healthier participants, as it takes about a month to screen them for the trial. If their condition worsens during that period, they may not be enrolled because they have to meet the same eligibility criteria as for other trials, he added. Salgo played the devil’s advocate and asked if there is a possibility that the drug might be over valued since these patients don’t have “real-life issues” in a controlled clinical trial. Klein disagreed, saying that payers believe the FDA approved the medication for a particular indication and therefore it will be covered. Klein alluded to the fact that both public and private payers are quite constrained with respect to setting guidelines on the usage of approved drugs. He pointed out that off-label use of approved drugs, a common practice, can prove expensive, especially with some of the newer oncology drugs.

According to Klein, the FDA has come a long way from simply approving drugs for their efficacy and safety. Narrow indications and the high costs of biologics have resulted in the FDA being more nuanced with drugs showing minimal or no incremental benefit. He suggested that the data from off-label use of drugs should be captured. Joseph agreed, adding that as a physician, he’d appreciate some prescribing flexibility. Salgo raised the economic argument that expensive therapies are worth it because they’ll be a tremendous cost saving down the road. Joseph agreed, pointing to ipilimumab as a case study. He said that 20% of melanoma patients treated with ipilimumab are alive at 5 years, and it’s worth the upfront cost when we see how these people will be contributing to society. He admitted that while 80% of patients on the treatment did not make it to the 5-year mark, there is hope that the newer I-O agents like nivolumab and pembrolizumab will shift the bar to include quality-adjusted life-years (QALYs) in the equation.

QUALITY, SAFETY, AND COST OF CARE

Salgo next asked the experts if they thought comparative effectiveness research (CER) and innovation clash at the federal or clinical level, and how the 2 could be reconciled. Klein disagreed, saying that innovative therapies like I-O will move through clinical trials quickly and even gain FDA approval, as they are prospective studies that collect data in real time. CER, on the other hand, evaluates what’s already been done, although the caveat with CER is identifying the right control cohort: are we comparing the people who were treated pre- and post treatment or are 2 different sets of people being compared, he asked. Underscoring the value of CER, Joseph hoped there were ethical ways of converting this retrospective method to being prospective. Both Klein and Joseph wish to see a more active influence of CER data, both in the clinic setting and in forming reimbursement policies. While the National Institute for Health and Care Excellence (NICE, which provides national care guidance in the United Kingdom) has adopted CER into practice in Europe, “In the United States, we are not really willing to jump over to that, and I think that’s actually more a societal issue than it is a clinical or medical issue,” Klein feels.

The discussion then turned toward the question that was the elephant in the room. Salgo asked the panelists how physicians can find evidence-based data that can help them develop a therapeutic regimen. This is a study that physicians have to conduct themselves on their patients because the data is just not out there. Joseph agreed that physicians do face this dilemma. Citing the example of melanoma, for which 3 good drugs were approved over the last 3 years, he asked, “How do we know which one to pick first? We have no idea.” Then there’s the cost discussion. When asked to comment on the cost versus benefit of some of the newer I-O agents, Joseph answered that while these drugs are expensive, close to $10,000 per month for the melanoma agents, “If you look at the 5-year survival, and the need for further therapy, then the immunotherapies will probably come out ahead.” From the payer perspective, Klein hopes for additional evidence that could prevent an unnecessary burden on the system. “Once the evidence is in, then a coverage policy will be developed,” he said.

When it comes to measuring QALY, though, Klein said that it’s a heterogeneous system with the various insurance groups involved; everyone is moving toward achieving a goal through their own, separate distinct business model. He added that these decisions need to be made at the population level, not the individual patient level. For Joseph, his practice, as yet, has not been affected by QALY measures.

Salgo asked the panel how they foresee the Affordable Care Act affecting the value of innovation, to which Klein responded that there has to be an obvious connection between patients, payers, and research. He referred to the model pilots being launched and funded by the Center for Medicare and Medicaid Innovation, aimed at saving healthcare dollars. Pointing to the need to look at our healthcare system in its entirety, he said, “Instead of discussing the specifics of drugs that cost $10,000 per therapy, maybe we should step back, make an overall observation, and discuss what is going on in our system and whether we can reduce waste.” And where does the patient fit in the discussion of innovation? Klein thinks that our heterogeneous payment system has so far prevented a formula that could embrace both clinical and economic goals. When asked if bundled payments would impact innovation, Joseph, who agrees with the principle, said that it could improve physician efficiency with more tests to support their therapeutic choices. However, he also thinks the system has problems, which, according to Klein are associated with the execution and governance of bundle payments and the resulting financial responsibilities. He believes in shifting the risk onto a provider or delivery organization, which is what accountable care organizations (ACOs) are about. ACOs need to have indepth knowledge of the clinical condition of the population they service, so they can risk-adjust based on the cost of treating that population, said Klein.

SURROGATE MARKERS AND INNOVATION

As the discussion transitioned to the impact of innovation on the drug approval process, Salgo said that back in 1992, the FDA accepted surrogate endpoints as a way to adopting the accelerated drug approval process. While overall survival (OS) is the benchmark used to measure drug efficacy in oncology, several disease progression-based end points—such as progression free survival (PFS), time to treatment failure, and time to progression—are currently being used. Salgo asked the experts to provide their insights and experience with using these endpoints in drug development. Klein said that a colleague who is involved in clinical policy prefers to rely only on OS because the other endpoints can be conflicting. Joseph, on the other hand, believes that every therapy needs a different endpoint. Citing the example of BRAF inhibitors, he said that they shrunk the tumors, improved quality of life, and were effective for 6 to 8 months. Patients also had better PFS, which then raised an ethical question of whether the patient on chemotherapy who progresses should be given the BRAF inhibitor, Klein said. This makes it difficult to assess the endpoint because 1 patient started earlier on the “good drug”. Joseph believes that quicker endpoints for drugs that are clearly effective would be a plus. “Are 2 surrogate end points better than 1? Is that where we should be going? Is it more efficient?” asked Salgo. Klein argued that surrogate markers have changed the picture because they measure quality of life, a metric that is dependent on the measurement approach. He said that with surrogate markers, we end up paying for quality of life, not cure or long-term remission. Joseph challenged Klein’s argument, saying that we are really paying for survival; it can be challenging to show OS in patients, he reasoned, especially if the study design includes crossover.

When asked about other endpoints such as objective response rate (ORR) and disease free survival (DFS), Joseph said that ORR is an imperfect science. Citing the example of BRAF inhibitors, he said while 90% of the patients have a reduced tumor burden, only 50% meet the ORR criteria. He said he would rather evaluate drugs based on a patient’s performance status, which is subjective, and Klein agreed. “When patients who previously needed someone to assist them into the office because of burden of disease then walk upright into the office, talk about their daily activities, self-care, and walk back to the car and drive themselves home, he can say that’s a goodness index,” Klein added. DFS, Joseph said, is similar to PFS, but is used more in the adjuvant setting.

VALIDATING AND ADOPTING PROS

Patient reported outcomes (PROs) are gaining increasing attention in mainstream discussions. When asked to provide insight on the value and validation of PROs, since they are an indicator of the patients’ perceived quality of life, Joseph referenced the COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial, which compared pazopanib and sunitinib in kidney cancer. While both drugs were equally efficacious, pazopanib was better tolerated, based on patient observation and physician objective findings, Joseph said, adding that he likes the idea of patientbased reporting. Klein said that PROs can be validated with quantity, if we canget enough surveys and if we can conduct quality-of-care studies. He thinks that surrogate markers, overall, would be valuable information for informing patient quality-of-life and independentliving decisions.

EBO

In closing, Klein summarized that we have a lot to learn with alternative markers of efficacy and there is discrepancy between cost and the final output. But he believes that the impact of these innovations will be felt over time as they are probably still in their infancy. Joseph concluded that, for a melanoma physician, I-O is an exciting field. While he has witnessed the benefits of the innovative therapy, he thinks it will be some time before payers recognize the benefits of I-O. There are still some data needed, he added, including duration of treatment and the need to make treatments more affordable.

Reference

Please visit Managed Care Insights on AJMC TV to watch the expert interviews.

Accelerated Approval Program. FDA website. http://www.fda.gov/Drugs/ResourcesForYou/ HealthProfessionals/ucm313768.htm. Accessed January 28, 2015.