Today, checkpoint inhibitor immuno-oncology (I-O) treatments are all the rage! Unlike traditional chemotherapies, I-O drugs enable a patient’s own immune system to identify and attack foreign cancer cells while leaving normal cells to continue to function unharmed. This is a huge opportunity to beef up cancer killing while maintaining the integrity of a patient’s quality of life.
Every company, start-up, investor, and physician is looking for a way to “get in” on the action. The last time I checked, there were at least 16 PD1/ PDL1 programs being actively tested in clinics and that number goes up to over 70 if you include recently announced pre-clinical programs. In addition, there are dozens of CTLA-4 programs going on and each of these molecules are included in hundreds of studies, either alone or in combination with other drugs. So far, four checkpoint inhibitors have been approved by the FDA: Yervoy (ipilimumab), Keytruda (pembrolizumab), Opdivo (nivolumab) and Tecentriq (atezolizumab). Opdivo alone has received regulatory approval for the treatment of melanoma, Hodgkin’s lymphoma, non small cell lung cancer (NSLC), kidney cancer, bladder cancer and head and neck cancer. Most of these drugs have also either been recently approved or are going through the approval process in multiple health technology assessment (HTA) agencies (i.e. NICE in the UK, IQWIG/G-BA in Germany, HAS in France, SMC in Scotland, pCODR in Canada, and PBAC in Australia). Staggering numbers and tons of excitement about this new technology!
Naturally, all of this activity raises several questions. How are all of these agents going to differentiate themselves in the market and is this even possible? Ultimately, there are only so many cancer patients to go around and companies, in the present “take no prisoners” competitive business model, are not as open to collaborate and share data to expedite the trials of these promising treatments. The situation also swings the door open to a barrage of other questions. With an already burgeoning toolbox of cancer therapies to choose from, what additional biomarkers or surrogates for efficacy will be required? Additionally, how complex will the disease models, treatment algorithms and protocols become and how will these be feasibly managed and executed in the clinic? Finally, who is going to cover the cost of these very expensive medications especially as more and more of them become associated with a companion diagnostic?
Due to the high costs associated with these drugs and the potential for their widespread use over multiple therapeutic areas, it is of no surprise that the rates of positive reimbursement decisions from global HTA agencies are similar to those achieved by more traditional therapies. Critics, however, continue to challenge these HTA agencies on their reduced reimbursement approval rates based on the I-O drugs’ phenomenal efficacy and safety profiles. One of the reasons for the lack of correlation between drug efficacy and reimbursement approval has to do with the variations in how each HTA association interprets and evaluates clinical evidence. In addition, there also appears to be disparities in how these organizations interpret other secondary endpoints, such as quality of life (QOL) criteria. Such was the case when the FDA approved Yervoy, the first checkpoint inhibitor, for the second line treatment of melanoma. Unfortunately, every HTA agency across the globe interpreted the drug’s overall survival (OS) and QOL data differently. Perhaps there is an opportunity for a global discussion to occur where assessment criteria and objective mechanisms of evaluation can be elucidated and a consensus can be reached on how a standardized approval protocol can be disseminated and monitored.
There is no doubt that cost plays a major role in the decision to pay or not pay for these novel I-O therapies. For example, in the US, it is estimated that the cost of Opdivo and Keytruda for NSCLC is $150,000/ year/ patient! With shrinking budgets and an aging population, agencies are looking for ways to minimize financial burdens on public and private payers. To push positive reimbursement approvals forward, many manufacturers are including a variety of different market access risk sharing proposals when submitting their HTA dossiers. The two main types of “risk sharing” programs most commonly discussed are 1) “price discount” models and 2) “manually managed discount” models. The price discount scheme allows a manufacturer to provide an upfront drug discount as a certain percentage of the list price. With pan agencies cropping up and representing larger numbers of payers, similar to the pan-Canadian Pharmaceutical Agency (pCPA), the “discounted price” ultimately becomes the new “reality” whereas the list price simply acts as a theoretical reference. The manual managed discount scheme involves the implementation of a specific HTA approved protocol whereby manufacturers are able to pass along the potential cost avoidances to the payers involved. Both are complicated. And both are not ideal for manufacturers as they scramble to deal with burgeoning drug development costs and shrinking revenues.
Other cost management measures often employed by HTA agencies are the use of population restrictions based on the subset of patients who achieved the greatest level of efficacy in the pivotal trial data submitted in the I-O drug submission. Population restrictions are often associated with gene expression (for drugs that are accompanied by a diagnostic or biomarker), patient age or performance status (i.e. ECOG). In some cases, agencies have also applied treatment “stoppage” rules so as to prevent “maintenance” or long term usage of certain cancer medications. This has often been applied in hopes of shoring up the potential for ballooning costs associated with anticipated overprescribing, “bolus” effects at the time of novel drug launches, and any off-label use that may occur for non-approved indications.
Even with significant investor interest and large government funding initiatives such as the Cancer Moonshot (i.e. $1.6B invested in 2016 to accelerate cancer research over a 7 year period), ultimately, both manufacturers and agencies are seeking ways to make drugs more affordable for patients. Manufacturers, who are feeling the heat of a continuous stream of new market entrants and an ever compressing reimbursement environment, are frantically seeking to find ways for their I-O drug to capture prominence in clinical care pathways and to ensure that their trial designs use the most HTA- appropriate comparators and benchmarks. It is important for manufacturers to engage with key stakeholders early on in the process to ensure clinical trials are properly designed and value is clearly demonstrated both in a drug’s utilization and efficacy.
Fortunately, Impetus Digital can assist manufacturers in preparing for FDA and HTA submissions, leveraging the expertise of select stakeholders, to give timely and expert advice on best options to maneuver through the reimbursement decision making process. Stakeholders can include ex-payers, health economic experts, and physicians if required. Enrolled advisors can be engaged through a series of online touchpoints either in the form of web meetings or online asynchronous assignments delivered as web form questions, discussion forums or annotation exercises. Through the online engagements, manufacturers can vet the Clinical Overview section of their submissions and verify that the best trials are being cited and that the limitations of the trial designs are adequately expressed in order to pre-empt any concerns that may arise with the HTA agencies in question. In addition, a virtual board that includes health economic experts can also assist with recommendations for the model parameters that should be incorporated in the Economic Overview section and the type of pharmacoeconomic evaluation that should be leveraged (i.e. cost-utility analysis, cost-minimization analysis, etc.). Finally, they can also help to review pre-developed materials that may have already been created by local or global teams and give recommendations on how clinical overviews and economic models should be tweaked in order to be accepted within each specific market. These experts may have participated in other company HTA submission meetings and can give “real world” advice on what may or may not be acceptable to the agencies in question.
The virtual nature of the boards and working groups can help to increase the engagement rates of advisors who are often extremely busy and being utilized by multiple manufacturers for similar purposes. Also, the assignments, which are compelling, relevant, and timely, can give the advisors or steering committee members time to pause, reflect, process and review their colleague’s comments on their own time, allowing for more thoughtful and granular insights shared through the online forums. All of the assignments are created, programmed, project managed and reported out by Impetus and their technical team (market access and health economic subject matter experts) so the manufacturer’s workload is minimal and so are the costs when compared to more traditional in person consultancy meetings. Virtual advisory boards and working groups are excellent tools for manufacturers who need efficient ways to validate assumptions, content, and models when submitting their FDA or HTA drug reimbursement dossiers.