Spring PharmAccess Leaders Forum – post-conference white paper
By Datamonitor Healthcare - July 07, 2014

Payers and pharmaceutical industry executives discussed current challenges and opportunities in market access at NextLevel Pharma’s Spring PharmAccess Leaders Forum in Paris on 19–21 May. Datamonitor Healthcare discusses key highlights of the conference:

  • Current experiences with various health technology assessment (HTA) harmonization pilots.
  • Regional and local variation in medicine funding and its influence on market access.
  • The growing need to work more closely with local payers to facilitate product uptake.
  • The need for a proactive approach in engaging in risk-sharing schemes and overcoming current obstacles.
  • Catalonia is trialing risk-sharing agreements to improve access to cancer drugs, but other Spanish regions may not follow suit.
  • The strategy used to achieve market access success with bendamustine, the chronic lymphocytic leukemia drug.

HTA harmonization pilots abound, but what does the pharma think about it?

With growing evidence demands and more complex and widespread health technology assessments, HTA harmonization is still at the top of pharma executives’ agendas. EUnetHTA’s early HTA dialogue, the European Medicines Agency (EMA) HTA’s parallel scientific advice, Shaping European Early Dialogues (SEED), and the rapid relative effectiveness assessment (REA) pilots all provide platforms for exploration into how more can be done to harmonize the HTA process between different countries or with the EMA. Some lessons have begun to be learnt with regard to the opportunities and limitations of such efforts.

The expectations of such projects and activities need to be realistic: “Harmonized HTA processes cannot be expected,” argued Thomas Mueller, head of pharmaceuticals department at the Federal Joint Committee (G-BA; Gemeinsamer Bundesausschuss) in Germany, “as methodologies currently used by various EU HTA agencies are too different”. However, the body of evidence is the same and there is scope to give the industry joint advice with the EMA on what is needed to satisfy both registration and payer criteria – “a one-stop shop”, he continued. Manufacturers can expect to gain information on endpoints, active controls, what comparator evidence is needed, which patient relevant outcomes could be appropriate in the study design, and which subpopulations to study.

While an agreement between participating HTA bodies is not expected to be found, dialogue opens up the opportunity to search for a consensus and understand similarities and overlaps, as well as different agencies’ requirements, facilitating the generation of core value strategies and differentiating factors that apply to multiple EU markets. According to Franz Pichler of Eli Lilly, early dialogue with HTA bodies gives manufacturers the opportunity to gain awareness of the evidentiary requirements, while at the same time allowing HTA voices to be heard and explain the reasons behind the differences in their requirements. Pichler also went on to say that while the ongoing pilots have been good for HTA agencies, they have not been so beneficial for the industry; the duplication of work drained resources and placed all of the risk on the industry. Manufacturers fear that if any negative information was revealed during the course of these pilots it could later be used in pricing negotiations at their loss, acting as a significant deterrent from participating in further programs.

While it is too early to be able to judge whether early dialogue with HTA bodies truly has the potential to facilitate HTAs and pricing and reimbursement negotiations, the entire fate of harmonization projects is uncertain. Francois Meyer of the Haute Autorité de Santé highlighted that they are all temporary with limited funding, and there still remains the need to find a way to make them into a sustainable long-term activity. However, one thing is clear; whether formally or informally, payers are talking to each other and learning from their experiences, so pharma may well learn to work with them rather than against.

Local money flow increasingly influences market access strategies

It goes without saying that gaining approval from a national HTA body is a critical hurdle that needs to be cleared to gain market access. However, that is only the beginning in many cases. For example, in the UK, the National Institute for Health and Care Excellence (NICE) does not hold any budgetary responsibility, and while NICE approval is a mandatory first step to getting UK reimbursement, regional and local budget holders have the final say, with a similar scenario also encountered in Italy.

According to Omar Ali, a formulary development pharmacist with the National Health Service (NHS), regional or local market access is more about the money flow, while national HTAs look at overall economics and whether it pays off to use the medicine in the long term. “Regions may not have the money to do what they would like to do or national HTAs say they should do if they can’t find the money,” added Ali. “Understanding money flow is critical for local market access”, concurred Gareth Williams, Market Access Europe director at Quintiles.

To make things more difficult, there can be several dozen variations of service delivery and funding flow in one country, necessitating a flexible commercial model. The groundwork necessary to build such a market access strategy needs to be done early on as tackling it later would cost a disproportionate amount of resources, said Williams. It is critical for local affiliates to work on mapping out what is happening in a healthcare system at a regional and local level. “Companies need to understand what the pressure points are for local payers in order to understand their data needs and inform the real-world data strategy, the need for a patient support system, or whatever else may be necessary”, added Williams.

According to Williams, such an approach, ideally done as a part of timely planning rather than as a knee-jerk reaction when things go wrong, can make a huge difference. He continued by presenting an example of a project Quintiles worked on with a client. Despite having gained a positive cost-effectiveness appraisal by NICE, the client’s product faced difficulties in getting reimbursement at the regional and local levels in North-West England where there were nine different ways in which that particular disease treatment was funded. Following unsuccessful attempts at using patient support programs, different types of pricing mechanisms, and boosting sales forces, the funding variability was identified as a key challenge. In short, new product use would in most cases result in someone losing revenue or jobs, explaining the reimbursement block.

Following the identification of a patient subpopulation where the new drug could make treatment more effective, Quintiles showed that minor changes to the treatment pathway would result in improved outcomes. Conversations with NHS stakeholders revealed that a 24-hour nursing telephone service was needed but was not affordable. The client reduced their investment in the region’s sales force and funded the service instead. The result was that the new drug was reimbursed and used in the whole of North-West England, the relationship with the NHS was strengthened, and the service cost less than investment in the sales force.

So what can pharma do to navigate the labyrinth of local payers and decision-makers without making the market access process overly costly? “Divide payers and local organizations into archetypes and then devise strategies to work with them”, advises Williams. Understanding patient journeys within each archetype and looking for similarities between them (similarities can often be found between some UK and Italian regions) will enable the different approaches to be scaled up so that data requirements for multiple regions can be answered at the same time.

Work with payers as partners and address their needs

Closer local relationships with payers are also driven by growing use of real-world studies. “50% of real-world outcome demonstrations will come at a local level,” according to Williams. “Companies need to develop a slick way of monitoring and tracking patients at the local level in one market and patient support programs in another. While working at a local level is important, the ability to translate outcome results from one market to another is also critical, as it is simply not financially feasible to do real-world studies in all localities”, added Williams. However, given the substantial national HTA and regional payers’ resistance towards acceptance of data generated in different geographies, the widespread extrapolation of a few studies is currently not feasible.

Furthermore, the competence of regional bodies in understanding different costing models and tools varies greatly, and the burden of showing value is on the industry, according to Andrew Hobbs, managing director of Pope Woodhead. Technical assessments have to be translated into simpler messages: “Hugely complex cost-effectiveness models do not strike a note with local payer needs,” Hobbs said. He went on to add that the quality of payer relationships makes a huge difference in negotiations and outcomes: “If a relationship is not approachable and payers are viewed as hurdles, then they are adversarial,” he said.

Instead, pharma needs to embrace working with payers as partners, which is seldom the case, added Ali. He said: “Companies are not good at asking payers what their needs and must-haves are,” and yet, according to Ali, payers, at least in the UK, would love to do some innovative contracting, provided it is designed to relieve their pain points. Furthermore, the scope to work with payers is increasing with the growing use of real-world data and the impending arrival of adaptive licensing.

Cue value-added services. Another popular term at the moment, but what do the payers and the industry really think about them?

According to Omar Ali, payers are open to working with pharma on improving the efficiency of healthcare delivery. However, they can also be suspicious, primarily due to past and current experiences of pharma offering extra services when they have failed to satisfy core payer needs. Instead, pharma should work with payers and providers to ensure the most appropriate and effective use of medicines – both on the patient side through patient support or adherence systems and physicians through ensuring they comply with evidence-based guidelines. Investing in services and systems to facilitate the appropriate use of medicines could have an added benefit for the industry in terms of reducing sales force expenditures, highlighted Williams. Indeed, there are signs that the industry is moving in that direction already, with most companies investing in market access functions instead of sales forces and key account managers increasingly targeting payers.

However, there is still a long way to go in terms of a more wholesale shift to a service-based business model, and such initiatives remain few and far between. Aside from management reluctance to change the current way of working which has worked in the past, and in many cases still is, there are other barriers that need to be cleared, including lower returns on investment from the service business compared to the core pharma pill-selling business model, and the payers’ need for services that address the management of a disease rather than a single pill. Offering services can therefore be seen as a part of a marketing ploy rather than a real opportunity to improve outcomes.

Risk-sharing – proactive rather than reactive

Rather than offering risk shares in reaction to a negative reimbursement decision, companies should be proactive in their approach and offer risk shares to payers as a real option, said Olivier Ethgen of Serfan Innovation. “Risk-sharing schemes should be part of the market access strategy from the beginning,” he added.

Francois Lucas of Pope Woodhead also added: “Risk-sharing schemes should ideally be co-created with payers,” while Florence Baron-Papillon, deputy director Market Access at Sanofi Pasteur MSD highlighted the need to be flexible in the design of such schemes, giving an example of a managed entry agreement for a vaccine product where the immediate budget impact of introducing a new vaccine was the payer’s main concern. The company worked with the payer to create a staggered vaccination schedule and spread the cost for the healthcare system.

Keeping local healthcare systems’ needs in mind is critical, as highlighted by the risk-sharing experience in the UK. Following the introduction of several such schemes in the late 2000s, their high administrative burden pushed UK pharmacists to advise against them and, since NICE’s Patient Access Schemes Liaison Unit (PASLU) gained oversight in 2009, only two free stock schemes have been put in place, with the remainder being simple discount schemes. However, there is still scope for outcome-based schemes to be implemented in the UK, provided they are designed so that they can be integrated into current NHS pathways and systems and do not create any additional cost burdens, as pointed out by Andy Stainthorpe, director of the PASLU. “Schemes need to use outcomes that already have systems in place to measure them and companies need to find imaginative ways of fitting into what the NHS is already doing,” he added. This can be quite difficult to achieve, given that the NHS does not necessarily have a unified process and it is not uncommon to find that each NHS Trust has its own way of collecting data. While there were some proposed schemes that were close to being accepted, they could not demonstrate a sufficient fit with existing systems, highlighting the difficulty of delivering risk shares in a cost-neutral manner.

Currently, one of the major problems with outcome-based schemes is that, by and large, the majority of health systems around the world are activity-based, where providers are paid on the basis of services they deliver rather than outcomes. The gradual move towards pay for performance, which is slowly infiltrating healthcare systems, may facilitate the implementation of risk shares in the future. Growing use of registries and databases may help, but ultimately the onus is on the industry in terms of funding any data collection. According to Bayer’s director of global public policy, Lars Bruenning, companies have little choice but to pay for any data collection that may be required, but given that payers may be collecting their own data, it pays to do it in collaboration. However, Bruenning further stressed that managed entry agreements should be kept simple and not linked to outcomes. Instead, collected outcome data should be used to renegotiate the price, but contracting should be kept simple. He also stressed that there should be an expectation that the price could also go up, which is not the case at the moment, with companies being able to keep the status quo at best.

Despite being widespread in the UK, Italy, and, to a lesser extent, France and Spain, some markets are still not receptive to risk shares. “Don’t come to Germany with real-world data or risk shares,” said Thomas Mueller. Neither are currently accepted in Europe’s largest market, although that may soon change. There are ongoing talks with the government over the introduction of a new category of drugs with great potential but unproven benefit, whereby controlled access could be granted through centers with registries at a special price, he added. The introduction of adaptive licensing and the need for a real-world effectiveness demonstration look set to influence German regulators and legislators, although the timeframe for such a change is not clear.

Risk-sharing deals improve market access to high-cost drugs in Catalonia

Risk-sharing deals are not widespread in Spain, and are typically negotiated at the regional level. However, the difficult financial situation facing the country, which varies in scale between regions, may spur greater use of such deals. For example, from 2015, Catalonia’s central strategy to provide access to high-cost therapeutics, such as cancer drugs, will comprise establishing risk-sharing agreements with the pharmaceutical companies that manufacture them. However, the other autonomous regions of Spain may not follow Catalonia’s example, meaning patients living in other areas could be denied access to important treatments in the future.

Speaking at the PharmAccess Leaders Forum, Dr Antonio Sarria-Santamera, director of the Agency for Health Technology Assessment at the Institute of Health Carlos III, discussed national and regional approaches that have been implemented since the economic downturn in 2008 to control healthcare spending while improving market access to high-cost drugs. “There has been a recent evolution in decision-making in Spain,” said Dr Sarria-Santamera, referring to the processes that lie between drug approval and publicly reimbursed access for patients.

At the national level, Dr Sarria-Santamera explained that the introduction of the Informe de posicionamiento terapeutico (IPT), the national therapeutic positioning report, “has not changed the decision-making process; it’s another instrument to add a layer of decision-making, to reduce costs.”

The IPT was implemented in 2012 by the Agency for Medicinal Products and Medical Devices (AEMPS; Agencia Española del Medicamentos y Productos Sanitarios). Its aim is to establish transparency in the pricing and reimbursement process, and to help guide regional authorities’ decisions on reimbursement for therapies. When it is clear that the European Medicines Agency’s approval of a drug is imminent, an IPT report is developed by the AEMPS. This focuses on a clinical assessment of the drug, attempting to establish exactly which patients will benefit the most, with the goal of preventing inappropriate prescribing and unnecessary expenditure. With pricing agreed at the national level, it is then the responsibility of the health technology assessment (HTA) authorities of the separate autonomous regions of Spain to determine cost-effectiveness, how a drug will be funded, and the local conditions of a drug’s use.

At the regional level, authorities have the power to control market access to high-cost therapies by directly controlling reimbursement. The recent approach adopted by authorities in Catalonia has enabled some pharmaceutical companies to get their expensive oncology drugs to market, providing some cancer patients with important treatment options.

From 2015, reimbursement of new high-cost medicines in Catalonia will be subject to risk-sharing agreements between the Catalan Health Service (CatSalut) and pharmaceutical companies. The conditions of these agreements will be agreed between the two parties on a case-by-case basis, and will remain confidential. Determining which patients, hospitals, and specialists will have access to drugs will be a key part of the dialog.

The central theme to risk-sharing is the “pay-for performance” principle, which sees pharmaceutical companies having to share costs with payers where their drugs have fallen short of their touted efficacy and safety. The objective of these arrangements is to optimize use of medicines, as both payers and pharmaceutical companies are incentivized to see them used in refined patient populations who are most likely to benefit.

Risk-sharing to improve market access to high-cost drugs was piloted in 2012, after CatSalut and AstraZeneca entered into an agreement to provide epidermal growth factor receptor mutation-positive non-small cell lung cancer patients with access to Iressa (gefitinib), an expensive oral targeted therapy. Other deals to bring oncology drugs to market in Catalonia have followed – Roche’s Avastin (bevacizumab) and Merck KGaA's Erbitux (cetuximab) are both now available to specific subpopulations of metastatic colorectal cancer patients.

It is too early to assess whether CatSalut’s recent approach to high-cost drug reimbursement will be successful in improving health-related outcomes while controlling spending, although so far it has been viewed as a positive step. However, Catalonia is only one of 17 autonomous regions in Spain, and therefore progress here does not mean the Spanish healthcare system is improving as a whole. Dr Sarria-Santamera pointed out that “all regions have equal power in Spain, so Catalonia may not necessarily lead by example.” It is up to the HTA of each autonomous region to interpret a drug’s IPT report and to decide how it will be funded in that region. Dr Sarria-Santamera further stated that he did not expect that all regions will follow Catalonia’s lead in making risk-sharing agreements a key future reimbursement strategy for high-cost therapeutics, including cancer drugs. As a result, the "postcode lottery"-type system, where access to medicines can vary significantly within a country, may continue in Spain, as is the situation in a number of European countries.

Bendamustine – a market access success story

Oncology drugs are facing increasingly difficult market access paths due to constrained healthcare budgets, the minor incremental benefits they often bring, and the uncertainty of real-life effects caused by the challenges of clinical trial design. However, the widespread public reimbursement of bendamustine for the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) in the EU is a shining example of market access success. Speaking at the PharmAccess Leaders Forum, William Dunlop, head of health economics and outcomes research at Mundipharma International, proposed that the same strategic criteria-based approach that secured market access success for bendamustine – marketed as Levact in the EU by Mundipharma – can be adopted by pharmaceutical companies seeking reimbursement for future oncology therapies.

Mr Dunlop explained that, as well as considering positive clinical trial data, it is necessary to apply the PICOP criteria to understand why health technology assessment (HTA) authorities across the EU have been eager to give the green light for the reimbursement of bendamustine in CLL. PICOP is an adaptation of PICO, a method that has long been used by evidence-based medicine practitioners to formulate clinical questions. Applied to drug development, companies should, for the best chance of a positive outcome in reimbursement negotiations with HTAs, address questions regarding a drug’s population (P), intervention budget impact (I), comparator (C), outcome (O), and price (P).

“To develop future oncology therapies with market access success, the PICOP criteria need to be applied across three dimensions – external, internal, and the therapy lifecycle,” said Mr Dunlop. In the external dimension, PICOP should be applied when evaluating new business development opportunities, such as building partnerships with leading biotech companies. Internally, companies should use PICOP in their research and development programs, and in conducting external research on appropriate populations, comparators, and outcomes for pipeline drugs. When considering the lifecycles of existing marketed drugs, the criteria can also identify which potential label expansions have the highest chance of market access success.

To illustrate the bendamustine success story, Mr Dunlop drew reference to the UK’s National Institute for Health and Care Excellence’s (NICE) endorsement of the drug for reimbursement on the National Health Service (NHS). NICE issued draft guidance to the NHS in December 2010, and final guidance in February 2011, recommending the public service reimburse bendamustine for first-line treatment of a subpopulation of CLL patients.

Based on NICE’s feedback, Mundipharma assigned bendamustine one- to five-star ratings for each element of PICOP. The drug rated four or five in every category. For example, bendamustine’s rating for population was four stars, as the drug targets high unmet need in a subpopulation of CLL patients who are “unsuitable for fludarabine chemotherapy.” A five-star rating was not attained due to the lack of a clear definition of what the criteria are for being unsuitable for fludarabine. Restricting patient numbers in this way also helped to limit the predicted “intervention budget impact,” resulting in a high score in this category. In its NICE submission, Mundipharma estimated that the net budget impact of reimbursement would be £2m in 2011, rising to £5m in 2014, a forecast that NICE agreed was acceptable given the unmet need.

A general theme running throughout the PharmAccess Leaders Forum was that appropriate selection of comparators in clinical trials is high on the list of essentials for HTAs assessing drugs for reimbursement. Bendamustine scored five stars here; in clinical trials, it was compared head-to-head with chlorambucil, as it was the clear existing therapy of choice recommended for the chosen patient population.

In terms of outcome, the bendamustine case may be one of good fortune combined with good planning. Choosing appropriate endpoints to achieve successful outcomes is currently a controversial topic in oncology market access. Although regulators, such as the European Medicines Agency, may approve drugs based on a significant progression-free survival (PFS) advantage over existing therapies, HTAs have often required a clear overall survival (OS) benefit before authorizing reimbursement, despite the number of factors that may make measuring OS difficult. In the absence of an OS benefit, the magnitude of a PFS benefit, if accepted at all, needs to be high. This was certainly the case with NICE’s decision regarding bendamustine. Phase III results demonstrated that bendamustine more than doubled PFS compared with chlormabucil (21.6 months versus 8.6 months), and that there was a trend towards an OS advantage with bendamustine that was “almost statistically significant.” When asked about the lack of a statistically significant OS benefit, Mr Dunlop stressed that NICE was convinced by the magnitude of the PFS benefit, and that “the gain in OS is included in NICE’s report, and they accept it.”

When talking about price, Mr Dunlop said that bendamustine was a case that went against “the myth that payers will not pay for anything new when the market has gone generic.” For cancer drugs, the sticking point for HTAs in most cases is price – how much will the drug cost? When considering reimbursement, cost is tied closely to treatment outcomes, and NICE determines whether the therapeutic benefit of a drug is worth the high price tag it may carry. Although chlorambucil (brand name Leukeran) is not available as a generic, it has been on the market for 50 years, and is considered cheap, at less than £100 per treatment course in the UK. In contrast, at NICE’s time of assessment, bendamustine was priced at £4,741.54 per course of therapy. This translates to a cost of approximately £350 per month gained in PFS, which Mundipharma considers highly cost-effective. NICE’s own assessment of cost-effectiveness in quality-adjusted life years (QALYs), measured as cost in pounds per QALY, agreed that bendamustine provides good value for money. Bendamustine’s cost-effectiveness was determined by NICE as £11,960 per QALY, well below the £20,000–30,000 ceiling that NICE cites beyond which treatments are not cost-effective.

Asked whether the drug price could not have been higher, Mr Dunlop explained that, at the price first proposed to NICE, the drug went straight to market with no further negotiations. He suggested that going in with a higher price would have meant negotiating with NICE, potentially resulting in delayed patient access to bendamustine and delayed sales for Mundipharma.

NICE’s, and other EU HTAs’, endorsement of bendamustine is certainly a success story, but ultimately other companies will struggle to satisfy the price component of PICO. Drug classes that are more expensive to manufacture, such as antibodies, cancer vaccines, and personalized therapies, may struggle to prove cost-effective even if they demonstrate a large clinical benefit to patients. This is because they will be priced much higher so companies can recoup development costs and still make profit. For instance, even if a novel antibody doubled PFS and improved OS in a patient population with high unmet need, a high price tag could push the drug’s cost-effectiveness above a pre-determined threshold for reimbursement qualification, and market access would be stalled or denied.