A Viewpoint by David Pruce, Practice Lead of Strategic Market Access at Amaris Consulting.

Pricing and reimbursement has long been recognized as the fourth hurdle of pharmaceutical development. Even before the COVID pandemic, the environment for pricing and reimbursement was tough; it could now become much tougher. We need to fully understand these changes so that we can launch new medicines with certainty and at optimal prices. Predicting price and access requires both good scientific and clinical understanding as well as the experience and expertise to interpret the changing environment.

HTA – a global phenomenon

Before a new medicine is allowed on the market, it must demonstrate safety, quality, and efficacy.  However, this does not guarantee that the medicine will be reimbursed by the health system.  Payers and Health Technology Assessment (HTA) bodies demand compelling evidence about how new medicines improve the standard of care and public health[i]. A key purpose of HTA in decision making is to achieve greater value for money[ii]. It is now used in most countries across the world either directly to assess and price new medicines or indirectly in pricing negotiations.

The limitation of HTAs

HTAs depend on good clinical evidence and are most effective when there have been large clinical trials comparing the new medicine with the current standard of care. However, there is a growing trend for medicines to be targeted at smaller patient populations. A good example of this is precision medicines, which is an approach that targets treatments to a genetic understanding of patients’ disease. There has been a rapid increase in the number and types of precision medicines ranging from cell and gene therapies to medicines targeting specific genetic mutations of cancers. Recently, we have seen the development of tumor agnostic medicines which target a genetic mutation in cancer irrespective of where they are located in the body. 

As medicines target fewer patients with more precision, the clinical trials become smaller and more focused. The same applies to medicines targeting rare conditions where there are also low numbers of patients to take part in clinical trials. The problem with these medicines is that the amount of evidence that can be generated is limited by the number of patients who can be treated. This gives HTA bodies less evidence to base their decisions on. 

HTA processes were developed for traditional medicines with relatively large clinical trials. These processes are not as good for rare conditions or precision medicines. HTA bodies have struggled to make allowances for the smaller clinical trial size and the clinical trial designs required for precision medicines. A similar issue is faced when a medicine shows particular promise during early trials and is allowed to launch early. Ironically, it has been more difficult for some of these promising medicines to receive reimbursement because of the lower amount of evidence that has been produced to support them at launch.

Balancing the commercial benefits of an early launch with the reimbursement issues of lower levels of evidence is critical. It is key to optimize the evidence package at an early stage to minimize any potential reimbursement issues.

Pressures on pricing and market access

Even before the COVID pandemic, there have been significant pressures on the prices and market access of new medicines. This is manifesting itself in different ways in different countries and regions. This pressure is not limited to price alone, as there are global calls for increased transparency in R&D costs and prices in different countries. Ultimately, the calls for increased transparency are to enable countries to use this information in pricing negotiations.

USA

The US spends more per capita on medication than anywhere else in the world. There has been significant rhetoric about the prices of medicines in the US and it has become an election issue, with both democrats and republicans taking aim at medicines prices. Proposals to reduce the spend on medicines have included importing medicines from Canada where prices are cheaper and allowing the Centers for Medicare & Medicaid Services (CMS) to negotiate on medicine prices.[iii] In turn, pharmaceutical companies have blamed Pharmacy Benefit Managers (PBMs) for artificially inflating drug prices by demanding big discounts that are not passed on the patient[iv]. In reality, there are no simple solutions and politicians may find that there are unforeseen consequences from attempts to reduce prescription drug prices[v]. 

Even if the political rhetoric is discounted, changes are taking place that may have an impact on access and pricing. The US has its own HTA body – Institute for Clinical and Economic Review (ICER).  ICER is an independent, privately financed body that undertakes HTAs on drugs and other technologies. It sees itself as “the nation’s independent watchdog on drug pricing”[vi]. Its true influence is debatable, but it is not the only US organization to use HTA processes in their assessments of new medicines. However, ICER is gaining credibility nationally and internationally, its independent standing being a key selling point.

EU

Most countries in Europe have their own HTA system, often resulting in different outcomes in neighboring countries[vii]. There have been attempts to bring together the disparate HTA systems and processes. The European Network for Health Technology Assessment (EUnetHTA) was established in 2009 and brought together over 80 organizations involved in HTA across Europe. EUnetHTA members collaborated in early dialogues and producing joint HTA assessments. However, these joint HTA assessments are not widely used, especially by countries with more established HTA processes.

The EUnetHTA project is due to end in 2021 and the European Commission has developed a proposal for a new regulation on health technology assessment (HTA) cooperation. The aim was to streamline disparate national HTA processes and generate a single, joint clinical assessment, the promotion of early dialogues, and the identification of emerging technologies and other opportunities for voluntary cooperation. The proposal is progressing through the European Parliament and is being modified along the way. It remains to be seen whether the original vision of the European Commission will emerge intact.

There are a number of other groups progressing the idea of collaboration in HTAs and joint price negotiations. The main groups are Beneluxa (Belgium, Netherlands, Luxembourg, Austria, and Ireland), FINOSE (Finland, Norway, and Sweden) and the Valetta Declaration group (Italy, Greece, Romania, Malta, Cyprus, Ireland, Spain, Portugal, Slovenia, and Croatia). The Visegard group is an alliance of Central European countries and is also contemplating joint negotiations on price. Beneluxa and FINOSE are already developing joint HTAs with Beneluxa also conducting joint negotiations after the HTA. Where these groups end up is open to speculation, but it is clear that some form of co-operation on HTAs and price negotiations is likely to remain.

Beyond the USA and EU

Pressures on access and pricing are not confined to Europe and the US. It is a topic that other countries, such as Canada, are trying to address with reforms to the national pricing body, PMPRB, as well as a change in reference pricing. Japan has steadily reduced drug prices at around 2% to 8% every other year since the 1970s and this trend is continuing.

Global calls for transparency regarding pricing and R&D costs

There have been calls for increased transparency on pricing and R&D costs for medicines. In May 2019, the World Health Assembly (WHA) in Geneva adopted a resolution on transparency in the market for health-related products. The final resolution was considerably weaker than the original draft proposed by Italy but still contains some measures that could have a substantial impact on market access around the world. The original resolution sought to promote greater transparency in four areas: pricing, R&D costs, clinical trial data, and patent information. A much weaker resolution emerged after countries like Germany and the UK objected. Significantly, several of the sponsors of the WHA resolution – Italy, Greece, Malta, Portugal, Slovenia, and Spain – are also members of the Valletta Declaration group, formed to collaborate on the assessment and procurement of new medicines.

Italy has recently published a decree requiring drug manufacturers to disclose data about public R&D funding and reimbursement prices in other countries during negotiations over pricing and reimbursement for any medicines.[viii] In a similar vein, Spain has published plans to address what it sees as pharmaceutical “overpricing” and is seeking to “achieve fair prices based on the development and production costs of medicines and a reasonable profit to stimulate innovation.” [ix] This is contained in a report developed by the Ministry of Health with input from an expert group. While the report has a wide-reaching action plan, it echoes the WHA resolution on transparency in seeking to link prices with R&D costs.

Transparency on pricing and research and development funding could have a significant impact on market access and pricing if it is pursued across Europe.

The impact of COVID

The COVID pandemic has had profound global impacts that go beyond the appalling death toll and serious infections. The International Monetary Fund (IMF) has predicted that the global economy will shrink by 3% this year. It described the decline as the worst since the Great Depression of the 1930s.  Governments have been forced to spend massively both to combat the effects of the virus and to prop up industries and workers as national and local lockdowns have been instigated.[x]

For the health systems, the pandemic has resulted in a shift of funding towards treating severely ill patients infected with COVID and to delay treatments for other patients. It is clear that funding for health will become ever tighter. Some surveys of payers suggest that they expect budgets to be cut by 15 to 25%.

The most noticeable reaction so far to the economic impact of COVID has come from the Spanish Government, which has published an action plan seeking to reform drug pricing to recover €8 billion per year of alleged drug “overpricing.” [xi]

An interesting note is that even the pricing of potential COVID treatments has come under scrutiny. ICER in the US reviewed remdesivir for the treatment of COVID patients and came up with two different pricing models[xii].

These were:

1. “cost recovery” for the manufacturer, representing an estimate based on peer-reviewed methods of calculating the minimum costs of production for a course of therapy; and
2.  traditional cost-effectiveness analyses looking at the incremental health benefits and costs within the health system.

The differences in the prices were $10 for a 10-day course using the cost recovery method and $4,500 for a 10-day course using their normal cost-effectiveness method. This is the first time that ICER has presented such an analysis and it has similarities with the Spanish proposals.

The economic impact of COVID on health systems should not be underestimated. Expenditure on medicines is an easy target for politicians and payers and we expect that this will be reflected in pricing negotiations. A serious paradigm shift as suggested by ICER and the Spanish Government is unlikely to be supported by countries that have sizeable research-based pharmaceutical industries such as the United States, Germany, the United Kingdom, France, Switzerland, and Japan. However, negotiations over pricing and reimbursement are likely to be tough and remain so for some time to come.

Predicting price and access in a changing world

Predicting how a medicine can achieve optimal price and access in the future is both a science and an art. Pharmaceutical companies want to be able to predict the optimal price for new medicines to achieve wide market access in multiple countries. This can be challenging when looking several years ahead, especially in the wake of a global pandemic. However, the principles behind how the price and access will be determined by payers are predictable – even if there are currently more uncertainties than normal. 

What are the key factors that determine price and access?

There are three main determinants of price and access – the level of unmet need, the clinical and patient benefits the new medicine delivers, and its value for money. The evidence package presented to payers must address all of these and be sufficiently robust to convince even the most skeptical payer.

Level of unmet need

A new medicine may be able to target more than one indication and have a higher impact in a particular sub-group of patients. The level of unmet need will be different in different indications and sub-groups. It is also partly dependent on what the standard of care will be at the time of launch and the impact of competitors in the same indication. This needs to be measured early to inform important R&D decisions and updated as the early clinical trial results become available. If a medicine has multiple potential indications, it may be better to start with the indication which will achieve the best price and add other indications later.

Clinical and patient benefits

Unmet needs are important, but what clinicians and payers really want to know is how well the medicine works and whether it is better than the current treatment. The benefits are measured in terms of clinical benefits/disbenefits and the impact on the patient’s quality of life. Quality of life improvement is more important to some payers than others but must be measured and presented to all payers.

The evidence package describing clinical benefits and adverse events must obtain regulators’ approval as well as persuade payers of the value of the product. A key issue for payers is to be able to compare the new product with the current standard of care. There are a number of things that payers and clinicians look for when assessing the level of clinical improvement. These include – the level of comparative clinical improvement, the appropriateness of the outcome measures, how well the patient population matches the indication and patient population being treated, the comparator chosen in the trial, the number of patients included in the trial, etc.

The choice of comparator for a clinical trial is a critical decision. Often, the comparator in clinical trials is placebo which means that there is no direct comparison between the new product and the standard of care. This is when an indirect comparison has to be relied upon to measure the level of clinical improvement.

Value for money

Payers are looking for value for money and affordability from products they purchase. This is measured differently in different markets but essentially comes down to the cost effectiveness of a medicine and/or its budget impact. Cost-effectiveness is highly dependent on the clinical effectiveness and the impact on quality of life. 

There needs to be sufficient data collected to be able to measure cost-effectiveness and budget impact. In reality, it is often not possible to collect all the data required in the clinical trials and plans must be made to fill any gaps. These plans are best started at an early stage as it may take time to collect any additional data required.

Optimizing the evidence package

Optimizing the evidence package is a balance between the practicality of collecting all the data in the clinical trial and the increased benefit that it may bring. Often there are other ways in which additional data can be collected to supplement the evidence package, such as real-world evidence (particularly relating to the comparators).

As consultants, we see situations where the clinical trials have been designed to satisfy regulators but do not answer payers’ questions. This can make reimbursement and pricing more difficult. It is frustrating because often these clinical trials could have been optimized if pricing and access issues had been addressed during the design of the clinical trial.

An important way to judge the data required is to look at how HTA bodies have reviewed similar medicines. We routinely review previous HTA reviews of medicines in the same indication or that have similar mechanisms of action. This is to learn from how HTA bodies looked at the evidence, what criticisms they had, and what precedents were set in previous reviews. An HTA review will show what HTA bodies liked and disliked about the evidence used to support previous submissions and the economic models that they found acceptable.

The science is fairly straightforward, but the art is in assessing how the multiple factors will affect the potential price and access of a new medicine. We have to understand the science, but also the future payer environment, how public policy will change, and the uncertainties with the data, competition, etc. This is when experience and expertise are important; to weigh the data, the market research advice from payers/KOLs, the future environment, and to provide advice that is future-proof.

Support in an uncertain future

Change is a constant fact of life, but we are going through an unprecedented period of change. COVID impacts the world’s economies, healthcare, and pharmaceutical companies, but it is only part of the changing environment. New medicines are being developed years before they reach the market with critical decisions made on the basis of how it will be received by markets and the potential return on investment. These decisions are informed by the best available evidence and expectations of how the market will look in the future.

Making accurate predictions requires a critical mix of science and art – science to assess the clinical evidence and expertise and experience to assess the future impact of health policy, HTA processes, etc. Launching a new medicine is becoming more and more complex; companies need to understand and work with this complexity in order to be successful.

Amaris Consulting has the scientific and clinical expertise and the access and pricing experience to help companies succeed in an uncertain future.

For more information on Amaris Consulting Life Sciences capabilities, visit www.amaris.com

Sources

[i] Buxfeldt C  Observations of a market access expert Pharmafocus 1 April 2019 p19

[ii] Banta D  What is technology assessment?. Int J Technol Assess Health Care. 2009; 25: 7-9

[iii] New York Times. Trump administration weighs allowing drug imports for cheaper prescriptions. July 31 2019 https://www.nytimes.com/2019/07/31/health/prescription-drug-prices.html

[iv] Thomas K. Meet the Rebate, the New Villain of High Drug Prices. The New York Times July 27, 2018 https://www.nytimes.com/2018/07/27/health/rebates-high-drug-prices-trump.html

[v] FiercePharmaPolitics—Trump and Big Pharma tussle over drug price proposal with 3 months until electionAug 3^rd 2020 https://www.fiercepharma.com/pharma/fiercepharmapolitics-trump-and-big-pharma-tussle-over-drug-price-proposal-3-months-til

[vi] ICER website https://icer-review.org/about/ Accessed 1^st September 2020

[vii] Vreman R, Mantel-Teeuwisse A, Hövels A, Leufkens H, Goettsch W. Differences in Health Technology Assessment Recommendations Among European Jurisdictions: The Role of Practice Variations, Value in Health, 2020;23: 10-16 https://www.sciencedirect.com/science/article/pii/S1098301519323411

[viii] Gazzetta Ufficiale Serie Generale n. 185 del 24-07-2020 https://www.gazzettaufficiale.it/do/gazzetta/serie_generale/0/pdfPaginato?dataPubblicazioneGazzetta=20200724&numeroGazzetta=185&tipoSerie=SG&tipoSupplemento=GU&numeroSupplemento=0&progressivo=0&numPagina=1&edizione=0&elenco30giorni=true

[ix] https://2opfle1yeg2f3zqyqbpfbx76-wpengine.netdna-ssl.com/wp-content/uploads/2020/07/Plan-de-acci%C3%B3n-para-la-transformaci%C3%B3n-del-Sistema-Nacional-de-Salud-en-la-era-post-covid-19%E2%80%99-v5.pdf

[x] https://www.cbo.gov/system/files/2020-06/56388-CBO-Scott-Letter.pdf

[xi] https://2opfle1yeg2f3zqyqbpfbx76-wpengine.netdna-ssl.com/wp-content/uploads/2020/07/Plan-de-acci%C3%B3n-para-la-transformaci%C3%B3n-del-Sistema-Nacional-de-Salud-en-la-era-post-covid-19%E2%80%99-v5.pdf

[xii] https://icer-review.org/announcements/alternative_pricing_models_for_remdesivir/