Why early P&MA planning is always a good investment.
By Rachel Galloway, Senior Consultant
Introduction
The sound of your footsteps echo down the empty corridor as you rush to the exam hall. You’re running late. In haste you find your seat and turn to the first page of the examination paper. You are enveloped by a sinking feeling as you realise you haven’t prepared adequately…and then you wake up.
Pharma companies can find themselves in an analogous real-world scenario to this common recurring nightmare as they plan for reimbursement and access for their product without the evidence they need to achieve their price and reimbursement goals.
In the past, the timing of market access activities on the path to product launch has led pharma companies to plan for market access in the latter stages of clinical development. However, as payers across the globe become more stringent and prescriptive about evidence requirements there is a need to think about market access much earlier in the development process. Some manufacturers are now thinking about market access before conducting any clinical trials in humans. What advantages can this early consideration bring and why should you think about market access for early pipeline assets? Let’s explore.
The Fourth Hurdle
Safety – check.
Efficacy – check.
Quality – check.
Navigate these three hurdles and your medicine has demonstrated enough to regulatory authorities for marketing authorisation, but in order to gain market access and reimbursement there is one more hurdle to conquer.
The fourth hurdle typically requires manufacturers to demonstrate clinical effectiveness (is it better than the standard of care?) and cost-effectiveness (is it value for money?). Its introduction marked the end of the era where regulatory approval alone could grant commercial viability.
These additional evidence requirements came with the establishment of new entities, such as NICE (the National Institute for Health and Care Excellence), and the emergence of legal reforms such as AMNOG (the Pharmaceuticals Market Reorganisation Act), which implemented new methodologies to assess innovative medicines.
Some examples include those highlighted below:
The fourth hurdle to obtaining product commercialisation has been viewed as an opportunity to demonstrate value and achieve ambitious price and reimbursement goals. However, as the gap between evidence requirements for marketing authorisation and market access has grown, the height of the hurdle has increased for many manufacturers.
While regulatory authorities strive to be more flexible to speed up the development and review process for medicines that address unmet medical needs, payer evidence requirements have become less flexible and more demanding. This is a particular challenge for manufacturers developing more complex technologies, such as gene therapies, or medicines indicated for (ultra-)rare diseases.
This divergence in evidence requirements can leave manufacturers with a difficult juggling act to balance as they try to meet the needs of both parties. This is especially true if phase III clinical trials are underway and there is limited scope to change study designs and/or conduct additional studies to address evidence gaps and market access-related challenges.
While there is no perfect evidence package and requirements may evolve with standards of care, some of these challenges can be avoided by planning for earlier engagement with market access stakeholders.
Early pipeline meets early engagement with market access
There are formal, early interaction processes to obtain advice from regulatory authorities, such as early scientific advice with the EMA and a pre-Investigational New Drug meeting with the FDA. Both have been shown to improve marketing authorisation success and reduce clinical development time.
Early input on market access is also offered by several payer bodies (e.g. NICE, the G-BA). However, given the huge number of agencies to cover across fragmented payer landscapes (with varying evidence requirements) it can be necessary to prioritise specific markets. In Europe, this process has been streamlined via parallel EMA/EUnetHTA 21 Joint Scientific Consultations that enable developers to obtain feedback on their clinical trial plans from regulators and health technology assessment bodies. The objectives of these consultations is to help developers generate optimal and robust evidence that satisfies the needs of all. Over the past few years, more opportunities for joint advice with regulatory authorities and payers have emerged as stakeholders attempt to address differences in evidence requirements.
Here are some of the early market access interventions you can undertake and the positive impact they can have.
Early consideration of market access
Validate the appropriate comparator
Placebo-controlled trials are almost a thing of the past when considering conditions for which alternative treatments exist. At a minimum, many payers will expect a trial of the new treatment in addition to best supportive care against best supportive care alone; however, the definition of best supportive care can vary by country. Absence of evidence against the appropriate trial comparator can result in an HTA/clinical dossier being rejected or the new treatment automatically being rated as having no additional benefit. The stakes are high so it’s important to consider which trial comparator(s) will address the needs of the most important markets.
By conducting comprehensive primary and secondary research, pharma companies can get an early view on the current treatment environment and standard of care in each line of treatment, or patient subgroup, to inform trial comparator decision-making. Of course, the standard of care may change, so such research should also identify potential future competitors that will impact your product’s evaluation, place in therapy and price potential.
Ensure your product addresses an unmet need
Early treatment landscape research can also confirm the (remaining) unmet needs for a specific indication or patient type. If your product doesn’t address an unmet need that is meaningful to payers, then their perceptions of value are going to be low; the “another tool in the toolbox” argument isn’t compelling when safe and effective treatment options already exist. Moreover, different dosing frequencies, formulations or administration methods are rarely sufficient to differentiate a therapy (at least not in the eyes of most payers).
Validate your phase 2/3 trial endpoints
Before you’ve decided on your trial design you may want to draw inspiration or guidance from payer reactions to evidence submitted by current or future competitor products. Early research on the competitive landscape can identify challenges other products faced and successful solutions. This is especially helpful when using a surrogate or new composite endpoint as it can help inform what additional evidence is needed to demonstrate efficacy; particularly where payers still have some reservations about extrapolating data from surrogate endpoints or how they will evaluate the statistical significance of individual components of a composite endpoint (which can inform the trial population size needed.)
It is critical to consider whether patient reported outcomes should be included and if not, will the chosen endpoints be considered as patient-relevant? The choice of PRO tool should take into account how well its validity has been established. If you are planning on conducting a health economic analysis that includes quality-adjusted life-years, do you have a measure that will allow you to assess utility, directly or indirectly?
Additionally, if you are seeking to make claims that your therapy can reduce use of other medical resources (such as the number of days spent in hospital or the need for medical procedures), endpoints evaluating these aspects should be considered for inclusion in clinical trials. If omitted, such claims will only be possible post-launch when real world evidence becomes available.
In addition to selecting payer-relevant endpoints, it is critical to consider the hierarchy of endpoints in the statistical analysis. This may be based both on the endpoints that are considered most critical but also those that are most likely to show a benefit. A consequence of getting the hierarchy wrong is having statistically significant results dismissed because they were lower in the hierarchy than those that failed to show significance.
Target the right patient group(s)
The target patient population is one of the key strategic decisions that needs to be made early on in development.
Should you target a broad patient population with some remaining unmet needs where payer willingness to pay is lower (particularly amongst budget impact-focused payer archetypes) or will you target a smaller patient population with a higher unmet medical need, where payer willingness to pay a price premium may be higher? Which strategy leads to the greatest ROI? It’s important to test different patient populations and price scenarios to inform early strategic decision-making.
What is the likelihood of demonstrating a benefit over current treatment in each potential target population? If there is a strong rationale for one subgroup benefitting to a greater extent, it may be appropriate to design the study with stratification of the population. It’s also critical to pre-specify any subgroup analysis for the results to be considered. Post-hoc subgroup analyses are unlikely to be taken into account in the regulatory label indication and not all payer types are willing or able to restrict reimbursement beyond the regulatory label.
Find a price benchmark
For many indications the standard of care or clinical trial comparator will be a clear pricing benchmark throughout pricing negotiations, but where do you start the discussion in an (ultra-) orphan indication with no approved treatment options and no established pricing benchmarks?
Early engagement with market access stakeholders can help you identify relevant analogues that may be considered by payers (i.e. on the basis of disease similarities, level of unmet need, population size etc.). It can also highlight other factors payers will consider when determining price, helping you define the target price potential more precisely.
Optimise price
The clinical performance of a therapy is beyond the manufacturer’s control but it’s not the sole determinant of a therapy’s price. By evaluating different P&MA scenarios, it’s possible to identify opportunities to increase price potential. How your product is distributed, how and where it is administered and from where it is dispensed can impact the funding flow and price potential of a drug in some markets. If there is scope to change the dosing, formulation or administration of your product then it can be helpful to do some scenario analyses early on to explore which option best aligns with your strategic priorities.
Identify other evidence generation needs
Developing an early value proposition can identify which aspirational messages are not supported by sufficient data and evidence gaps that need to be addressed before launch. That could be the validation of a surrogate or composite endpoint, determining the proportion/ number of severe patients or collating data on the cost of treatment failure. Often these activities can take years to complete so the sooner you identify them the greater the likelihood they can be addressed before you reach the fourth hurdle. However, some evidence will be more of a “nice-to-have” rather than an urgent and important need, and payer testing can help highlight which aspects of the evidence would be most critical to pricing and access success in each country to inform local level market access planning.
Early value message development can also identify real-world data requirements needed to support longer-term aspirational clinical or economic claims.
Conclusion
Early consideration of market access is not a silver bullet; but it can remove blind spots that pose a tripping hazard at the fourth hurdle. Manufacturers who are proactive and diligent from an early stage of development will be better equipped to tackle that hurdle and better informed on which time, cost and risk trade-offs can be accommodated to navigate it.
For those planning to launch therapies in Europe from 2025 onwards, early consideration of market access will be imperative as EUnetHTA21 is likely to transform the HTA landscape and manufacturers will need to adapt to changing needs and requirements.
Whichever approach you choose, early P&MA planning is always a good investment.