Designing for Success: A Multi-stakeholder Approach to Clinical Development to Optimise Patient Access

Designing for Success

A Multi-stakeholder Approach to Clinical Development to Optimise Patient Access

Developing new drug therapy is complex, taking many years to move from proof-of-concept to final data read out from the Phase III pivotal trial. After years of substantial investment, the end goal is to bring the therapy to patients in need. A significant number of pharmaceutical or biotech drug development companies are based in the USA, which is often the first market priority for commercialisation. Where companies are not commercially present in Europe, they have much to gain from a successful market entry into Europe, considering it generates the second largest global pharmaceutical sales revenue (approx. 20%) after the USA and Canada, which account for approx. 50%1 .

The European Union offers a certain degree of harmonisation; however, only with regard to the coordination of drug approval. When a drug is approved, it is valid for all countries within the European Union. Europe is a diverse and complex marketplace made up of more than forty distinct country-centred markets. Beside the more obvious differences in languages, each have their own specific methods to evaluate new drugs entering the market, and have differences in supply chains, patient demand, healthcare system setup and medical standards. Given these differences, bringing a new therapy to market in Europe takes time. According to the latest European Federation of Pharmaceutical Industries and Associations (EFPIA) data (Figure 1), the average time between marketing authorisation and patient access for a new drug varies from 119 days up to 925 days across Europe. Where a company has developed an orphan drug for a rare disease, time to market increases, and the average time between marketing authorisation and patient access increases, varying from 113 days up to 1141 days across Europe. In order to ensure patients in need can access new therapies as quickly as possible, it is critical that a multi-stakeholder approach is taken early on in the drug development process to maximise long-term success. Designing for Success - A Multi-stakeholder Approach to Clinical Development Planning for successful patient access for new drug therapies must start early in the life-cycle of the drug, right at the time of clinical development.

Traditionally, drug development has operated in a siloed approach, whereby functions that are critical to the drugs success post-Phase III are missed from early consultations with research and development teams. Over the years, many companies have adopted a multi-stakeholder approach to drug development, involving other critical functions, such as regulatory, medical, commercial and patient access, and importantly, patient groups, early in the development process.

For a new drug therapy to be commercially successful, it must satisfy the three critical external stakeholder needs; physicians want to prescribe it, patients see the benefits and individual market budget-holders are willing to pay for it. Research and development teams will engage with relevant clinical experts in the field to provide input into the acceptable minimum efficacy outcomes, trial design and likely best patients to include into the trial. However, all other functions should be consulted and involved thought the whole development programme. Commercial and Medical Input and Opportunities Commercial and medical aspects can easily be missed at an early stage of drug development and can have severe consequences in the future. For example, working closely with the regulatory team to have a clear idea on the future label is critical. Small wording differences in the label such as “and”, “or” or “with” can have a significant impact on future positioning and promotion for commercial field force teams.

Understanding the patient pathway and how physcians would intend to use and prescribe a new product is often a key medical input. However, understanding how the new drug may impact patients, and how they will use the product, should not be overlooked and should also be considered in early planning. Receiving input from patients early on can help inform R&D teams on aspects that may not have been considered before. For example, considerations regarding packaging, such as size and shape, especially if the drug requires cold storage in the patient’s home refrigerator, considerations to the type and size of syringe used, items included in ancillary sets or size of tablets and frequency of dosing. Patient Access Input and Engagement Opportunities Patient access (market access) input from an early stage is often missed. In cases where new drugs are developed in companies solely focusing on R&D, input is often overlooked and may not be considered until after Phase III initiation. Often the focus is just on pricing and reimbursement and the likely “achievable” price. However, patient access considerations should not just be focused on price, but also consider appropriate and relevant trial endpoints and evidence requirements from a budgetholder's perseptive that will allow them to clearly understand the value demonstrated by the new therapy.

Healthcare budget-holders vary across markets; those at national level, often involved in health technology assessments (HTAs), regional level commissioners for primary or secondary care, and hospital pharmacists and hospital business managers at the local level. All the different budget-holders are key stakeholders for engagement. And each type of budgetholder requires different types of evidence and they assess value in different ways. For example, the UK and Sweden focus more on cost-effectiveness and health technology assessment (HTA), whereas Germany and France focus more on clinical evidence and the “added benefit” that the new therapy brings compared to existing therapies.

Companies must understand the budgetholder mindsets and differences in applying “value” and should seek opportunities to engage early, either via formal engagement routes that allow companies to discuss trial designs and data in more detail early in the development process, or via informal engagement pathways.

Experience with early engagement has shown that companies are able to build longer-term partnerships. Such partnerships give companies time to consider and plan for endpoints that can deliver evidence that is aligned with budgetholder valuation needs and time to develop a strong value story, which is especially important when developing a therapy that may come to market with a high upfront price and potential long-term cost (e.g. gene therapies). With well executed engagement, new therapies have the potential to gain access to patients quicker, resulting in a win-win for companies, budget-holders, physicians, and ultimately the patient. Considerations for Early Access Opportunities and Planning In addition to planning suitable clinical trials, there has been a recent trend across large pharma to formally include preapproval access planning (compassionate use, managed access, expanded access early access) into the clinical development process. Increasingly, pre-approval access is seen as a key aspect of the commercialisation pathway of a drug. Typically, large pharma are making an assessment at the end of Phase II as to when and if pre-approval access will be granted to that medicine.

As part of the decision process to help a company decide where and what type of pre-approval access is applicable and available, some of the key questions (below) should be addressed in order to provide clarity as to whether pre-approval access is likely to achieve the intended objectives. Key questions to address: • Is there a high unmet need? • Have access requests been received which have been denied or not actioned? • What is the expected future demand? • What does the safety and efficacy profile look like at end of Phase II? • Is there enough stock available to allow pre-approval access supply? • What, if any, data collection is required? • Have preparations been made to interact early with HTA bodies? • What are the commercialisation priorities and are there any territories which require extended pre-approval use support? Data In recent years there has been a greater focus on outcomes data collection in the pre-approval access environment. Any realworld data (RWD) collection during preapproval access should not be viewed as a substitute for clinical trial data. The scope and depth of data which can be collected means that any RWD should be considered as supplemental only.

That said, data collected during preapproval access programmes can provide insights into how the product works in a patient population more similar to the commercial patient population and can help feed in to planning for subsequent clinical trials.

Usage of RWD in HTA decision-making processes varies across Europe, but is still generally agreed to lack the robustness of controlled clinical trials. However, some HTA bodies do accept that in rare diseases, where patient numbers in a clinical trial are low, data collected through other mechanisms may be used for decision-making.

Once companies have navigated the clinical trial pathway, their attention soon turns to commercialisation, and how to ensure patients can access the new therapy across the world. In the next section we explore the different options available to companies for commercialising in Europe. Commercialising in Europe – Key Considerations Despite the great potential of Europe, some pharmaceutical and biotech companies that do not have a European operational footprint can be put off from launching in Europe and question the need. But the question should not be if you should enter Europe, but rather when and how.

An initial question to address is: what is the long-term objective of the company? For a company that has started out as an R&D company and is considering moving to commercialising, is a commitment to commercialising your product on your own the best way to maximise value? Or is it better to divest the IP immediately? Still another option is to enter Europe through a commercial partnership and hold the option for IP divesture open and by that create a higher longer-term value for the asset and the company. The importance of reflecting on this question comes from the fact that entering Europe requires you to make certain strategic commitments that may both open and close future options.

Although there is a continuum of strategic options to enter the European marketplace, these can be summarised into the following three: 1. To establish and build up the company’s own complete commercial infrastructure in all targeted countries. 2. To establish a partnership in all countries in Europe. 3. To engage in partnership in Tier

II countries whilst establishing the company’s own commercial infrastructure in Tier I countries – hence a combination of the above options.

These options all have pros and cons, with differing risk, investments requirement and level of future strategic flexibility.

1. To establish your own complete commercial infrastructure in all targeted countries The advantage of this approach comes from retaining full control over your assets and receiving all revenues.

Establishing commercial infrastructure in Europe requires a large set of operations, including: European medical approval, patient access with reimbursement approvals, preparing and executing the market launch with key opinion leader targeting, launch-sequencing of European countries, supporting operations such as medical, pricing and reimbursement, marketing, communications, sales, legal, logistics, finance, and managerial capabilities.

Establishing such operations requires significant upfront investment some two to four years ahead of first revenue streams, and can limit a company’s ability to invest in other opportunities, such as R&D efforts or a successful US launch.

Establishing your own commercial platform in Europe may be attractive in the case your company’s strategic goal is to become a global pharmaceutical company. In the situation when you have a very strong product at hand or you have a portfolio of products to bring into Europe, then the large upfront investment and its risks can be justified for establishing yourself in Europe. 2. To establish a partnership in all countries in the region A second option for an entry into Europe is to engage in a partnership. The more classical approach to partnership is to strike a deal with a large pharmaceutical firm that has a regional or global presence and already commercialises its own products. The other kind of partnering option represents the specialised commercialisation companies. a. Partnering with big pharma A large or big pharma company that has many assets and a commercial infrastructure with dedicated resources and financial muscles may be attractive from a partnering perspective. Such partnership deals normally offer a certain upfront fee and then an ongoing payment, such as smaller royalty and/or milestone fees. This is attractive in itself, as it may provide you with quick access to needed cash and simultaneously eliminates most of the challenges inherent in building your own commercial infrastructure. Experience shows that deals with a large pharma company may give poor terms and conditions in terms of royalty levels, and since the large pharma company typically holds the rights to your asset for a long time, it effectively means that you are locked in and prevents you from exploring other strategic options that may emerge in the future, such as divesting the product or the company. A deal with a large pharma company may be good in a situation when you do not have other financing options for your company, can’t find an alternative partner, and are very dependent on quick upfront cash. b. Partnering with a specialised commercialisation company Due to the limitations inherent in both options above, a third strategic alternative has emerged that attempts to offer the advantages and eliminate the disadvantages of the two alternative partnering options. There are many partnering companies that offer niche services limited to certain countries or operations. There are also a handful of commercialisation companies that offer operations in all or most countries.

Given the complexity of Europe, it is often recommended to choose one pan-European partner. From a business perspective, a commercialisation firm that operates

across the whole of Europe generates a unique understanding of the dependencies between the various local markets and countries in Europe which may mean a difference between success and failure when entering Europe. In addition, working with one partner avoids the complexities of managing multiple partners, each potentially with different compensation models and challenges posed by reference pricing and parallel trade.

Partnering in this way offers flexibility for the markets you wish to target, of the operations you need support with, the length of the deal, and the payment model. 3. Engage in partnership in Tier II countries whilst establishing your own commercial infrastructure in Tier I countries This option is good in terms of gaining experience in Europe and establishing a European presence. However, it still requires a focused approach and a significant upfront investment even if the company just plans to launch in the major Tier I European markets; France, Germany, Italy, Spain, and the UK. Choosing a partner that the company could launch together with usually reduces the launch cost dramatically while increasing the quality of the launch, as your team can focus on the customers and launch strategy instead of the details around supply chain, permits, office set-ups, etc.

Conclusion Planning for patient access for new therapies must start early in the lifecycle of the product, right at the time of clinical development. By engaging relevant stakeholders early in the clinical development process, it is ensured that the therapy meets the expectation of the prescribers, patients and importantly, the budget-holders. Carefully consider the different options to enter the European market, either by going it alone or through partnering to enable new therapies to reach patients in need. To design for success is to take a multi-stakeholder approach, to engage and plan early, and optimise patient access through a carefully considered commercialisation strategy. REFERENCES

1. EFPIA The Pharmaceutical Industry in Figures, Key Data 2020 2. EFPIA Patients W.A.I.T. Indicator 2018 Survey, IQVIA, February 2019 Any general recommendations, considerations and interpretations are Inceptua’s views, and should not be relied upon as specific recommendations or guidance for a reader and or recipient.

Clive Whitcher

Clive Whitcher, Ph.D., is Executive Vice President, Head of Inceptua Pharma, and is an expert in commercialization and patient access and brings experience from both pharma and consulting across a wide range of therapeutic areas. Clive joined Inceptua from Swedish Orphan Biovitrum (Sobi), where he held the role of Vice President, Head of Global Patient Access & Community Engagement. He was responsible for developing and delivering patient access launch strategies, including launch sequencing and innovative pricing and contracting strategies to secure sustainable access for rare, specialty, and orphan therapies.

Stuart Bell

Stuart Bell, Ph.D., is Vice President, Consulting, Inceptua Medicines Access, and has more than 20 years of healthcare consulting experience, with a particular focus in unlicensed medicines and pre-approval access. Stuart is responsible for Inceptua’s consulting covering strategy and policy, real-world evidence, communications and market access. Prior to Inceptua, Stuart pioneered the development of global corporate strategies on preapproval access and developed the first pre-approval-specific EDC for realworld data collection at Idis/Clinigen.