Bench to beside is a deceptively simple phrase. Only 15 characters and relatively jargon-free (assuming you know what bench and bedside are referring to), it’s rather easy to drop into documents or presentations without compromising space or time limits. And, perhaps most critically if you happen to be an academic researcher, it’s also very desirable at the moment, especially if found in grant applications.
But so much goes on in the between – who would guess that four small characters (space, t, o, space) could be so laden with importance and fraught with challenge?
Take, for example, the notion of value and reimbursement. This one facet of the bench to bedside pathway holds a certain amount of tension within the clinical translation setting and is prone to misunderstanding, particularly by those critical of a development process that seeks to define outcomes in dollars and cents. I’ve heard more than one person say that it is the elephant in the room in many discussions related to the stem cell and regenerative medicine space, as the field begins to see and grapple with the many hurdles still in its path to the finish line. The reality of a market-driven economy dictates that nothing moves forward unless it has value – value to consumers, but perhaps more importantly in its incubation period, perceived or real value to those with the means to invest or reimburse the costs (not always just monetary) of development (for more on reimbursement and therapeutic headroom, read this post by Mark Curtis). Noble as it is, altruism does not drive therapies into the clinic.
These and other themes central to a bench to bedside pipeline emerged with great frequency over the three day World Stem Cell and Regenerative Medicine Congress that took place in London in late May. Several speakers spoke about the interconnectedness between regulation and reimbursement, between manufacturing and commercialization processes, data and approvals, marketing and customer identification and of course value in every step along the way (such as benefit to patients, investment, production processes).
So it is hardly surprising that the opening speaker on May 22, Sven Kili, Senior Director of Global Medical Affairs – Cell Therapy & Regenerative Medicine at Sanofi, charged with the daunting task of condensing a clinical development and commercialization strategy into a 20-minute talk (hence the title of this post), would have begun his presentation by emphasizing the need to embark with value planted firmly in mind. What follows is a summary of his presentation, a quick and dirty guide, if you will, capturing key things to keep in mind if you’re beginning to think about getting your product or therapy into the clinic. Kili covered several key areas, which I’ve placed into sections to help organize the material.
Why take the time to develop a clinical trial strategy?
Kili started with a look at some of the challenges facing personalized medicine, all of which require careful consideration:
- Cost of production
- Regulation pathways are still being defined; for the most part regulators still see cell therapies through a drug development (Big Pharma) lens – lots of dialogue still needs to take place to change this (echoed by other presenters on day 2) and you will need to have conversations with regulators as part of a successful strategy
- Need for surrogate outcomes requires careful consideration – these will need to give clear indications of long-term outcomes (i.e. 20-30 years) in a short window (2-3 years)
- Long term efficacy – this is particularly challenging given the difficulty in projecting health outcomes in the absence of long-term data
- Improvement over current standard of care – how do you go up against cheaper but less effective drugs?
If the goal is to get a therapy or product to the clinic, then a strategy will help do several things, both on the development and the commercialization side. In terms of development, a well-planned program will optimize the entire process, shorten the clinical stages, reduce costs and help you identify and generate the best clinical and safety data, all of which will get the therapy or product to the market faster. On the commercialization side of things, the strategy will put key pieces into place, such as market understanding, engagement of key opinion leaders, a management framework and effective launch in order to ensure market uptake and reimbursement.
Designing a clinical trail program to support commercialization
> In the design stage, there are a number of items to keep in mind:
- Understand the market – invest in market research or do some on your own.
- Think in terms of commercialization, not just research.
- Get to know the regulations and regulators — this was stressed not just by Kili, but by several speakers at the conference. One of the first goals will be to define your launch regions and become familiar with their regulations. However, it is recommended that you talk to all the regulators, not just the ones in the jurisdiction of first trials, and not just the ones you think will present the biggest roadblock. Speaking with them will help identify possible hurdles and allow you to get advice. It will help you plan your trial and consider your product’s market profile. And it could possibly help pave the way for regulatory changes that will make it easier for cell therapies to be approved. For example, you can help them understand and justify why you don’t use the same kind of data in cell therapy and why making assessments based on criteria defined by traditional (Big Pharma) pathways may not be appropriate. The two do not always overlap and these differences can be crucial to the approval process.
- Data. What kinds of data will you need in the pre-clinical phase in order to get approvals (species, safety dosing, toxicity, carcinogenicity, etc.) If such tests are not appropriate, you’ll need to justify it.
- Aim to be first-in-man. This is part of the data gathering profile and in itself is a very complicated topic, but you’ll want to think about: the amount of data you will get (most from lowest number of subjects), whether your approach has been done in the academic setting, patient recruitment (healthy vs. patients) and disease needs/severity, dosing, delivery, safety signals as well as whether the manufacturing is optimized.
- Develop phase II/III trials that optimize patient exposure and data gathering, using larger patient numbers. Will you need to define a comparator trial and if so is it acceptable to regulators and investigators? What are the clinically relevant endpoints (biomarkers or surrogates?) and the quality of life outcomes?
- Dissemination. Once you have the data, you need to leverage it, keeping compliance in mind. This is the communications piece – presentations, posters, meetings, media releases and interviews, online media (blogs, podcasts, social media), marketing materials and of course your peer to peer networks.
- Finally, and perhaps most importantly: Stakeholders have conflicting goals, so the overarching one must be high value for patients.
Launch strategies and timing
> Begin planning for launch very early. Think about:
- Where will you launch?
- What will be the (best) timing for launch?
- What is your market?
- Who is your customer (patients, government, insurers)?
- What is your marketing strategy?
- What are the regulatory concerns and approvals required?
- What is the product profile?
- What is the patient profile?
- What is your risk management strategy?
Kili pointed out that there are other considerations for a successful launch, including the need for draw up contracts, material distribution and approval, printing, sales and other logistics. A key milestone is securing approval, but approval is not the only goal. Gaining it does not necessarily mean you’ve succeeded because approval is NOT EQUAL to reimbursement. More on this below, but this is why they are not equal:
- The market wants value
- Consider the stakeholders and their needs
- Buyers do not necessarily care about the suffering you went through during development; time and personal sacrifice might be important, but cannot be quantified to impact either approval or reimbursement
Marketing activities – Key Opinion Leaders and reimbursement
> Engage Key Opinion Leaders (KOLs) – among other things, KOLs can set up structures, develop protocols, speak with authority, represent you or your product at meetings, sway public opinion and develop guidelines that include your product. To engage them, consider:
- You will need a strategy first
- Determine who these people will be for your product (PI, author, physician, other?)
- Where do you find them?
- What do they cost (less expensive in Europe, very expensive in US)?
- How do you track them (could be as simple as an excel spreadsheet you make yourself or a purchased software product)?
Back to reimbursement. Once again, this is emerging as a critical piece so worthy of careful consideration. Without it, you may go nowhere. Kili emphasized that it is critical to understand the marketplace:
- What are the current treatments?
- What is the cost of current treatments and of your product?
- Who will pay (government, individuals, health insurance or a mix)?
- What do you offer that is different and/or better and why is it worth a cost increase over the current standard of care?
- What are the criteria that will be used to decide – what data will you need?
- What are the regulatory requirements and hurdles and the mechanisms for reimbursement across different markets and/or countries?
> With all these pieces outlined in the strategy, the path to the clinic becomes significantly clearer. Kili wrapped his whirlwind talk with a final note to keep in mind: Compliance is key: you must be compliant at all times. On the medical side, this includes promotion, presentations, studies, safety and risk management, management of the key opinion leaders as well as new indications. In terms of commercialization, it includes market access, promotion, sales training and sales team management. The overall vision for this development framework is one that links industry, regulators, clinicians, patients and payers in a common goal to deliver faster and better outcomes. Considerations or experiences to add or share? You are invited to post them in the comments below.
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