Innovative Drug European Associates


It’s hard to consider a bright side to the current coronavirus pandemic the world finds itself in, but the delays and temporary suspension of many clinical trials do present an opportunity to step back and address gaps in many trial processes.

The question, then, is how can you use this time efficiently and effectively to improve clinical outcomes?

One of the problems companies often run into is that their trials lack a patient impact assessment. Companies need to show that the product has an appreciable impact on patient-centred outcomes – in other words, does it improve the patient’s quality of life? And can that be demonstrated? This is important, since payers are unlikely to agree to reimbursement without this data.

Let’s consider a diabetes drug. The value of a new diabetes medicine is not measured by reducing blood glucose but by appreciable patient benefits, such as avoiding amputations, ulcers, and even untimely death. It’s about understanding what parameters are going to be beneficial and providing the statistical data to the payers in a way that demonstrates a product’s value to patients and the healthcare system.

Demonstrating value starts with having a good understanding of the patient’s story, how their lives could be improved, and where their priorities lie, and then building those tests into clinical studies. That might be a walk test or a detailed patient diary that takes daily measures of mood or stomach upsets or whatever disease signals the patient is dealing with daily. Ask yourself whether these parameters have been accounted for in the trial design and if not, take the opportunity to design a new patient reported outcomes (PRO) checklist and ensure it has been properly qualified and tested.

Building relationships

Use this time when many trials are suspended to talk to the patients. Do you have a solid relationship with the relevant patient advocacy group and have you included that group’s input into the study design? If not, now would be a good time to ask how you can involve them in any amendments you will have to make when the study restarts.

Above all, ascertain whether you have a clear understanding about the patient’s struggles, that you can clearly articulate how the disease affects that patient’s day-to-day life, and that you have ways to measure those effects. There may be simple changes that can be made to the trial going forward, such as adding some information to the case report forms or patient diaries, or perhaps including a new questionnaire for patients to fill out. There are potentially activities that patients could be doing now, depending on how the study is being held, such as using a patient diary as a control diary in preparation for restarting the trial, and providing input to get a new PRO validated for use

Rather than dwell on the potential setbacks to suspending trials during the pandemic, it’s worth remembering that time is only lost if it isn’t used productively now. Use this time to carry out a review of your regulatory and clinical trial strategy so that when trials resume you can demonstrate, with statistical data, the value your product brings to patients.

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It’s understandable that companies tend to be focused first on getting their products approved. But that’s just part of the battle. The other part is getting your products paid for. In July 2017, EMA began offering consultations in parallel with the European Network for Health Technology Assessment (EUnetHTA).

The objective is to ensure that you not only have the data needed to approve your product for marketing authorisation, but also the economic effectiveness data to support reimbursement arguments.

To date, however, most companies have shied away from the joint consultation process. There are good reasons for this reticence. First, it’s a new process and many companies don’t know how to do it or what to expect. But perhaps a bigger barrier is that once you’ve had the parallel consultation, you can’t talk to the individual member states (to avoid potential for conflicting advice). This can feel like you’re shutting down your options. Another potential issue is if the regulatory and HTA recommendations conflict, which may sometimes be the case.

But by talking to both at the same time you can ensure you don’t just receive the green light to sell your product but also the support of the payers, and you are fully aware of any potential setbacks and problems. This allows you to plan your development strategy according to your priorities, with an understanding of where issues might arise in future. If you are entirely focused on getting MAA approval without considering reimbursement from early on, you could well spend precious years jumping through additional hoops to get it on the market post authorisation.

As with any process, any undesirable responses that arise during your conversations with EMA and the HTA representatives can be addressed if you start early enough. If your product is for a rare disease, you might be providing surrogate endpoints rather than the traditional pivotal endpoints. If that’s the case, you need to be looking at building patient-reported outcomes in your phase 2 trials, which will help with your economic analysis later. Having that conversation early and knowing what to expect may well improve your position later when it comes to the decision about reimbursement.

As I’ve stated before, the regulators want to get good products to patients – as do the HTA representatives. But they want to know that what they’re paying for will make a difference to patients compared with what is already on the market. And they need to understand how your product works. If you have a first-in-class molecule that requires HTA bodies to install new diagnostic equipment to diagnose the biomarker, they need to see the value of investing in your product. That’s a reasonable expectation. So, the sooner you discuss those needs with all the key stakeholders, the better your chances of getting your product on the market and starting to make money from it.

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The regulatory process is complex and can be very difficult to navigate. It’s not just about gathering data and meeting milestones, but also about understanding the regulatory language.

Often,  young biopharma companies come to me after completing a scientific advice procedure with the regulators and are under the impression that the agency in question have agreed to their proposal or that they have the desired answers and are following an appropriate course of action. Whereas, on examination of the correspondence, that’s not exactly what the authorities have said.

After spending time and money preparing their scientific advice request, it turns out that the questions they put to the authorities either weren’t specific enough, or failed to address a critical component of their development, meaning their product development plan won’t translate into the ‘easy’ approval they are expecting. There are details that may be missed if the question asked doesn’t have the right target, the right focus, or if the company didn’t have the right regulatory support to help them through the process.

Unfortunately, if left too late, what might have started out as a simple programme becomes more expensive to do because of early missteps like this. It might mean redoing aspects of clinical and pre-clinical studies because the data doesn’t support the proposed indication or formulation, or improving methods of validation and analysis to improve manufacturing techniques and repeating testing to improve the quality of the data required for the CTD Module 3.

Another issue that many young biopharma companies from the US often confront when entering the EU is just how heterogenous the marketplace is. While regulatory processes are centralised to some extent, each member state has its own requirements with regards to what should be in the submission documents, what data needs to go into a clinical development package, or how standards should be met. That means while there is a core EU submission dossier, there are always different requirements for each EU country.

Understanding what the regulators expect and what will be needed to develop products is highly complex. Understanding how to communicate with the agencies effectively, and ensuring the advice received is clearly understood and incorporated appropriately into the product development plans is an art and a science;  it requires clear knowledge of the product, it’s development, the company’s ambitions for it, the regulatory requirements, and asking detailed questions that are supported by sound data-backed, and scientific justifications. That can be a huge challenge for companies new to the EU market.

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In a previous blog post (Linked here), I raised the issue of patient-centricity and my concern that it is being used more as a marketing tool than a way to build truly patient-centric products. To shift that thinking, there needs to be broad commitment to bringing patients into the fold at every stage of the development process.

Have patient advocates come into the company periodically to talk to the whole team – from the chief executive officer and chief financial officer to the clinical research associates, regulatory personnel and others involved in the development of the product. Get the patient to explain how the disease affects their life and what their wants and needs are. How can you design a product and put it on the market if you don’t truly understand your customer?

The fact is that those of us in this business aren’t here primarily to make money: we’re in medical research to help bring treatment to patients who need them. So, bring them in. Have them speak to your partners in the clinical research process so we can hear from patients or their carers – even if it’s by video or webinar – what they need and what their main challenges are. In so doing, it would help clinical research organisations and others to design studies better, build recruitment plans around the needs of those patients, and establish better compliance endpoints, because trials would be designed in a way that supports the needs of patients.

While discussions with patients may well be happening in the background, if everyone involved in the clinical design process doesn’t hear and can’t contribute to them, we can’t build products and protocols that meet the needs of patients.

When that starts to happen, studies will become more patient-centric and endpoints will be geared towards the needs and concerns of patients. And when that occurs, the authorities are more likely to not only be more open to approving a product, but also to reimbursing it.

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There is very often a them-and-us mentality when it comes to how biotech companies think about the regulators. New companies, in particular, tend to view what is said by the regulators as prescriptive and are afraid to speak to them or get the scientific advice that is available.

However, if they did take time to speak to the authorities early in the development process, they could learn what the regulatory difficulties with their planned dossier might be, rather than risk long delays to their marketing authorisation as they scramble to gather the necessary information later. The earlier companies speak to the regulators and get their advice, the better off they will be in terms of understanding weaknesses in the development strategy, gaps in information about the product, what data will be harder to source, and which aspects they should be making a priority.

For example, if a company has a first-in-class molecule and doesn’t yet know how to identify it, it’s possible they haven’t refined the crystallography. But it’s likely the regulatory authorities will have scientists who can offer advice or recommend an equivalent test that would provide the information needed. Reaching out to the regulators is an invaluable way for companies – particularly small innovator companies – to get the answers they need.

I have spoken to regulators who have gone so far as to provide a detailed template protocol to a company that didn’t know how best to design a study for their orphan drug, when they took a COMP advice procedure as part of the orphan drug incentive. That is a huge saving, since companies can spend thousands on KOL’s and medical writers for a protocol.

The fact is that the regulators want to help companies bring good products to market, especially orphan drugs. They have established programmes such as the SME (small and medium-sized enterprises) and Orphan Drug Designation to facilitate this and are there to guide companies through the regulatory process. They do not expect absolute agreement with the guidelines and regulations either and acknowledge and welcome the expertise of the company’s scientists. If companies feel a different approach is best for their product, they can debate it so long as they justify their argument with data and scientific evidence. Indeed, this is actively encouraged, especially for innovative products where no precedent is available in the guidelines.

Working with the regulators to bring a product to the market can be a wonderful, collaborative, process. It’s a shame to fear it and miss a golden opportunity to advance promising products.

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