Innovative Drug European Associates


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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Start-ups and emerging biotech companies often start out with lofty goals about what their products can do. That’s very noble but it’s also an easy way to run out of money halfway through the development process.

While it’s good to have long-term goals, success depends on developing a well-defined target product profile (TPP). Start with a clear understanding of what your product can do and what your label would, ideally, say at the end of the process, considering the key attributes and taking advise from all functions to align the goals. By starting with the end in mind, your programme will be much more focused and effective. With a clearly documented TPP, you can more efficiently design your product development and prepare for the regulatory interactions that will be needed.

For example, too often oncology start-ups hope their therapies will cure all — or at least many — different kinds of cancer. They begin with preliminary trials and talk to the regulators about multiple cancer indications, then start work on them all at once. While perhaps that product does have huge potential, at the end of the day you need to get it to market and make money in order to conduct the extensive research and gather the data needed to demonstrate the safety and efficacy across all of those indications. That means you need to focus on one subset of cancers or take an even more specific and focused route through the orphan drug designation to get to market. You may even be able to cover multiple indications using adaptive advanced trial designs. Once you’ve proven your mechanisms of action, have carried out preliminary efficacy and safety studies in the clinic, and are well on the way to building your first marketing authorisation dossier and bringing in revenue, that’s the time to scale up investment in the rest of the pipeline.

It all comes down to starting with the end in mind and maintaining a single, clear and powerful focus.

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Patient-engagement or patient-centricity is now widely spoken about, but it’s rarely brought into the process of product development early on. As a regulatory consultant, my role is to fulfil the objectives of our clients as I help them navigate the clinical trial approvals process and I strongly believe that this would be a good point to bring patient organisations into the discussion. Unfortunately, this isn’t something that I have seen very often.

This demonstrates a clear disparity with the goal and the reality of patient-centricity in the current drug development landscape. I believe that true patient-centricity comes back to ensuring good study design, with end points aimed at improving quality of life based on patient insights, and a product placed on the market that puts the customer, the patient, first. Having the patient involved during early regulatory discussions would be a true reflection of patient engagement, but these vital elements are typically missing during the design stage.

While strides are being made to improve the situation, sadly, patient-centricity is still all too often used as a marketing tool, and often in unethical ways. For example, if the National Institute for Health and Care Excellence (NICE) decides not to fund a product after it has received approval, we sometimes see companies riling up patient groups to lobby against that decision, encouraging them to write to their doctors, the press, or on social media, to demand access to a drug. To me, that’s using patients at the wrong end of the process and for the wrong reasons entirely, and it’s the kind of behaviour that gets called out time and again earning so-called ‘Big Pharma’ it’s bad reputation.

If a company is developing a product for a rare disease, for example, what they could be doing is bringing in patient advocates early on and asking what matters most to them. Which aspects of their disease do they wish they could overcome or manage better in order to improve their life? It could be something as simple as having fewer blood tests or being able to have these done from home, so they don’t have to visit their doctor so often. A simple change in formulation to make the product slower release might address an issue like that, not only improving the product for the patient, but the knock-on positive effects on study compliance and thus on the clinical data generated also seem a no-brainer.

By talking to patients from the outset, companies would be in the best position to create not only a study design with the most relevant end points, schedule and logistics, but deliver a product (from formulation, to dose schedule, to packaging, and more) based on meaningful quality of life considerations. That would be true patient-centricity.

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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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