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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In drug development, it’s often the area you least expect that causes the most problems. In my experience, one of the biggest hold-ups to completing regulatory submission dossiers relates to manufacturing, not the safety and efficacy data. The information needed for the Investigational Medicinal Product Dossier (IMPD) or CTD Module 3 (M3) — stability testing, validation methods, impurity detection, DMF/ASMF’s, and the product specifications and certificates of analysis, or distribution and supply chains – these are where the most time-consuming problems typically lie.

To avoid these setbacks, companies need to have those conversations with manufacturers from the outset. Ensure you have the information you need, the right stability data, and other key data that the regulators will expect to see. This is what most often holds up clinical trial or marketing authorisation submissions and creates cost headaches for companies as they come across unexpected delays to their milestone payments.

Often not having all the data needed for an IMPD/M3 leads to questions from the regulators, rejections, and panic, but that’s not necessary. Instead, companies need to consider the type of product they’re developing and where they are in the process, and then build a plan, based around the principles of Quality by Design (QbD) for acquiring the necessary data, and offer sound justifications where it is not available. Some data will be needed upfront, such as the stability data to support the claimed shelf-life, but in the early phases it’s okay to tell the regulators you’re still working to gather data on method analysis and validations. That’s normal when we’re talking about a new product, because no one understands fully how it works until development progresses.

The other problem that often arises with manufacturing is whether novel manufacturing methods can be scaled up later. Some methods may be fine in the laboratory when you only need 500ml of a product, but will you still be able to carry out extraction methods when you need 5l or 500l? These are complex considerations for young biopharma companies, especially those developing a first-in-class compound.

To avoid problems – and disappointment – later, new companies should get expert regulatory CMC advice, and for more complex issues or gaps in the data for quality and manufacturing aspects of their product they should seek formal scientific advice. After all, the FDA warning letters that are frequently sent out are mostly due to good manufacturing practice (GMP) problems – something unwanted got into the formula, a manufacturing plant isn’t up to GMP standards, and so on.

These are a vital part of the process, because if your manufacturing has problems, isn’t GMP compliant, can’t be carried out in a consistent, cost-effective way, or the batch works but can’t be replicated, then no matter how good your clinical data is, you won’t have a product to bring to market.

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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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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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The global coronavirus pandemic, or COVID-19, has brought about both a health crisis as well as personal and business uncertainty. Yet bringing new life saving and life changing products to market remains a pressing priority. Patients are waiting for cures and their needs cannot be postponed.

As a leader in providing regulatory affairs expertise and EU legal representation for clinical trials and orphan drug developers, IDEA Regulatory understands just how crucial it is that the drug development process is not unduly interrupted. Our processes and systems are set up to enable us to work remotely so we can continue to deal with all client activities consistently and securely.

At this time of uncertainty for everyone, we also understand how important it is to connect and actually see the people who are supporting your regulatory and legal needs. As such, we’ve set up web-based meeting capabilities so we can have face-to-face meetings through video conferences. This also enables us to provide real-time visual updates to you and to offer the reassurance we know is so important right now.

One significant concern many clinicians and orphan drug developers have is how the crisis will impact clinical studies. IDEA Regulatory is happy to talk to any organisation or individual to help you work through these concerns. We have extensive experience working with regulators to address regulatory and legal issues and we’re happy to reach out to those authorities on your behalf to ask the right questions and provide you with the information you need to plan your clinical trial strategy.

Throughout this unsettling time, our team stands ready to provide you with the support and services you need. We will continue to monitor developments in this rapidly changing situation, ensuring we are taking all necessary precautions to protect our staff, our clients, and the products and projects that are so important to patients in need.

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