Innovative Drug European Associates


There is much talk today about patient-centricity in the clinical trials, from discussions about how to ease the burden for patients, to how to empower and engage patients. But to my mind a central aspect of patient centricity that is poorly addressed is how patients and advocacy groups get better access to medical research, or even pharmaceutical companies, or how a small advocacy group would go about building a registry.

There is very little clear, understandable information in the public domain that would help rare disease patients or their carers in their search for studies or support. Many carers are struggling at home with a critically ill child with a rare disease and no one to provide them with information or support.

In my search, I came across a guide on the Patient Engagement Management Suite site that offered some good examples, with case studies and recommendations for how pharmaceutical companies and patient groups should interact. But while it was interesting, I struggled to find relevant information with any clear actions that would be useful for a lay person. The language used was complex and sophisticated, which is great for scientists and those working in the industry, but not particularly useful for carers and patients desperately seeking help.

The reality is when the industry is designing patient information sheets or instructions, they must consider the reader age of the market they are trying to reach, and in the UK and the U.S., that’s around the age of nine. That is the lay understanding that the industry needs to cater to, which can be hard for someone who understands the subject deeply. Once someone takes the time to explain to a parent or carer what they need to know about their child’s illness and what support is available, those people are extremely proactive in expanding their knowledge and advocating for their child, but they need the support from someone with knowledge about the condition or similar conditions, who is able to educate them in a way they can easily understand, to get them started.

Certainly, there is significant support through large rare disease organisations, such as NORD and EURODIS, but often these are unknown to anyone not in the industry. The information they are generating needs to filter down to those tiny groups of patients with ultra-rare, even the rare non-life-threatening diseases (which are often completely overlooked by industry and healthcare systems).

How, then, can the industry go about changing the way information is shared so it reaches those in greatest need? The fact is, now we have big data. Collectively as an industry – companies, regulators, and so on – we must start pulling all this information together and ensure it is centrally organised with a large database that covers potential symptoms and genetic links. That information must be properly regulated and managed by the regulators or healthcare systems within each country, and there must be international collaboration to ensure those ultra-rare diseases, which may only affect 10 (or fewer) people worldwide, are accounted for.

With large, easily accessible, well-managed disease databases, carers and patients can get the support they need from their local doctor, who otherwise will likely have had no exposure to a rare disease. Certainly, I have seen instances where doctors have carried out additional research and made connections that can be life-changing for that patient. However, without that central resource, many don’t get the help they need and their carers continue to struggle to gain the support and insight that might help them to, at the very least, get answers and potentially even get treatments that would alleviate their child’s symptoms.

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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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Despite having talented teams, small companies are forced to work with limited resources and access to specific expertise. They often lack the resources and experience in navigating specific regulations, the nuances of working in different countries and have limited time to spend on regulatory intelligence.

Working with a regulatory expert who is familiar with your product development and can provide on-call services or advice can make all the difference. Through our Regulatory-on-Call service, IDEA Regulatory offers a team of experts at the end of the phone or email, ready to answer any questions or carry out regulatory tasks.

Our Regulatory-on-Call service can supplement your existing team, allowing them to focus on managing and delivering your overall regulatory strategy. IDEA Regulatory’s experts know the relevant guidelines across all EU markets and stay on top of local developments. We can quickly answer questions about a process, regulation, guideline, or submission in the EU, or you can simply call our experts, who can point you in the right direction. With clinical trial uncertainty due to the coronavirus, if you need to make an urgent protocol amendment or a submission to temporarily halt a study, having an expert partner lined up at IDEA Regulatory means there’s always someone to guide you.

How does Regulatory-on-Call work?

You pre-purchase agreed hours of consultancy advice per month and IDEA Regulatory will have a team of qualified regulatory consultants who are familiar with your product and development plans available ‘on-call’ to answer your questions. The service includes:

  • A kick-off call to determine the potential types of advice and assistance needed
  • Familiarisation of our team of experts with your product and development plans
  • Assessment of the complexity of each query/task to determine the service needed
  • A flexible rolling balance of hours in credit allows you to roll-over unused time in to following months, or in more busy months, spend in advance from your future balance.
  • Regular reviews to ensure you are on the right plan

Whether it is supplementing your team or providing quick pieces of advice on-demand, IDEA Regulatory can support small businesses with stretched resources and small teams.

Contact IDEA Regulatory to learn more.

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When regulations change there are always a few aspects where the careful reader finds themselves asking “did they really mean that?”. In that vein there is a somewhat ominous clause in the new Clinical Trial Regulation, at least from the point of view of the legal representative.

Article 74 of the regulation states: “Such legal representative shall be responsible for ensuring compliance with the sponsor’s obligations pursuant to this Regulation, …..”. What that means is the EU legal representative now takes on the role of overseeing the sponsor’s compliance and potentially the role of “whipping boy” if the sponsor fails to fully step up to the line.

When the regulation was first published many believed that the decision of whether to require an EU legal representative would be made on a country-by-country basis. However, when asked about the basis on which the decision would be made the European Medicines Agency recently replied  “…the decision to appoint or not a legal representative in the EU, should the sponsor not to be based in the EU, will apply on trial-by-trial basis and would be at the discretion of the Concerned member states (CMS) where the sponsor intends to conduct the clinical trials”. This raises the very real possibility that the member states will look at the sponsor, and, based on their evaluation of them, decide an EU legal representative might only be needed in cases where there are concerns about compliance.

Perhaps not surprisingly, several of the larger and more risk aware clinical trial outsourcing companies (CROs) are starting to set strict stipulations regarding the role of the EU legal representative. They are declining to take on the role of the legal representative unless all clinical trial activity is carried out by them.

This cautious approach is understandable, especially for large businesses which have a lot to lose. Companies seeking legal representative support in the EU typically are smaller companies and have no presence in Europe.. Add to that the possibility that EU legal representatives will only be required for “riskier” trials then should something go wrong – however unlikely that is – the CRO partner stands joint and severally responsible for the failings of the sponsor. And that could be extremely costly.

Given that the EU legal representative role is not by any manner or means the most lucrative aspect service delivery to trials, it does seem like an unbalanced risk/reward profile for all but the most specialist providers to take on this role.

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The long-awaited new Clinical Trials Regulation looks set to be introduced in 2020. Initially adopted in 2014 and due to go into force soon afterwards, it was held up by technical difficulties with the database, which is necessary to underpin the new environment. The latest testing suggests these problems have been resolved.

The new regulation will provide a far more streamlined process for sharing clinical trial information, create a more efficient assessment process, and facilitate trials being conducted across multi-member states.

There is, however, one subtle, and easily overlooked consequence of the regulation, which is with regards to the EU legal representative. At the moment, any trial where the sponsor is outside of Europe requires a formal legal representative in the EU. Once the regulation is implemented, this will change – either making life easier for the sponsor or potentially adding a layer of complication that many have not foreseen.

If, on one hand, all the regulators who are dealing with the trial agree to do so, they can waive the requirement to have a legal representative requiring only a contact person instead. However, if they don’t agree then the EU legal rep will become a more significant role than it has been previously.

Under the new regulation, the legal representative will be responsible for the sponsor’s compliance with the regulations. In practice, what that means is the EU legal representative will have to provide quality assurance oversight across the full extent of the trial, including not only aspects conducted in the EU, but also those potentially conducted outside the EU but linked to the trial.

If we look at many of the life sciences companies that will need a legal representative – the small biotech companies with no presence in the EU – the reason for this change becomes clearer. These companies can have immature systems in place and are typically led by someone relatively new to the industry, or at least to their level of responsibility. The likelihood of something major going wrong is low, but far higher than if the sponsor was a major multi-national. Making the legal representative responsible for the sponsor’s compliance is a way for EU regulators to ensure that there is someone to pursue in all circumstances

That said, those companies offering EU legal representative services will need to closely assess the potential risks involved as the regulation moves closer to implementation and the portal goes live…

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I’m a huge believer that even in the very worst of circumstances, there is always a silver lining (or two) to be found. We  have already seen some of these playing out during this pandemic in the many ways people are coming together to spread hope and goodwill between and across communities. One positive that the coronavirus might bring specifically to regulatory processes for medicine and medical devices, is a shortening of response times from the regulatory authorities and better ways to share information simultaneously between global authorities, leading to improved harmonisation. The COVID-19 pandemic has forced regulators to find new ways of communicating on global projects and to act urgently to deal with this unpredictable and critical situation.

To address the coronavirus effort, regulators have adopted new processes and are making use of interoperable databases and systems to share information. They are using these systems and processes to ensure studies and data from coronavirus research are widely and rapidly shared in order to speed up the process of bringing vaccines and treatments to patients.

I certainly hope – and expect — that there will be some trickle down from those learnings once this crisis is over. Allowing the life sciences industry and academia to push forward with efforts to improve global harmonisation when it comes to sharing data and study results. More rapid, harmonised approaches will ensure that everyone in the research community is aware of what is working and what is not in each disease category so that discovery efforts and clinical trials aren’t focused on areas that have been shown to be ineffective elsewhere.

These next few months will be crucial for achieving the breakthroughs needed to tackle the pandemic, and good regulatory processes will be key to advancing those objectives. Times of crisis are often the catalyst for positive change and there’s every reason to be optimistic that this current sense of urgency will help us improve the regulatory landscape and lead to better processes for all breakthrough therapies in the future.

The fact is that, as an industry, we’re good at recording what we do day-to-day. It is what researchers do, and it’s part of our Good Practices – we carefully record data because if we don’t write down what we did and what we observed, it didn’t happen (according to the audit trail at least). If we record the learnings we gain from this period and transfer those to regulatory processes more generally, we can at least say that some good has come out of a very dark period in our history.

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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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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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