Blog series: Maintaining Regulatory Momentum in the Covid-19 era:

In early December, the EMA announced that it had been hit by a cyber-attack and that documents related to the Pfizer-BioNTech Covid-19 vaccines had been accessed. The agency issued a brief announcement after the attack to say a full investigation had been launched but provided no further details.

The incident is a reminder to both regulators and companies of the importance of data security and adherence to the General Data Protection Regulation (GDPR), especially for companies transferring data outside of the EU that must adapt their data security systems.

Over the past year, the focus has largely been on bringing vaccines and treatments to market to address the Covid-19 pandemic. However, as we start to adjust to a post-Covid world, companies – especially those transferring data out of the EU – will need to ensure they understand and adhere to GDPR requirements for clinical trials within the EU.

Questions companies will need to ask include: Do they have the proper change control and access control processes in place? Do they have the appropriate software to detect whether they have been hacked? And for those countries operating in the UK, will data protection requirements stay within the GDPR or will new UK rules be introduced, and what new measures must they put in place to remain in compliance?

With so many complexities to consider, it is incumbent on companies to select an experienced data protection officer (DPO) to ensure compliance with the GDPR, for example that a suitable GDPR statement is included in all informed consent protocols for clinical trial subjects, that it is adhered to when including information about clinical trial investigators, and that all data management plans are adhered to.

There are other complexities that companies must consider when it comes to the GDPR and data protection. Although it is an EU-wide regulation, it is implemented differently in each country within the EU. For example, Germany has regional supervisory authorities in addition to a federal authority, meaning a study in one part of the country may have a different way of interpreting parts of the GDPR than one elsewhere in Germany.

Therefore, the DPO that a company works with needs to be able to adapt the advice based on these differences, and that requires the support of an experienced team of lawyers and clinical research experts.

As data privacy becomes a growing priority globally – for example, with the introduction of new data protection laws in China, India and Australia – life sciences companies will need to ensure they have the processes and technologies in place to meet current and future requirements.

To help you stay abreast of regulatory changes our Regulatory On-Call service provides personalised responses to your ad hoc regulatory enquiries by way of a monthly retainer, get in touch for more information. Also look out for the other blogs in this series relating to Medical Devices, MHRA Guidance on Orphan Drugs and the Clinical Trial Regulation (CTR); work programmes that have not gone away but may have drifted from focus in the current environment.

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A recent perspective piece published in the New England Journal of Medicine highlights an issue that I have long felt reflects poorly on the industry, and that is public mistrust in ’Big Pharma’.

This issue has come to the fore with the race to bring a Covid-19 vaccine to market. While the authors talk about the highly politicised nature of the vaccine, with attempts by the US Federal Government to push forward a vaccine before the November presidential elections (even if the manufacturer has not requested approval), the issue of public trust is a very real concern. Indeed, distrust is only serving to further fuel the rising problem of anti-science rhetoric.

Public perception of the industry has grown more and more negative in recent years, with rising criticism over companies’ business practices and behaviours. There are very valid reasons for that distrust, which boil down to transparency. This lack of transparency is sadly apparent in how the industry reports and shares clinical trial data, particularly negative study results.

Companies are supposed to report the results of all their studies, but all too often companies won’t invest in developing reports that show the outcome of molecules that failed to meet clinical endpoints. As the legal representative for companies, IDEA Regulatory is supposed to help ensure that sponsors publish those results but we have had experiences where we have chased clients to report the data, in keeping with the regulations, to no avail. Until now, there has been nothing to force companies to follow through since, although the regulations require that they report clinical study outcomes, there is no onus or punishment if they don’t.

Recently, the FDA announced a change in policy with plans to introduce fines for companies that failed to report trial results. My hope is that EMA will follow suit.

There are so many reasons why clinical trial transparency is crucial. Aside from regaining public trust, such data can help to prevent other companies from spending time investigating the same or similar molecules, or can provide guidance on what manufacturing adaptations could be made to build a better product, based on the pharmacodynamic and pharmacokinetic data from the failed product.

Not repeating the same mistake is not only about helping other companies avoid similar mistakes; it’s also about patient safety. Every time you carry out first-in-man trials to determine safety and dosing you put your patient volunteers at risk. If data is available to demonstrate how, when and why a product failed, other companies could avoid initiating a programme that is doomed to fail.

As an industry, we learn from achievements, but we can learn even more from mistakes since if we know what went wrong, we won’t keep repeating the same error over and over. Clinical trial transparency is about improving science and information and ensuring we provide patients with safe, effective products.

As an industry, we must work together to overcome conspiracy theories and the troubling anti-science movement, and there is no better way to do that than to be ethical and open. When companies do anything that is unethical, underhand or secretive – whether it’s skipping some of the testing or hiding data – it will put those companies at greater risk when problems arise and harm the reputation of the industry as a whole.

Let’s work collectively to make sure we share data that can help to eliminate future unnecessary mistakes, and bring back trust to an industry that does vital and life-saving work.

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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.

Click here to download a service description

Contact IDEA Regulatory to learn more.

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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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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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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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