by Dr. Sunni Patel, medeuronet clinical scientist
There is little doubt that getting clinical studies and approvals in place within the EU can be easier than in the US. However, it is very easy to fall for the classic mistake of underestimating what is involved in terms of time and preparation. Based on our experiences we see this time and time again, and with proposed changes coming in to this already complex equation, it is vital that the right solutions are in place to guarantee success.
Interestingly, it was reported in 2013 that the costs involved with studies isn’t the biggest deciding factor as to where a study should take place, but weighs more heavily on the investigator, environment and hospital. We believe that environmental factors such as the availability of eligible patients and the speed of the approval process (if managed properly), are major reasons as to why Europe is a great springboard for clinical studies.
In 2013, for example, it was suggested that Germany, the UK and the Netherlands were the best markets in which to conduct clinical studies. However, with budget and administrative changes, it is unclear whether this still holds true.
We hear on many occasions of comparisons between the US and EU with regards to the effectiveness and timeliness of conducting studies, especially as more and more health authorities require clinical investigations for medical devices.
Although the EU can provide a simpler and quicker process than the US, it is still a challenging environment as each member state enforces the Medical Device Directive and ethical approval requirements differently.
With a recent sneak peek of the proposed regulation (also on medeuronet magazine) we are certain that it will pave the way for the future medical device approval process in Europe, so much so that it will guide us on how clinical studies will be registered, conducted and monitored in the future. So a word to the wise – keep watching this space as it continues to evolve, as it will shape clinical strategy from the outset.
Clinical Studies: Key Considerations
Many companies come to us for assistance with clinical studies on medical devices, and ask us where to start – the protocol, the agreements, the budgets, or the KOL agreements? Well, we would advise none of these to begin with!
Of vital importance in running successful clinical studies, and imperative for any good company, is to ensure proper communication and preparation from the start. The turbulent nature of any regulatory landscape, even within the somewhat ‘easier’ EU countries, means it is vital to prepare and garner as much country-specific knowledge, usually through research partners to ensure that the clinical trial process runs as smoothly as possible.
The team at medeuronet tries to sum up the key features to consider when running a clinical study and getting approval in Europe.
Although this schematic only highlights a brief overview of the overall study process, the intricacies of each stage can vary by country, and so the key to success is that local and regulatory assistance is sought in clinical study management.
medeuronet also spoke to Prof. Michael Mrochen, founder and CEO of IROC Science, to get his take on what he feels companies can do to make each stage run as smoothly as possible.
Regulatory: Prof. Mrochen notices time and time again that many companies fail to define their desired outcome measures effectively. Remember, if you want to demonstrate that your device is better, then one must determine how that can be achieved and proven clinically. This will ultimately shape and determine your clinical pipeline from the outset.
A good exercise that many clinical and regulatory consultants do is to brainstorm and work heavily on this aspect with their clients. This will ultimately help decide what is needed to fulfil essential criteria and also identify outcomes that can be used to differentiate your device from others.
Prof. Mrochen also adds that it is vital to understand early on what claims (and supporting claims) that the company wants to make in relation to the device so that the appropriate clinical evaluation can also be performed in support of these.
It is also important to be aware of the standard document lists for Health Authorities, and realise that these can differ from country to country, and therefore must be integrated into the clinical planning and strategy.
The regulatory landscape is changing and all the countries of the EU are following suit. Implantable devices, whether CE marked or not, will have to go through Health Authority approval; many countries are already choosing to adopt this approach according to the proposed legislation.
We are also noticing that Notified Bodies are increasingly enforcing stringent guidelines as the norm. Post-marketing surveillance plans are becoming increasingly under the spotlight and bodies are now preparing clients for more rigorous changes in the process.
“Remember that there are, and will be, extra costs, activities and time involved at this stage” adds Michael.
Investigator/Site selection: It is wise to invest time on researching the patient base and recruitment planning at the site in advance. As a rule of thumb, Michael’s experience has taught him that you can probably only enrol 30% of a total patient base.
Therefore, we advise you to recognise how many patients are seen in a clinic on a monthly basis and assume a third will be enrolled so as to give you an appropriate timeline on how many subjects will be enrolled for that site.
Another critical element on selecting a site depends heavily on the team. There has to be a “like-it” factor; you cannot merely select a site based solely on the kudos of the investigator. Michael notes that he finds it so much easier to work with sites that have bought in to the project, as the team will likely be more motivated, experienced, educated, and trained. Whether a site can appropriately manage the disruption that can occur during a clinical trial from their normal day-to-day activities and clinics is another factor to consider.
Finalizing Clinical Documents: Michael feels the biggest element that is underestimated is data and document management. He adds that “that it important to know there is a document element to all aspects of a trial, including patient follow-up, timing and sequencing”. Therefore, the person who helps to manage that is equally as important.
We have also noticed that the management of documents is increasing overlooked. All relevant changes have to be approved by the authorities; only then can changes be implemented.
Clinical Study Process: This can appear quite straightforward, and can be if managed and structured appropriately. Two fundamental elements of the clinical study lifecycle are the clinical monitoring process and data monitoring.
Michael enthuses the importance of having good data by stating that “garbage in can only mean garbage out!” Why have a study if the data is not usable? You cannot and must not compromise the quality of data, thus data monitoring is vital. Many companies underestimate the importance and need for monitoring visits, but it is vital to ensure compliance of GCP and integrity of data.
A take home message here is that as a company and a Sponsor, you have an obligation to monitor your study appropriately.
CE Mark Approval: If all the early stages are planned for properly, and you have measures in place to manage most eventualities, the approval process can be relatively easy. In line with our thinking and advice of others, Prof. Mrochen also advocates that companies should start early as possible and that it should be a part of the planning process. Be Prepared!
So How Can You be Successful in Europe?
The new legislation will allow outsourcing of many of these tasks. While some companies have internal staff to manage these processes, it can be difficult for smaller companies in terms of the investment required.
Therefore, contracting CROs and regulatory consultants will become of more practical use to companies (small and large) as the new proposed changes come into place. Furthermore, authorities are more likely to respect data that comes from external management processes as opposed to internal structures as this can add a great deal of credibility.
So how can you make clinical studies, which are often seen as complex and time consuming, as easy as possible? Simply put, keep things simple! Harmonise your processes and ensure that there is a high level of preparation, communication, transparency and management from the initial development stages to the running and completion of the clinical study. It is also important to keep all key stakeholders (R&D, clinicians, investigators, notified bodies for example) in the loop. The use of clinical study managers or CROs can help during all of these stages and keep communication active between everyone involved so that clinical success can be guaranteed.