Ann Marinus, Assistant director and Head of the Clinical Operations Department at EORTC, explains how to ensure compliance on an international scale to avoid unnecessary trial setbacks, losing money and time.
CTA: What type of regulations should be taken into account to avoid trial problems?
AM: Before you start to organize and plan a clinical trial you should make sure that you are familiar with the legislation that has been applied in different EU countries following the Directive . This can be quite challenging because although we all work according to one Directive the variability of the implementation can go from a very wide range. For example, in Poland you first need to have the site contract signed before you can even go to the competent authorities. This can sometimes delay your activation. In Spain, you can go to the authorities and to the ethics committee in parallel, but it is the approval of the ethics committee what will trigger the approval of the authorities. You also need to have the signature of the director of the hospital. In Germany, if you want to go to the ethics committee you need quite a lot of documents in the local language from the hospital that demonstrate that you have the infrastructure and capabilities to do the trial. As soon as you go out of the EU, you should know what the national regulation is. Even though we all think it is an EU country, Switzerland is not and has a different legislation on clinical trials. You will need to have a legal representative in that country to submit your clinical trial. You also need to take into account that you might need to import drugs into Switzerland. In some eastern European countries you will need to have local delegates in your country, otherwise you will not be able to submit to that country.
CTA: What do you think would help solve the complexity of the regulations?
AM: What the EU has put in place now as legislation, with a central entry port and with a competent authority looking to the methodology of the study and the ethics committee is a good way forward. But we do not yet know whether countries in Eastern Europe might still require legal representatives, whether Poland will still require a contract before you can even go there. These are things we can only now once we are in the situation.
CTA: What are the challenges caused by regulations?
AM: They are mainly related to time and cost. It can take time to get all the documentation ready and some documents even have a validity of only one year. Also, the resources that you need to collect these documents have a cost. There are also changes in prices across authorities and clinical trial insurance requirements can vary from 200-300 Euros for covering a territory to sometimes 15,000-17,000 Euros. That will vary according to the legislation in each country as this is not reasoned by the Directive, so each country defines what kind of insurance you need for your clinical trial. You will need to know this figure ahead of time because it has an impact on costs. Hiring a local CRO to be in charge of the legal responsibility of course adds on cost as well.
CTA: What would be the best way to ensure compliance on an international scale?
AM: I think it is important to do all the preparatory work. For example, to establish which territories you want to go to and make sure that you have good knowledge of the requirements on that territory for conducting your clinical research, and to have an adequate staff available to waste as little time as possible.
CTA: What are the consequences of not doing this?
AM: By default, you will have a request from the authorities or the ethics committee to comply with their regulations. This means you will not get approval for your trial, so you will not be able to open your territory and you will have to look for other territories and sites instead. As such, you will lose your investment and lose time, as you will have to go somewhere else to do your trial. It also means there will be a delay in coming up to full recruitment speed for your study because obviously you might already have started in some countries where you were compliant with the legislation and if at the very end one country refuses to continue unless you comply, you will have to seek for patients somewhere else. This might also create a risk for your drugs in the supply chain as drugs would be labelled in all the languages that you initially planned to submit. If you open a new territory and you suddenly need a new translated label in a language that you did not plan, the whole drug campaign will have to be relabelled.
CTA: What does your organization do to anticipate international regulations?
AM: We have been closely following the development of the Directive in the past and we have been following up on the development of the national regulations since the beginning of the Directive. We have some people that are very close to the EU, where the new legislation was developed and implemented, so we are now anticipating the implementation of the new EU legislations.
Across our operational units, we are reading the Directive in order to identify how this regulation might have an impact on our current standard operation procedures, to see if there will be need to be an increase of administrative or specialized functions. Once we have that together, we will identify which units will need to be reinforced with resources.
We are also looking to the list of trials that might have to migrate into the new regulation between 2018 and 2020.
CTA: Have you seen any results for anticipating already?
AM: We will get together in September or October and then come up with a plan on how to address these things in the next year or year and a half. We hear a lot of presentations about what the new legislation is going to bring, but aside from the Step 1 authority review process, the Step 2 national review processes (including the Ethics review) is all guessing because no one today knows how it will really work.