Medicine is constantly evolving to invent effective ways to treat diseases. This progress is a never-ending process: life science industry develops new molecules and treatments and improves existing ones continually. Experimentation and testing have long been a part of medicine, and it is up until now as clinical trials have an essential part in the development of new treatments. As mentioned already, new drug development and improvement of existing treatments is a never-ending process, also, as you can see from the video below, the interest itself in one or another disease is recurring and constant. These reasons allow us to assume that the relevance of clinical trials will not diminish in the future and, as the clinical researchers, we are here to play an essential role in these processes. In this article, I will try to review one of the parts of every clinical trial, a start-up phase, its timelines in France, Germany, Poland and the Baltic states, as well as to review the processes and compare them in-between these countries.
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A good beginning makes a good ending. Every clinical trial starts form regulatory start-up phase, and each client aims to have this period as short as possible and want to begin recruiting patients into the study with no delay. At this moment, a good knowledge of local requirements in each country is a key factor to succeed in the future.
The way clinical trials conduction are proceeded in the European Union (EU), currently varies country by country. However, with the new Clinical Trial Regulation (Regulation (EU) No 536/2014), the submission process will undergo major changes. It will create an environment that is favourable to conducting clinical trials in the EU with the highest standards of safety for participants and increased transparency of trial information. This Regulation will also increase the efficiency of all clinical trials in Europe, with the greatest benefit for those conducted in the multiple Member States. Though, while the EU has not implemented the new Regulation, we will take a closer look at the submission process in some EU countries individually.
Differences by countries
In most countries, there are two bodies where you need to perform submissions and obtain approvals – Regulatory authority (RA) / Competent authority (CA) and Ethics Committee (EC) (Local and/or Central). Though, some countries might have supplemental bodies which might require submission and might lead to longer timelines. Let’s take, for example, France, where we have two additional agencies – CNIL and CNOM.
The processing of personal data in the healthcare sector for research, study or evaluation purposes must be authorized by the National Commission of Informatics and Civil Liberties (CNIL – French data protection authority). The CNIL must also authorize research involving humans after the relevant committee for the protection of persons (a French ethics committee) has rendered its opinion. To simplify the authorization procedure, the CNIL has issued standard methodologies. In particular, the CNIL adopted reference methodology MR-001 for interventional studies and, on 21 July 2016, reference methodology MR-003 for non-interventional studies. These methodologies are used to simplify the authorization process for the processing of personal data in France. In line with this, if Controllers in the field of clinical research comply with the requirements of the reference methodology, they are able to process personal data, for such specific purposes, by the self-declared complaint to the CNIL.
Since the Law Bertrand of December 2011, the role of the National Council of Physicians (Conseil National de l’Ordre des Médecins, CNOM) has been reinforced to ensure that reasonable fees are paid to the health professionals and to review the content of the contracts with physicians and sites. Complete transparency is now mandatory on financing between the industry and all health professionals, including hospitals, study coordinators, professional associations and physicians. The physician’s fees must be paid via a bi-partite contract with the physician, or a tri-partite with the physician and the hospital. Associations are not allowed anymore to receive payments for tasks performed by a physician. A full dossier together with a request for advice has to be submitted to the CNOM two months before any site initiation in France, and, it is strongly recommended to begin contract negotiation as soon as possible.
While starting a clinical trial in Germany, the priority is to consider if your study will require the Federal Office for Radiation Protection (BfS) submission and approval. Radiological and/or nuclear medicinal examinations for therapy or diagnostic purposes may be included in the design of your clinical study, especially in oncology trials. Since these examinations are fairly new (radiation and x-ray regulations came into force on 1 August 2001 and 1 July 2002 respectively), conducting clinical trials with them may require official approval from BfS. This approval is additional to the ones from the CA (Federal Institute for Drugs and Medical Devices (BfArM) or the Paul-Ehrlich-Institute (PEI)) and the relevant EC. When planning study start-up activities in Germany, you must consider this possibility of BfS delay, as BfS has no obligatory timeframe, by which it is required to approve, and the process itself is very time-consuming. Also, while setting up a clinical trial in Germany, you shouldn’t forget Local Regulatory Authorities (Länderbehörden). Their notification is needed once EC/CA approvals are in place (according § 67 paragraph 1 AMG).
In comparison, countries like Poland or the Baltic states offer shorter timeliness and most important lack of supplemental agencies with their submissions and/or approvals.
A couple of years back, Lithuania had supplemental agency as well, State Data Protection Inspectorate (SDPI), and you had to obtain submission and approval to it before the site initiation. This extra step led to an additional 60 days period, as you needed to include both EC and CA approvals in the SDPI submission package. However, with new General Data Protection Regulation 2016/679 (GDPR) this SDPI approval is no longer needed, and you can start a clinical trial as soon as you receive EC/CA approvals and fully executed contracts with sites.
Other Baltic states (Latvia and Estonia) with submission requirements and approvals timelines are very similar to the ones in Lithuania. Moreover, in all Baltic states, you can provide submissions electronically, and this makes the process much easier and faster.
Poland, for example, is as well very often considered as a country with great potential in the scope of conducting clinical trials. Especially after the amendment to the Polish Pharmaceutical Law Act came into force on 18th October 2018. This regulation simplified the procedure of applying for a clinical trial and significantly reduced the time of waiting for Regulatory Authority (RA) and Ethics Committee (EC) approvals.
Based on the new regulations, neither RA nor EC requires to include the signed contracts with PI and/or the site in the initial submission. It is enough if the Sponsor provides a brief description of the financing of a proposed clinical trial as well as information about the financial transactions and the compensation provided to participants, investigators and institutions. The application should also contain the description of every contract between the investigator and the institution. Therefore, the initial submissions to EC and RA can be done in parallel with contract negotiation. This time-saving process makes Poland an attractive and very competitive country for the conduction of clinical trials. Here, the first RA step is administrative review during the validation period that can last up to 30 days. If RA does not have any questions, sends a validation letter. After that, the evaluation starts, and it takes 60 days. Maximum rounds of comments for validation is 2, and 2 rounds of evaluation queries, and the central EC approval, is usually obtained within 40-45 days.
[ngg src=”galleries” ids=”24″ display=”basic_thumbnail” override_thumbnail_settings=”1″ thumbnail_width=”1920″ thumbnail_height=”1080″ thumbnail_crop=”0″]Furthermore, over the years in Poland and the Baltic states, Clinical/Cancer Hospitals and privately held companies established quite a few modern and fully equipped early clinical trials units. These sites mostly specialize in Phase I, bioequivalence and bioavailability studies, including first-in-human, multiple applications (MAD), drug-related interactions (DDI) and proof of concept (POC). The biggest advantage is that these dedicated centres usually have an efficient Quality Management System based on written procedures that establish and ensure the quality of processes, data, and documentation associated with clinical research activities. As well, they guarantee the highest standards for patients’ safety and their service includes intensive patients’ monitoring and access to the emergency care unit, what makes them really great choice for Phase I and Phase II clinical trials.
To summarize, good knowledge and know-how of local requirements and procedures is a key in clinical study start-up. If you have the right expertise in regulatory start-up, Western or Eastern Europe variations don’t make a significant difference, and you can reach smooth processes with no waste of time everywhere. However, if a goal is to conduct a Phase I or Phase II clinical trial, Eastern Europe and countries like Poland, Lithuania, Latvia or Estonia, look more attractive due to modern early phase units, lower clinical trial density, submission/approval requirements and timelines.
If you want to get more information about the clinical study start-up and timelines in specific countries, contact us!
Ineta Sumskiene, MSc
Manager Clinical Operations