The objective of clinical trials is to find and examine more and more safe and effective ways for prevention, diagnosis, or treatment of various diseases. So, every drug that is used in treatment today was once studied in clinical trials in order to confirm its safety and efficacy. Along with basic research, results from clinical trials thus represent the basis of medical advances. Conducting patient-oriented clinical trials is of tremendous importance, as clinical research is the essential requirement for the successful development and market approval of new pharmaceuticals and other forms of therapy and constitutes an important foundation of evidence-based medical care.
Germany as a location for clinical trials, is currently well-positioned and internationally competitive. This is evident in its position as number two in Europe and number three worldwide – behind the US and UK – in clinical trials of pharmaceuticals sponsored by pharmaceutical companies.1 Maintaining and further improving this favorable positioning as a location for clinical trials is in the mutual interest of all parties involved in the field of clinical research in Germany as well as patients, trial sites and sponsors of clinical trials. For patients, clinical trials offer opportunities to gain early access to innovative therapy options. In addition to the scientific interest from medical faculties, clinical research is a core task for university clinics in Germany as they fulfill their medical care mandate. Their involvement in clinical trials gives physicians the ability to lay the foundation for evidence-based decisions, to gather experience with new treatment approaches at an early stage and to pass this know-how on to their patients.
Clinical research is thus an important competitive factor in terms of international comparison of medical research as well. Industry-sponsored clinical trials likewise benefit from the favorable research infrastructure in Germany, which currently provides rapid patient recruitment and outstanding quality of results obtained and can thus contribute to the timely approval of new drugs.
What’s good – in an international comparison Germany offers good, basic conditions for clinical research:
- High population density with dense network of health facilities, physicians, universities - Germany is number two in the number of potential study centers.
- High quality of the universities, health and research institutions – together they provide a good infrastructure for clinical trials.
- Good patient recruitment rates in international comparison.
- Approval procedures by the higher federal authorities for clinical examinations are timely, scientific assessment of the applications comprehensible; appropriate requirements in the procedure.
- Overall, very high quality of clinical research performance.
Room for improvement - Germany is not fully exploiting its potential:
- Still unsatisfactory with regard to the number of performed clinical trials per capita – e. g. due to lower willingness of patients to participate; alleged bad reputation, complex approaches by NCA and ECs in Germany.
- Problems with clinical trials that fall within the scope of the Germany X-ray/Radiation Protection Ordinance – hopefully solved with new regulation since January 2019!
- Problem with multicenter trials: Improvable culture of cooperation and harmonization across federal states, institutions and local authorities may hinder an easy conduct of clinical trials.
- Regarding the total number of peer-reviewed publications of clinical trials, Germany does not occupy a leading international position compared to other major reference countries (e. g. US, United Kingdom, Netherlands).
- As in most other countries, collaboration between university hospitals and sponsors should be simplified, contracting is still complex and therefore takes too much time.
- From the perspective of the authors, it is therefore essential that Germany remains a stronghold for conducting clinical trials, given that the number of clinical trials is decreasing overall and specific problems have been identified in regard to the set-up and conduct of clinical trials. This should strengthen the future competitiveness of trial locations in Germany. Also sponsors of clinical trials – in this publication mainly pharmaceutical companies - themselves are in international competition internally and externally, which often creates a certain pressure on trial preparation and thus on the start of a clinical trial. To ensure that a clinical trial can be set up and started as quickly as possible, a swift agreement of key contractual and budgetary aspects is therefore in the interest of all stakeholders.
Against this background, the German Association of Medical Faculties (MFT), the German Association of Academic Medical Centers (VUD), the Coordination Center for Clinical Studies (KKS-Netzwerk) and the German Association of Research-Based Pharmaceutical Companies (vfa) have held joint discussions regarding two important aspects in relation to clinical trials - contract negotiations and remuneration considerations of clinical trials.
As a result of these discussions, these organizations have agreed and published the following joint recommendations:
- “Recommendations for establishing a total services calculation for remuneration related to the conduct of a clinical trial in a trial center”2
- “Model contract clauses for clinical trials with drugs, conducted under the responsibility of a pharmaceutical company (industrial sponsor)”.3
The involved players are convinced that recommendations offering examples of regularly occurring cost positions will help to more precisely determine remuneration related to the conduct of a clinical trial. Also, a common set of model clauses for the setup of the contracts associated to clinical trials will speed up contract negotiations significantly. This article provides an overview of core items of the recommendations for establishing a total services remuneration and the model contract clauses.
Core items of the joint recommendations for remuneration2
The parties agreed that complete re-financing for all expenses arising from the conduct of a clinical trial must be ensured for the trial sites. This also includes indirect costs or costs for the research infrastructure required for the conduct of clinical trials. In any case, care should be taken to ensure that the trial site is remunerated in full for the service rendered.
The recommendations also ensure that double billing will be avoided, as no additional remuneration would be made for standard of care activities that were already reimbursed by the German health insurance funds – even if the patient is enrolled in a clinical trial. To ensure this a clarification in the Investigators Brochure needs to determine which of the measures performed in a clinical trial, according to the protocol, are a required part of the standard treatment of a patient under the provision of the German health insurance funds. Similarly, elements of the protocol that are performed specifically in connection with the conduct of the clinical trial and its goals need to be specified. On this basis, the services provided by a trial site will be remunerated by the sponsor, including all services in direct connection with the conduct of the clinical trial that are provided to or with the patient, such as a consultation (patient information), blood draws, physical and instrumental diagnostics, ECG, etc., and the preparation of necessary trial-specific documentation (reports, certificates). This might also include internal transportation costs for patients, such as to diagnostic centers if e.g. x-ray exams are needed. In addition to patient and treatment-specific expenditures, the full indirect costs also need to be considered. These are likely to be covered by lump sum payments and include items such as electricity costs, telephone/fax/internet, office supplies and the use of other existing materials and facilities.
If the respective trial protocol and the present joint recommendations2 are considered, they should help facilitate comprehensive remuneration of all trial-related costs in connection with a total services account based on the principle of payment for services rendered. The recommendations should be regarded as supplementary to the payments/activities listed in the trial protocol. Firstly, the core aim of these recommendations is to provide guidance for precisely calculating costs derived directly from the trial protocol. In addition, indirect costs/general expenses are to be reflected in the respective employee rates. Along with the purely tariff-based remuneration, these recommendations consider calculated indirect costs/general expenses, as is customary for other services. Site-specific indirect costs/general expenses and possibly other operational costs must be considered in the respective total services account, if they are directly related to the conduct of the clinical trial. From the point of view of the organizations that have developed these recommendations it is also clear, that no other percentage lump sum surcharge (so called overhead) should be applied, if the trial remuneration is based on these recommendations.
These recommendations2 cannot be binding due to antitrust legislation, but they are intended to be a jointly adopted orientation for the negotiation of clinical trial contracts by members of the above mentioned organizations and other third parties. The recommendations include tasks that may be performed depending on the project in the context of conducting a clinical trial and are not - or only insufficiently - described in relevant service specifications.
Core items of the model contract clauses3
The conduct of clinical trials is often subject to many time pressures, playing an important role in international competition, particularly in the period leading up to the start of a clinical trial. In order to be able to begin a clinical trial as early as possible, it should be possible to negotiate the contracts between the parties involved quickly, fairly and easily, with comprehensive content.
The model contract clauses are intended to consider the various interests of all involved players. The considerations within the model contract clauses should also offer indications for similar contractual relationships in the field of health research. In practice, trial contracts are typically concluded either between the sponsor (or one of the sponsor’s group companies) and the trial site (institution/contractor) (two-party contract) or between the trial site, the investigator and the sponsor (three-party contract) as contracting parties. The model ontract3 clauses are based on the two-party contract model. As it is necessary for the investigator and other medical members of the investigating team to accept certain obligations in the form of a declaration, a corresponding model text is annexed to these model contract clauses (Model Annex to Obligations within the scope of a clinical trial involving medicinal product). If the model contract clauses are also used in trial contracts involving one or more CROs, it is advisable to clearly delineate the respective areas of responsibility and services between the parties involved in the trial contract.
Currently the model contract clauses in Germany include the following basic areas:
- Publications
- Confidential information
- Trademark clauses/use of name
- Liability
- Audits/inspections
- Archiving
- Equipment or materials provided
- Termination/cancellation of the contract
In addition, two model annexes were agreed upon:
- Model Annex to Obligations within the scope of a clinical trial involving medicinal products
This model annex is addressing the obligations for the investigator or other physicians of the investigating team within the scope of a clinical trial involving medicinal products.
- Model annex on data protection declaration of consent
The data protection declaration of consent should be submitted individually and in person by all members of the investigating team at the trial site. It is addressing necessary data protection issues in relation to the set up and conduct of a clinical trial.
The model contract clauses3 cannot be binding but are intended to provide guidance to members of the drafting organizations and other third parties for the negotiation of trial contracts for Phase I-IV clinical trials. They should be regarded as suggested wording for the regulation of individual matters that regularly form part of such negotiations. Also, the model contract clauses are not representing a complete contract template. For example, model contract clauses for inventions and property rights or responsibilities for data protection are as yet missing. To address these important areas respective model contract clauses are already under discussion and should be added soon.
Summary
Clinical trials are an essential requirement for the development and adoption of new pharmaceuticals and other forms of therapy. They constitute the foundation for evidence-based medical care. Germany is an important and attractive location for conducting clinical trials with good basic infrastructure, high quality of clinical research performance and high population density. But room for improvement is clearly stated and contracting generally takes too much time before a clinical trial can be started in Germany.
The authors of these joint recommendations2 and the model contract clauses3 are united by their interest in boosting Germany's international positioning as a location for clinical trials and in maintaining the high standards established in Germany.
References
- Analysis by the vfa based on www.clinicaltrials.gov – Search items: “Interventional Studies”; „Country“; “Industry”; Phases: early 1, 1, 2, 3, 4; date 01.01. to 12.31.2018 and previous years. The mentioned analysis was conducted in June 2019 on the www.clinicaltrials.gov-Webpage.
- The “Recommendations for establishing a total services calculation for remuneration related to the conduct of a clinical trial in a trial center” are available from the following links: https://medizinische-fakultaeten.de/medien/stellungnahmen/erstellung-einergesamtleistungsrechnung-der-verguetung-bei-der-durchfuehrung-einer-klinischenpruefung-in-einem-pruefzentrum/ www.vfa.de/Empfehlungen-Gesamtleistungsrechnung The document can be downloaded under both links in German and English as a pdf-files or Word-files. Both links were accessed on July 31st, 2019
- The “Model contract clauses for clinical trials with drugs, conducted under the responsibility of a pharmaceutical company (industrial sponsor)” and the mentioned annexes” are available from the following links: https://medizinische-fakultaeten.de/forschung/themen/aktuelle-themen/mustervertragsklauseln/ https://www.vfa.de/de/arzneimittel-forschung/klinische-studien/mustervertragsklauselnfuer-klinische-pruefungen All documents mentioned (the model contract clauses and the mentioned annexes) can be downloaded under both links in German and English as pdf-files or Word-files. Both links were accessed on July 31st, 2019
Acknowledgements
The joint “Recommendations for the preparation of a total services calculation for remuneration related to the conduct of a clinical trial in a trial center”2 and the “Model contract clauses for clinical trials with drugs, conducted under the responsibility of a pharmaceutical company (industrial sponsor)”3 were discussed and formulated in joint working groups in 2017/2019. Members of the working groups included representatives from different university clinics in Germany, different sponsor companies and the mentioned associations. The authors explicitly thank all involved colleagues for their contributions, knowledge and commitment.