A report on a Conference on the Future of Independent Academic Clinical Research in Europe held on the 2 September 2010 at the Royal Academy of Medicine, Brussels, Belgium with the support of the Belgian Presidency of the Council of the European Union
Francoise Meunier, Director General of the European
Organisation for Research and Treatment of Cancer, Belgium
Silvio Garattini, Director of the Mario Negri Institute for Pharmaceutical Research, Italy
Europe needs to carry out more independent academic clinical research to establish the optimal standard of care, speed up access to treatments, ensure the most efficient use of limited health budgets and maintain leadership and competitiveness.
However, the field is tremendously complex and the level of bureaucracy involved creates a considerable workload, deterring clinicians from becoming involved in international independent clinical trials, what is known now as Investigator Driven Clinical Trials (IDCT).
It is acknowledged that much of this bureaucratic burden is generated by the implementation of the European Clinical Trials Directive 2001/20/EC. Moves are now in hand to reform the Directive, and the conference was organised with the support of the current Belgian Presidency of the European Union to pull together all stakeholders to share views on the shape of this reform and to discuss wider issues around EU funding of IDCT. It is hoped these discussions will contribute to recommendations for streamlining, simplifying and harmonising the conduct of international investigator driven clinical trials.
There is concern that the way in which the Directive has been enshrined in national law is hampering academic clinical trials in some countries.
The variability of the implementation of the clinical trial directive in each Member State explains the difficulties, hence working internationally raises different concerns as when working nationally. Originally initiated by the Directorate General Enterprise, the Clinical Trial Directive did not take into account the full clinical research environment of which academic clinical research is part. Therefore today two main features result in exponential difficulties:
- Academic nature of clinical trials
- International set up of clinical trials
This is why the focus of the conference was international academic trials only and concentrated on how the Directive could be reshaped to foster more cross-border research.
In his Welcome and Introduction Benoit Cerexhe, Brussels Minister for the Economy and Employment and President of the Research Section of the Competitiveness Council of the EU, welcomed the 200 participants from 18 countries, and underlined the commitment which the Belgian Presidency has made to improving international cooperation in research.
“New treatment strategies rely on fundamental laboratory research and transforming scientific findings as quickly as possible into therapeutic strategies,” Cerexhe said. “We need to guarantee the continuation of laboratory work at the patient’s bedside.”
Given this, it is unfortunate that too few patients are aware of the benefits of clinical trials, and that doctors are deterred because of a lack of time and the complexities of accessing funding, said Cerexhe.
However, in Framework Programme 7, “Budgets are going in the right direction,” and there is particular emphasis on clinical trials. “We all have to go further, and I hope the message of this conference is heard,” Cerexhe told delegates.
The European Commission agrees that the complexity around Framework Programme 7 grants, “Has reached a level of complexity that is frustrating [FP7’s] objectives,” Cerexhe said, adding that the Belgian Presidency is committed to simplifying this area.
Another priority of the Presidency is the future research and innovation plan, Euro2020, which is due to be published at the end of September. This will include measures for funding technology transfer, removing obstacles to innovation – for example by pushing forward with the creation of the single EU patent – and addressing the shortage of researchers and qualified scientific and technical support staff.
At the same time the Belgian Presidency will promote the development of the single European Research Area, building on the recently established pan-European project on Alzheimer’s Disease, to encourage more joint programming by national research councils, seek greater convergence of national research policies, and open up EU research programmes to the rest of the world.
“One of EU’s strengths is to have the biggest research programmes in the world and the ones that are most open to external collaborations. This is the route to further development,” Cerexhe said. He added, “Finally, beyond all this there is the matter of resources. We have to reach the objective of spending three per cent of Gross Domestic Product on R&D.”
Ruxandra Draghia-Akli, Director of the Health Directorate at DG Research emphasised the extent to which European Commission funding for clinical research has been reinforced in recent years in her talk, “Clinical Research in Europe: the DG Research Perspective.” Of the money devoted to health research in Framework Programme 7, the largest portion is dedicated to translational research in major disease areas, and the 2011 call, published on 19th July 2010, has a major focus on investigator driven clinical trials.
Draghia-Akli made a commitment that this focus will be maintained in the remaining calls under FP7 which runs until 2013. At the same time, she noted that clarification on how this funding is disbursed was provided in a recent memorandum. In parallel, the Health Directorate has funded the development of the infrastructure to support the conduct of multi-centre clinical trials in ECRIN – the European Clinical Research Infrastructure Network. ECRIN can provide support for investigators applying for FP7 funding and can act as partner or subcontractor.
Another initiative, to promote international Phase II and Phase III trials of treatments for HIV/AIDS, malaria and tuberculosis in Africa, originally funded under FP6, has been extended into FP7. Currently, international trials are in progress as part of this programme, noted Draghia-Akli. “This shows we can carry out international clinical trials, even if it is complicated.”
The European Commission has funded work to increase patient involvement, including children and the elderly, in clinical trials. “We hope patients and patients’ organisations will be involved in a much more consistent and intelligent way,” said Draghia-Akli.
The Health Directorate also funded ICREL (Impact on Clinical Research of European Legislation), a one year investigation into the impact of EU legislation on clinical research. This has provided important input into the discussion taking place currently on reforms to the European Clinical Trials Directive.
Furthermore, EU funding of clinical research has borne fruit. Examples include:
A. Demonstrating the efficacy of gene therapy for X-linked severed combined immunodeficiency, in work carried out under FP5 and FP6
B. Development of treatment guidelines for the use of antiretroviral therapy in treating paediatric HIV-1 infection
C. Funding in FP5 and FP6 laid the foundations for the current FP7 project Alpha-man, a first-in-class human clinical trial of recombinant lysosomal acid-mannosidase in treating the rare disease alpha-mannosidosis
In addition, nine clinical projects have been funded to date under FP7, including NEMO, which is investigating the use of bumetanide in treating neonatal seizures, and Loullaphilla, which is developing 6-mercaptopurine and methotrexate oral formulations for maintenance treatment of acute lymphoblastic leukaemia in children.
“In other words, we are not working in a vacuum. There’s a long history of funding in this type of investigator driven clinical trial’ said Draghia-Akli.
At the same as funding investigator driven clinical research, the Health Directorate is contributing to discussions on reform. On 10 November 2009 it sponsored a workshop on how the European Commission can facilitate such independent research. “This helped demonstrate the need to change the rules in order to promote international clinical trials,” Draghia-Akli noted, concluding, “We need your help: I am hoping that the discussion today will help us to get a consensus.”
The Grand Challenges Europe is facing in the shape of ageing, allergy, obesity, mental health disorders, cancer and cardiovascular diseases, can only be overcome through medical research, said Liselotte Højgaard, of the Rigshospitalet, University of Copenhagen and Chair of the standing committee of the European Medical Research Councils at the European Science Foundation in Strasbourg in her discussion of the “European Biomedical Research Area.”
Medical research is the source of new knowledge that will both improve treatments and constrain costs. At the same time this will have the important economic impact of promoting the development of Europe’s medical industry. Research carried out by the UK medical research charity the Wellcome Trust shows investment in medical research gives a return of 39 per cent for each of the following years.
Højgaard noted such medical research encompasses basic, translational, clinical and epidemiological and prevention research. “The scope is very broad, and we don’t want competition between one and another – it’s not basic versus clinical.”
At the same time, science is global and Europe can draw on research from the rest of the world in seeking to address the Grand Challenges. The US remains pre-eminent in medical research, and on top of spending three times as much on research as Europe, the US also has the advantage of a single regulatory framework for research.
As an example of how this is leveraged to promote innovation, Højgaard noted that Margaret Hamburg of the FDA and Francis Collins of the NIH have agreed to team up in the development of personalised medicine. Europe too needs to combine its resources in this important field, and in particular shared biobanks and databases are needed to drive personalised medicine forward.
In addition, the European Research Areas needs to be developed, and there must be mobility for researchers.
While the recently formed European Research Council is becoming a significant force in the funding of basic research, only a small proportion of its grants have gone to biomedical research. The European Science Foundation has been at the forefront of moves to strengthen medical research in Europe with the publication of a Foresight White Paper on investigator driven research. This made five key recommendations:
- Improve the education, training and career structure of clinical researchers;
- Increase the levels of funding for investigator driven clinical research;
- Adopt a risk-based approach to the regulation of investigator driven clinical research;
- Streamline the procedures for getting approvals for investigator driven clinical trials;
- Ensure investigator driven trials are appropriately designed.
Højgaard also called for more joint programming noting that this happens in other scientific fields. “There is collaboration in nuclear physics, so why not in medical research?” she said. In this respect the Innovative Medicines Initiative is an important exemplar. “I do hope this area of pre-competitive research really does develop into something,” Højgaard, concluded.Harold zur Hausen, of Deutsches Krebforschungszentrum and winner of the Nobel Prize for Physiology and Medicine in 2008, took his 48 year career as a researcher working to elucidate the role of infections in cancer as a case study to demonstrate that improving cancer treatments relies on many different strands of research, from basic research into the mechanics of cancer development, to applied research to devise the best therapeutic regimes.
In his presentation, “Perspectives for Basic and Applied Cancer Research in Europe”, zur Hausen said he “feels very strongly” that the past separation of the chemical, physical and biological factors that cause cancer is becoming more and more outdated. “Biological carcinogens – that is specific infections – regularly interact with physical and chemical carcinogens,” zur Hausen said.
Fifty years ago the role of infection in cancer was unknown. Now, it is understood that more than 20 per cent of cancers are linked to infections – making infection the most important risk factor, exceeding even smoking tobacco. “It’s clear that research on the infectious causes of cancer has permitted a better understanding of events leading to carcinogenesis,” zur Hausen said.
This fundamental insight has made it possible to prevent cancer by dealing with the infection that trigger it. Examples include the use of antibiotics to prevent stomach cancers promoted by Helicobacter pylori, and vaccination to prevent cervical cancer caused by human papillomavirus.
Of the 21 per cent of cancers caused by infections, 71per cent are now preventable by treating the infection. These types of prevention do not require a change in lifestyle and have a very low risk of side effects, zur Hausen noted.
This success, coupled with emerging evidence pointing to a role for infections in a number of other cancers, highlights the need for increased research in cancer prevention.
It also underlines the importance or studying cancer epidemiology to find clues to the factors involved in specific human cancers. Colorectal cancer is an example of how good epidemiological studies can help in identifying mechanisms that initiate the disease process. A number of studies have proposed that eating red meat can cause colorectal cancer. It is suggested that this is due to chemical carcinogens produced when red meat is cooked. However, frying or grilling white meat such as chicken or fish, promotes the production of similar heterocyclic aromatic hydrocarbons.
In addition, the higher risk attributed to red meat appears to be mainly restricted to beef. So for example, the risk is low in China despite a high proportion of pork in the diet, and in Arab countries where a high level of lamb and mutton is eaten.
Prof. zur Hausen suggested the differences in carcinogenic risks could be explained by thermo-resistant infections, for example by a polyomavirus that is present exclusively in beef. He noted that a large number of infectious agents are likely able to survive the low temperatures at which rare beef is cooked.
Even for lung cancer, where the role of chemicals in tobacco smoke is well understood, it is not possible to exclude infection as the event that triggers the cancer to develop
“This demonstrates that curiosity-driven basic research, basic application-orientated research, and applied cancer research are all closely interlinked, and underlines the importance of knowing causation to improve prevention,” zur Hausen said in conclusion.
There is often a perception that regulators are more sceptical about academic clinical research than they are about industry-sponsored research. “This is absolutely not the case: rather they distinguish between well-conducted, well designed trials and ones that are not,” said Francesco Pignatti, Head of Oncology, Haematology and Diagnostics in the Unit for Human Medicines Development and Evaluation at the European Medicines Agency (EMA), in his discussion of the EMA’s view of the role of academic trials, “Acceptance of Academic Trials in Europe: New treatments Approval”.
Academic trials are judged by the same criteria as company trials, Pignatti said. They must meet the same standards in terms of establishing safety and efficiency and being in agreement with good clinical practice.
Pignatti himself has come across examples of both good and bad academic trials. In one example of a single arm academic trial in an orphan indication, the efficacy and safety objectives were met and the study was published in a peer reviewed journal. However, the Good Clinical Practice inspection showed the sample size had been increased without the protocol being amended; 60 per cent of the patients were not eligible, 30 per cent of patients had received other anticancer therapy. These and other irregularities led to the Marketing Authorisation being refused.
Ultimately, the company seeking the Marketing Authorisation is responsible for the quality of the data, regardless of who carries out the trial. There can be problems with applications based on academic trials, and, Pignatti said, more dialogue is needed to avoid this and to maximise the impact of academic trials on public health. “We need to try and talk much more. Usually, it is the industry and the regulators talking; there is very little direct dialogue between regulators and academics.”
New products are approved on their own merits with no reference to how they will fit into the existing framework of therapies. Pignatti suggested that putting a new treatment into context presents “a major opportunity for academic trials to make a contribution.”
At present, Europe has a patchwork of different national bodies that are responsible for such relative effectiveness studies, and, Pignatti said, harmonisation is required. “Currently, we approve drugs on absolute efficacy; we need to move to trials with external validity on how to use drugs, and that’s where we need more academic trials.”
Health Technology Assessments and getting reimbursement are post-approval hurdles, and, Pignatti said, in future the paradigm could be to integrate these processes into drug approvals. “This would not be possible without academic trials,” he concluded.
The reform of the European Clinical Trials Directive represents an important opportunity to enable patients to become fully engaged and properly represented in the trials process, said Kathy Oliver, Co-Director of the International Brain Tumour Alliance in her discussion on, “Patient Perspectives on clinical trials: recruitment, rights and ethical issues”.
For a start, few lay people have any understanding of clinical trials and the potential benefits of taking part in them. Instead, they are concerned about being guinea pigs, about not getting treatment if they are in the placebo arm, and that consent forms protect the interests of researchers and drug companies, but not of patients.
These misconceptions, combined with a shortage of reliable, digestible, information, leaves people confused about whether or not it is a good thing to enrol in a clinical trial. In consequence, there is a low level of engagement. In cancer, for example, less than 5 per cent of patients take part in trials in the US, 5 – 6 per cent in mainland Europe and 11 per cent in the UK. “There are certainly problems with clinical trial recruitment from a patient perspective,” Oliver said. And yet, she noted, innovation can be driven by patients.
The Brain Tumour Alliance often hears from patients who have not been offered the chance to be in a clinical trial. While there may be many reasons for this, there should be full disclosure and information about trials that are open. Online trial information and trial matching services are starting to be established.
Oliver suggested that the possibility of taking part in trials should be discussed early in the treatment process, and patients, families and caregivers should be helped to understand the benefits of clinical trials.
For this to happen, doctors need more training about clinical trials. There is also a need for properly-trained patient advocates. Other issues to be addressed to enable patients to become equal and engaged partners in clinical trials include insurance coverage, providing assistance if patients have to travel to take part in a trial, ethnic, cultural and language barriers that may prevent patients from enrolling in a trial, the fact that teenagers and those over 65 years of age are seldom offered the chance to be in trials, and the right to access healthcare in different EU countries.
Rather than thinking of them purely as “subjects”, patients should be viewed as allies in the research process, by, for example, involving them in clinical trial design. “Patient preferences may be crucial to a trial’s success – reducing dropout or boosting recruitment,” Oliver noted.
There is also a need for greater patient involvement in ethics committees, Oliver said, pointing out that patient groups have been involved in the consultation on reform of the European Clinical Trials Directive. “Use our experience as patients and caregivers to create a clinical trials environment free of mystique; building patient involvement will improve European Clinical Trials,” Oliver concluded.
The task of consulting on and drawing up reform of the European Clinical Trials Directive is the responsibility of DG Health and Consumers. Stefan Führing of the Pharmaceuticals Unit gave an assessment of the current situation and an update on progress in analysing responses to the public consultation and drafting revisions in “Revision of the Clinical Trials Directive 2001/20/EC – Improving the framework for clinical excellence in Europe”.
Painting the backdrop to the review, Führing noted that the number of applications to run clinical trials in Europe fell by 10 per cent between 2007 – 2009. Not only that, the number of participants in proposed trials fell too, from 535,481 to 358,429. “As a policy maker and regulator, these figures are highly dissatisfactory,” Fuhring said.
Of the 4,491 trials running in 2009, only 21 per cent involved sites in more than one European country. However, the 933 multinational trials that were running involved 249,944, or 70 per cent of all clinical trial participants.
Alongside work to draft a new Directive, the Commission’s response has been to try and make the existing 2001 Directive work better. This has involved moves to strengthen cooperation between Member States, through an ad hoc group on implementing guidelines, chaired by the Commission, and through the formation of the Clinical Trial Facilitation Group, which is chaired by Member States. “These involve down-to-earth cooperation among Member States. We are not just talking about broad regulatory principles and guidelines, but about Member States working together and developing trust,” Führing said.
At the same time as fostering cooperation, the Commission is strengthening the implementing guidelines. This work has included compiling a Question and Answer guide to implementation, and revising the guidance document CT-1, which sets out very detailed rules and advice on applying for, and conducting, clinical trials. “We are really trying to improve the situation and want to know if these guidelines work: please provide feedback,” Führing said.
In parallel, the Pharmaceuticals Unit is progressing the revision of the European Clinical Trials Directive 2001/20/EC, as announced in December 2008. Führing said it is important to remember that passing of European law consists of two phases. In the first, the Commission consults and draws up a legislative proposal and associated impact assessment. In the second phase, the proposal is submitted to the Council of Ministers and the Parliament, where it may be subject to amendments.
Currently, the impact assessment is in progress, and the Commission hopes to make a firm proposal by 2011.
In conclusion, Führing said the Commission really is committed to improving the regulatory framework. It is open to ideas, but these need to be specific. “Don’t just say it’s all bad. And remember, the Commission is not the legislator.” La Commission propose, le Parlement et le Conseil disposent” as Draghia-Akli reminded the audience.
Roundtable one: Ethics in Clinical Research
The afternoon session opened with a roundtable discussion on Ethics in Clinical Research which tackled five topics with the aim, not of rehearsing the issues, but making specific recommendations to deal with them. Chaired by Sandor Kerpel-Fronius, Semmelweis University, Hungary and taking part were Etienne Sokal of Cliniques Universitaires St-Luc, Belgium; Rury Holman of the Oxford Centre of Diabetes-Endocrinology, UK; Jean-Marie Maloteaux of Universite Catholique de Louvain, Belgium; Wim Wientjens of the International Diabetes Foundation, based in Brussels, Belgium; Marc Bogaert of the University of Gent, Belgium.
1. The harmonisation of procedures for authorising international trials and the submission of amendments
Recommendation: Each country should have a single national ethical approval process to authorise trials, with local ethics committees to supervise the performance of trials.
It was suggested that one possible model for this is the French approach with the submission to the Competent Regional Ethics Committee (CPP) of the national coordinating investigator. The advice of this CPP is valid for all French sites. Hungary too, has a central ethics committee established ten years ago. While it is the sole body for making scientific and ethical assessments of proposed trials, local ethics committees are still needed to supervise trials.
Although Belgian law says there should be a single ethical opinion, it can be hard to achieve this. Different ethical committees have different questions and there is not enough interaction between them to reach a common view. While a single national ethical committee might solve this, there is no strong will to introduce such a body. At the same time there are concerns about the quality and competence of some local ethics committees.
The setting up of national ethics committees would also raise the question of who selects committee members. Ethics committees should be independent, yet in Belgium, for example, they are appointed by hospitals which can lead conflicts of interest. In addition, researchers which are members of Ethics Committee should not vote on their own studies.
2. Risk assessment and insurance coverage of trials
Recommendation: There should be risk categorisation at an EU level with data sharing; if a trial is multinational it should be insured by the same company, under a single policy
The discussion considered whether clinical trials should be categorised into different risk groups and if national requirements for clinical trials insurance should be harmonised. This is acknowledged to be a difficult problem, but it was suggested that trials could be evaluated to distinguish different levels of risk and there should then be a link between the risk and the level of insurance coverage.
In Belgium, for example, there are frequent complaints from investigators who question the current legal requirement to insure a trial¸ even if there is no risk.
At present, there is no link between the level of risk and the amount of insurance cover. One suggestion is to classify trials on a scale of 1–3: 1-“high risk”: trials with new drugs; 2- “Medium risk”: trials using drugs well documented for other indication and 3- “Low risk”: trial using approved drugs.
The investigators would propose where on the scale a trial sits, and the ethics committee would approve this assessment, leading insurance companies to scale their premiums accordingly.
There are no guidelines in existence for assessing risk in terms of types of therapy, for example, embryonic stem cell therapy versus adult stem cell therapy, or in terms of type of patient.
It was suggested that insurance should not be required for trials involving licensed drugs since patients are protected via product liability.
The transposition of the Clinical Trial Directive 2001/20/EC into the member states national laws has lead to a significant heterogeneity in term of insurances requirements regarding the level of indemnity and the duration of the coverage. Insurances requirements should be harmonized and simplified increasing patient protection but also relieving the financial and administrative burden from the shoulders of trial sponsors. There is a need for insurance expertise and for competition in the clinical trials insurances market.
3. Dealing with pharmacovigilance issues associated with clinical trials
Recommendation: The monitoring and reporting requirements of academic clinical trials should be the same as for commercial trials
The requirement in the European Clinical Trials Directive that all side effects are reported, regardless of context, or if they are known side effects of the treatment being tested is causing “absolute chaos”. Local ethics committees cannot cope with counterproductive parallel reporting of SUSARs (suspected unexpected serious adverse reactions). Furthermore, it is not evident that local reporting increases the safety of patients.
This raises a number of questions:
- Should all SUSARs be reported directly to EudraVigilance, with automatic notification to a national level?
- What is the best way to optimise information flow to ethics committees?
- Do ethics committees have appropriate training and resources to handle adverse event reports, or should reporting be at a national level?
- The position is further complicated by trials of diagnostics and non-interventional trials. How can the quality of these trials be ensured? Should they also report to EudraVigilance?
It was suggested that all trials should be run to the same standards and be subject to the same legislation.
There is a need for single system for aggregating information, and rules would have to be drawn up on how this information is disseminated. The aim of any reform should be to ensure that within any trial, the safety signals are seen as quickly as possible.
4. The harmonisation of ethical requirements associated with the collection of human biological material for genetic research within clinical trials
Recommendation: Currently, there are different ethical guidelines for clinical research and genetic research. These need to be combined, to underpin the development of personalised medicine. It should be possible to use donated tissues for future academic research project approved by Ethics Committee e.g. the one of institution hosting the researcher without having to re- consent the donor.
There are several hurdles in the way of DNA and RNA biomarkers (that are indicative of both normal and disease processes) becoming embedded in clinical trials. For a start, different agencies, research bodies and countries use different terminologies to classify tissue, there are differences in types and levels of consent and on rules for anonymising and identifying tissue samples.
It was felt that consent forms should specify different options:
- general consent for tissue to be put to any valid use;
- possible future opt-outs;
- consent limited to unlinked, anonymised use.
The current situation is confusing and bureaucratic. In one trial in which having a KRAS mutation was a prerequisite, patients were required to sign three different consent forms.
It was suggested that a single European consent form be drawn up which would allow patients to opt in, or out, for each use that may be made of a tissue.
But while this form may apply in the context of a particular trial, it would not cover other uses, for example looking for newly-discovered biomarkers in old tissue.
It was agreed action is needed, because more and more European Ethics Committees are prohibiting the collection of tissue for future research.
5. Harmonisation of the essential legal and administrative information to be included in informed consent forms
Recommendation: Devise a template for harmonising the way in which legal and administrative information is presented in consent forms
While it was agreed a template would be useful, this would not overcome the basic problem that drawing up patient information sheets/ informed consent is difficult – and that they may be changed by the ethics committee. For a start, the rules governing what must be included in a consent form mean they are inevitably far too long and difficult to digest.
One approach to trying to make forms more usable is to test them on patient panels.
Roundtable Two: The challenges of pan-European clinical research
The chair was Robert Souhami, University College London, UK and taking part were D Brasseur, HUDE, Belgium; Françoise Meunier, EORTC, Belgium; Daniel Pipeleers, VUB, Belgium; Martine Piccart, IJB, Belgium; Roger Bouillon, KU Leven, Belgium; B.Winograd, Celgene , US; Silvio Garattini, Mario Negri Institute, Italy; Jacques Demotes-Mainard, ECRIN, France; Greet Musch, AFMPS, Belgium; Stefan Führing, DG Health and Consumers, Belgium.
1. Funding of independent multinational clinical research
Recommendation: Establish a pan-European fund for international trials, modelled on the European Research Council.
Funding of independent clinical research is a significant concern. Organising international clinical trials is extremely time-consuming and expensive. Although Framework Programme 7 is providing some grants for clinical trials but mainly phase II trials and not large phase III, there is no pan-European funding agency comparable to the National Institutes of Health in the US.
To bridge the gap between national and industry-sponsored clinical trials a new body should be set up, modelled on the European Research Council – called the European Investigator Driven Clinical Trial Fund – to fund trials that will give healthcare providers the data to ensure patients get the best treatment and enabling them to allocate scarce resources for the maximum benefit.
For example, a trial in cancer running currently is using a novel diagnostic test to discriminate between patients who need chemotherapy and those who do not. This will mean less chemotherapy is prescribed, lifting the burden of treatment and also saving money.
It take a lot of time and energy to get funding for such large-scale trials like this which seek to answer important questions that are relevant to the treatment of thousands of patients.
A possible role model for a pan-European funding body might exist in Italy, where pharmaceutical companies pay five per cent of their promotional budgets to fund investigator driven clinical trials. In the five years since the fund was established, it has supported 75 trials. Spain has a similar scheme. These existing bodies do not fund international IDCTs. Therefore, reaching the pan-European scale of funding remains a real challenge.
Another approach would be take advantage of specific funding in different countries and build a virtual network to carry out international trials, based on the ERA-NET scheme. ERA-NET was established to step up the cooperation and coordination of national research through networking and the mutual opening of national and regional research programmes.
An ERA-NET for academic clinical research (IDCT) could form the basis for more joint programming by national medical research funding bodies, as has been agreed in Alzheimer’s Disease research.
2. Legislative and administrative frameworks for clinical research
Recommendation: Academic investigators need to define the changes they want to see as the basis for harmonising the rules for conducting clinical research
A. Risk-assessment – one measure to strengthen academic clinical research would be to have a risk-based approach, which for example, allowed the conduct of trials to differentiate between new compounds and marketed drugs. It was noted that the FDA has such a risk-based approach for academic clinical studies.
Discussions have taken place to try and come up with a way of calibrating risk. A complicating factor is that risk varies according to the type of product being tested but also according to the protocol and the means of administration.
Risk-assessment involves very complicated decision trees. While two levels of risk – one for academic and one for commercial trials – is not appropriate, any system of risk assessment does need to be simple if it is to be enshrined in a single, workable, EU law.
One possible classification has been suggested:
Level 1: “high risk”: trials with new drugs
Level 2: “Medium risk”: trials using drugs well documented in other indication
Level 3: “Low risk”: trial using approved drugs
There would be a different approach to setting up trials in each category
B. Harmonise procedures for approving clinical trials
One route to establishing a harmonised procedure for approving trials would be to allow one national agency to carry out the assessment and then invite other Member States to submit questions.
However, it was noted that the roles of the competent authorities and of ethics committees differ from one Member State to another. It will not be possible to have a single clinical trial authorisation unless these roles are clarified and defined.
C. Ensure amendments to clinical trials need only be notified if they are significant
Changing the design of a clinical trial is a substantial amendment, changing the phone number of an investigator is not. Handling both in the same way causes unnecessary delays to clinical trials, costs money, and is of no benefit to anyone.
The Commission has published guidelines to clarify what constitutes a notifiable amendment, but it is not applied by all Member States
3. Collaboration with industry
Recommendation: establish a code describing how clinical trials will be run in the interests of patients. A steering committee representing all stakeholders will then apply this code to individual trials, to protect academic freedom in trials run in collaboration with industry.
There is a need to maintain academic freedom. But trials with industry are valuable and mandatory to establish new agents into the therapeutic armentarium.
Guidelines for academic/industry collaborations need to be pragmatic and to acknowledge that such collaborations are to be encouraged. However, the rules in one EU country state that such trials cannot be used for the purpose of commercialising a drug, meaning there is no incentive for a patient to take part, or for a company to get involved.
Two particular topics relating to academic/industry collaboration are attracting particular attention at present:
A. Intellectual Property Rights – this is becoming a problem area since there is growing awareness amongst academics about possible loss of opportunities when giving away their property rights on discovery which might arise from trials financially supported by industry. A fair balance in term of return should be achieved between the sometime risky financial investment made by the industry and the know-how and expertise engaged in the trial by the academics.
B. Academics should assess carefully the scientific and medical quality of industry sponsored trials before signing in. Sometimes study design is guided by marketing consideration more than scientific rationales. In example, industry sponsors might privilege the highest dose and the longest course of treatment.
4. Studies in different areas
Recommendation: Currently, most academic trials are in cancer. Mechanisms must be developed to fund international academic trials across all areas of healthcare.
Academic trials tend to focus on cancer. In the UK for example, 68 per cent of large-scale academic trials are in this field. Moves are needed to encourage more academic trials in other areas of high medical need, including immune and inflammatory disease, neurodegenerative and central nervous system disorders, sexually transmitted infections, paediatric trials, the 7,000 rare diseases and emergency medicine.
However, it was suggested it may not be appropriate to apply the existing frameworks for running academic cancer studies to other indications. There is no doubt, though, that large-scale academic trials in fields apart from cancer can have had a big impact. A famous example is the Crash 2 trial which investigated the use of an antifibrinolytic agent in trauma patients with significant haemorrhage. This trial, sponsored by the London School of Hygiene and Tropical Medicine, included 20,211 patients in 274 centres in 40 countries. The study concluded that administering a clotting agent to trauma victims with severe bleeding would save 100,000 lives a year globally.
5. Training and Careers
Recommendation: A career track should be set out, showing people coming into the field what training they can expect and how they can advance their careers
Becoming an academic clinical investigator is not seen as a good career move. In the time is takes to set up a clinical study, a laboratory scientist working on mouse models is likely to have published three papers. As a result there is a shortage of clinicians coming into the field of academic clinical research.
It was noted that while the aim of the conference was to consider how to promote international academic trials, education and training of clinical investigators is locally anchored. However, a pan-European approach is needed to attract young medical doctors into the field.
It was suggested that qualifications for clinical investigators could be linked into guidelines for risk assessment, so the question would be posed: Are the investigators running this trial suitably certified?
Skills shortages exist at more than one level – there are not enough clinical investigators or staff qualified to carry out data analysis.
Currently, there is no school for clinical trials medicine covering, for example, trial design, and people have to learn on the job.
The EU-sponsored Innovative Medicines Initiative (IMI) is addressing these issues in its PharmaTrain programme. This is a modular scheme that can be completed in different EU countries.
Overall Recommendations and Conclusion of the Conference
Francoise Meunier, Director General of EORTC thanked delegates for taking part in a “very successful” brainstorming on the challenging aspects of conducting independent international clinical trials, and how the European Clinical Trials Directive should be reformed to support and promote this crucial area of research.
The key to any changes must be to put the patient at the centre, and to recognise that academic clinical research embraces the circle from basic science, to translational and clinical research, approval and registration of drugs, teaching and promoting findings and changing medical practice. “The best way to change medical practice in Europe is to participate in pan-European trials,” Meunier said.
Viewed from this perspective, clinical research is not a luxury or a way for clinicians to add a line to their CVs. It is the route to:
- promoting innovative research and access to treatment;
- translating laboratory research to practice;
- defining the state of the art in terms of treatment;
- identifying ineffective and/or redundant treatment.
It falls to academics to provide full and objective answers to these questions because industry has no interest in doing so. This again underlines the importance of international investigator-led clinical trials which:
- are not done for the purpose of registering drugs;
- should be run at a large scale;
- deal with diseases that are common throughout the EU and elsewhere;
- can bring scale to trials and therefore progress in rare diseases;
- help Europe address ageing and its associated co-morbidities;
- are the one trusted source for independent, objective evaluation;
- will pave the way to personalised medicine.
Given this, it is extremely important that:
- capacity for running independent investigator-led trials is maintained in Europe;
- costs are constrained;
- participation and access to trials is increased from the current level of 5 per cent;
- academic clinical trials are acknowledged to be an important element in maintaining and building Europe’s competitiveness, and reducing brain drain;
- the importance of international collaboration and partnership must be highlighted;
- academics must collaborate with the pharma industry and with biotech companies
Above all, it is critical that the revised version of the European Clinical Trials Directive delivers clarity and simplification on the following issues:
- procedures for authorising clinical trials and the submission of amendments;
- simplified and harmonised insurance requirements are put in place;
- there is the ability to deliver a single opinion in a national ethical review;
- a streamlined, but effective, safety reporting system is established;
- there is a more effective framework for writing patient information sheets and informed consent documents;
- there is a risk-based approach to assessing trials;
- ensures consistency between the Directive and national legal requirements;
- sets out an education and career track for academic clinical investigators;
- includes measures to increase and promote patient access and involvement;
- avoids any duplication or fragmentation of effort and ensures clinical trial results are disseminated;
- creates a European fund for international investigator driven clinical trials.
The revision of the European Clinical Trials Directive provides a great opportunity, but it also requires a vision, Meunier concluded. “We need to see where Europe will maintain its scientific leadership.”
Closing the conference, Janos Frühling, Secretary of the Belgian Royal Academy of Medicine told delegates, “Our task is to ensure the highest level of clinical research.” This will assure the safety of the patient, underpin collaboration with industry and assure Good Clinical Practice.
This requires that the legal and administrative framework set out in the European Clinical Trials Directive is optimised. “We need to modify the European Clinical Trials Directive 2001, to make it fit the needs of patients, physicians and other stakeholders,” Frühling concluded.