Starting next year, trial sponsors can negotiate ethical approval in a member state of their choice, and have the same terms applied across all EU countries. Daniela Ovadia looks at the implications of the new regulation
Conducting research on human beings is ethically challenging. It requires respect for patients, their priorities and expectations, and it requires trust on the part of the patient.
Because of the toxicity associated with most cancer drugs, oncology trials tend to involve patients instead of healthy subjects, even at the earliest stages of the tests. Usually this will be patients who are in the late stages of the disease, who have the most to gain and the least to lose, as an experimental treatment may be their last hope.
When such experimental treatments have shown strong early evidence of meaningful benefit to patients in great need, with an early side-effects profile that appears to be within the bounds of acceptability, ruling on whether there is an ethical basis for trialing the drug may be easy enough.
The more usual case, however, is far more finely balanced. The benefit–risk equation is typically less favourable, and with health services and health insurances beginning to take a harder line on reimbursing costly new drugs of only incremental value, there are ethical questions about the value of running a trial for a drug that may well not be widely accessible even if it reaches the market.
Judging which drug trials are ethically worth pursuing, and which are not requires expertise. But it also requires value judgements. This makes it essential for all stakeholders to have an input – from doctors to patients, but also hospitals and health service representatives and drug manufacturers. It also raises questions about the extent to which value judgements made by one community or country can be translated to other settings, where different cultural values or objective contexts may apply.
Under the new rules, clinical trial applications
will be submitted through a centralised electronic portal
Currently, responsibility for giving ethical approval for clinical trials is in the hands of individual member states, according to their own criteria and procedures, which may be national, regional or even operate at a hospital level. This is all set to change, however, when the new Clinical Trials Regulation comes into force, in January 2017.
Under the new system, ethical approval will be centralised, so that sponsors of trials set to run in more than one European country – which account for more than a quarter of all clinical trials in the EU and enrol almost 70% of all trial subjects – only have to obtain ethical approval in one member state.
The move has been welcomed by some, because it will relieve the financial and time burden associated with getting ethics approval on a country by country basis, and should address some of the worst variations in levels of expertise between ethics committees in different countries. Others, however, are concerned that the new regulation could narrow the range of stakeholders involved in ethics evaluations and open the way for trial sponsors to seek ethical approval from member states most likely to comply with their wishes.
A matter for expert evaluation
Elmar Doppelfeld, Board member and former President of EUREC, the European Network of Research Ethics Committees, believes it’s high time the ethical evaluation of new trials was given the attention it deserves, and says the complexity of assessing the ethicality of proposed new trials is often underestimated. “Ethics assessment of a drug trial is not only an administrative task nor it is limited to the evaluation of the process leading to informed consent. It also involves evaluation of the scientific validity of a trial, of its goals and design,” he explains.
While considerable effort has been put into improving the assessment of the scientific validity and integrity of clinical trials in recent decades, says Doppelfeld, there is still “a discordance in the degree of attention clinicians devote to dealing with the scientific dimension and the ethical dimension of clinical research.”
Most oncologists who are involved in trials and have to deal with research ethics committees (RECs) feel that they lack sufficient expertise in the field, he says, adding that it is common for them to conduct a very superficial assessment of the ethical issues raised by their trial, applying local norms and requirements in a formulaic way.
Mark Bernstein, a neurosurgeon at the University of Toronto, Canada, who authored a seminal review on ethics assessment in oncology published in 2006 (Curr Oncol 2006, 13:55–60), agrees that a superficial grasp of ethical issues is not enough. “Although most clinical investigators are virtuous and well-meaning doctors, it is easy to unknowingly and unwittingly transgress ethical boundaries, just as it is easy for a clinical oncologist, without proper training in clinical trial design, to use improper methodology,” he says.
“Some ethical dimensions are obvious because of common sense, common practice, or common law – for example, the requirements to submit the design of the clinical trial to the relevant institutional research ethics board and to obtain informed consent from research participants.
“Other dimensions are subtle and nuanced – such as the non-financial conflicts of interest experienced by clinical investigators during the course of clinical research, and even the interpretation of the results in terms of clinical meaning”.
The new EU regulation
Under the Clinical Trials Regulation, clinical trial applications will be submitted through a centralised electronic portal. Applications will then be evaluated by the national research ethics committee of the country where the request originated. The national REC will be free to ask other national RECs for information and opinions, but it alone will be responsible for the final decision.
The assessment of a proposed trial will focus on three main areas: compliance, patient safety and scientific value of the trial itself.
“In the absence of a common health system,
the perception of what is valuable for a patient
can be hugely variable”
Francesco Perrone, Director of the clinical trials department at the National Cancer Institute in Naples, Italy, and former consultant to the Italian Drugs Agency (AIFA), believes the requirement to assess the scientific value of the trial is an important step forward.
This aspect of the evaluation is already carried out by research ethics committees in some countries, he says, “but in others it is not, so this will be a major improvement for many European countries.”
The aim of this aspect of the evaluation, he explains, is to weigh up the ethical value of the clinical goals the researchers want to achieve. “The goals of the drug company can be very different from the goals of the clinician and even from the goals of the patients,” he says.
The design of clinical trials involving new targeted cancer therapies can also raise ethical challenges, he argues. “For instance, there are issues of accessibility and affordability of the new treatments to the health service and to patients. Even the choice of the criteria to define a successful trial can be problematic.”
With the new rules, the assessment by the reporting state will be valid across the European Union. Individual member states will be able to prevent the clinical study from taking place on their territory, but they will not be able to modify it in any way, to adapt it to local needs or structures.
As the main goal of the new regulation is to harmonise the rules for ethical assessment of drug trials, this could be considered a necessary step, but it raises some concerns.
For instance, while the new EU regulation spells out procedures for the assessment, rules governing the composition of ethics committees will still be based on national laws. In some countries this means patients, lay persons, legal experts and religious representatives would all participate in the ethical evaluation; in others only doctors and experts will get a say.
One procedure, diverse values
The new Clinical Trials Regulation is a good example of what is going on in the EU in the field of ethics. While the Commission is putting a lot of effort and money towards pushing for common procedures and ethical criteria, ethicists highlight the fact that values still differ greatly from country to country , which is reflected in the feelings of doctors and patients. “In the absence of a common health system, the perception of what is valuable for a patient can be hugely variable,” says Örjan Brinkman, President of the European Consumer Organisation (BEUC).
BEUC was one of the first civic bodies to scrutinise the new directive, says Brinkman, who describes the original proposal as ‘deregulation’ rather than a new regulation. “The aim of the proposal was to deregulate research conducted on human subjects: all reference to ethics committees was expunged, and certain measures would have left member states incapable of protecting participants in clinical trials conducted on their territory.”
The first version of the proposal, he says, put “impossibly short deadlines” for evaluating applications for authorisation to conduct trials, and stipulated that the conclusions of one reporting member state were to be binding on all member states.
It was only thanks to the mobilisation of many organisations representing civil society that several measures to protect trial participants were introduced, including the right for countries to refuse to allow a trial to run in their territory if their national ethics committee issues a negative opinion. A more reasonable timeframe for assessing applications was also introduced: 45 days in total, with the possibility of prolonging this deadline for certain categories of drugs.
Things to look out for
Despite these amendments, major issues remain, which will need to be addressed in the coming months, and will require close attention from patient advocacy groups and civic organisations.
Neither the members of the European Parliament nor EU health ministers seized the opportunity offered by the adoption of this new regulation to insist that new drugs must be tested against standard treatments.
The new regulation also contains what some feel amounts to a potential loophole, in that it considers certain clinical trials in which a drug is used outside its authorised indications (off-label use) as ‘low-intervention’ trials, which are subject to less stringent regulation.
This provision may be welcomed by the rare cancers communities, as it should make it easier to trial in rare cancer patients drugs that have already been approved for more common cancers. But the converse is also true. Drug companies will have an interest in applying for marketing approval in settings where it is easiest to get approval – where small patient populations can be used to justify small trials and lack of existing therapeutic options set a low efficacy bar. They may then be able to promote off-label use of the same drug, applying for additional indications based on ‘low-intervention’ trials.
In effect this makes it easier to pursue a strategy that has already become established for targeted cancer drugs, which are typically initially tested on a narrow group of patients, with very specific and restricted genetic mutations, then extended to a larger number of cancer types and so to a larger population.
In a joint position paper published last year in the Annals of Oncology (vol 26, pp 829–32), the European Society for Medical Oncology (ESMO) and European Organisation for Cancer Research and Treatment (EORTC) argued that the new Clinical Trials Regulation represents “one of the most important changes in the field of clinical trials in the last decade.” They welcomed the opportunity it offered “to facilitate clinical cancer research in Europe and reduce some of the burdens that have proven so costly in the past.”
However they also raised concerns, about whether clinicians are equipped to use the centralised electronic portal, in terms of understanding all the ethical issues that need to be flagged up, and having access to the administrative back-up needed to compile and input all the data.
They also flagged up key issues around which they hope to stimulate an inclusive debate, particularly within national oncology societies, in the hope of reaching “a consensus for a common position on clinical trials throughout Europe”.
Key among these issues is the need to safeguard the patient voice within the ethical approval procedure, which the authors argue requires agreement on a “comprehensive definition” of patient involvement. “Cancer patients clearly have a high degree of interest in participating in the design and decision‐making of clinical trials,” write the authors. “They should be given the opportunity to become involved with a subject that will frame how research on their disease needs to be conducted, and how the data gained from studying their data and tissue is to be used.”
Transparency: in principle and in practice
The new Clinical Trials Regulation was supposed to bring more transparency and facilitate access to the raw data of all clinical trials, commercial or academic. This is something the academic community has long been calling for, to maximise opportunities for learning, to allow independent scrutiny of all trial results, and to enable clinicians to select the most appropriate population to be treated with new compounds, especially when budget limitations don’t support their widespread use.
The final version accepts the principle of public access to “all information submitted in the clinical trials application and during the assessment procedure,” but with the exclusion of data where “confidentiality of the information can be justified on the basis of the protection of commercially confidential information or the protection of personal data.”
This is considerably more permissive on access to personal data than had been envisaged in the first draft.
The changes were made in response to feedback from a public consultation together with concerted pressure exerted by a number of research, professional and patient organisations, which called for a sensible balance between protecting the patient and freeing up vital data to progress research and personalised medicine.
The final wording acknowledges that “the processing of special categories of personal data may be necessary for reasons of public interest in the areas of public health without consent of the data subject,” and it rules out the use of such data for other purposes, by third parties, “such as employers, insurance and banking companies”.
The regulation also accepts the right of companies to restrict public access to trial data to protect their commercial interests. This could effectively thwart progress towards greater transparency, as sponsors will be able to cite commercial protection as a reason to keep the raw data secret.
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