Regulation on clinical trials - Comments and points of interest for academic clinical trials

In July 2012, the European Commission prepared a ⇒ proposal for the European Parliament, which is not a directive but a regulation. Couching the legislation as a regulation rather than a directive will ensure that the new rules, once finalized and adopted, will have an immediate and binding impact across the EU, avoiding the fragmentation and vagaries of interpretation that have plagued Directive 2001/20/EC. Furthermore, the European Commission has apparently identified many of shortcomings of the current directive and suggested a number of reasonable approaches for international trials:

• Central submission of all documents for fast authorization procedure
• Risk-adapted assessment of clinical trial applications with shortened procedures for low risk trials
• Definition of low risk (minimal interventional) trials with registered drugs and risks comparable to current standard of care
• Clearer definition of investigator responsibilities (one responsible investigator per center)
• Electronic reporting of suspected unexpected severe adverse events (SUSARs)

The new regulation may help to harmonize pre-requisites for clinical research throughout Europe. However, there is still a number of ambiguities.

Comments of the European LeukemiaNet on the Draft Regulation

On behalf of the European LeukemiaNet, Dr. Nicola Gökbuget wrote a comment on the proposal and the draft reports from the Committees on the Environment, Public Health and Food Safety (ENVI), Industry, Research and Energy (ITRE), and Internal Market and Consumer Protection (IMCO). The comment was sent to the Rapporteurs in the beginning of April.

Comments

Dr. Nicola Gökbuget, lead participant of the European Leukemia Information Center, comments on the new regulation and rapports that came from different Committees of the European Parliament.

Draft regulation

Overall the new draft regulation represents a positive attempt to improve harmonization of clinical trial organization in Europe. A number of suggestions from coordinators of academic trials have been considered (see above). Still a few details could turn out to be problematic for academic trials as summarized below.

• Although the draft regulation contains a definition of low intervention trials, there is still no option to perform a non-interventional trial as soon as a pre-defined treatment is given. This means that there will be no way to conduct academic treatment optimization trials with IRB approval but without competent authority approval as it was successfully done in the past.
• The regulators again do not acknowledge trial types – treatment optimization trials - where no investigational drug can be specified but treatment principles are tested.
• The regulation mentions EU portals for submission of applications and SUSARs. It is not clear whether these software solutions will be easily usable and free of costs for academic sponsors.
• The deadline for sponsors to respond to questions from regulators is only 6 days which will be extremely difficult to meet for academic sponsors.
• The draft regulation states that all studies cited in an application have to be conducted according to the current or previous EU regulation or comparable regulations. It will be impossible to assure this e.g. for historically published trials which still may contain important valid data. Regulators should restrict this requirement to pivotal trials.
• The regulation states that only trials registered in a public registry (primary registry of the WHO) can be cited in a clinical trial application. This kind of censorship of scientific knowledge and scientific freedom cannot be accepted. Sponsors should be free to cite whatever published trial they consider necessary for the purpose of the trial. It is ethically unacceptable not to consider important published information due to regulatory arguments only. The clinical trial registration needs should be separated from the scientific rationale of a trial. It cannot be the duty of scientists applying for clinical trial approval to take care for registration of other historic clinical trials. In addition, the most frequently used trials registry – clinicaltrials.gov – is not a WHO primary registry!
• The draft regulation does not clearly define who is responsible to assess the qualification of investigators and sites. If this remains the duty of ethical committees (IRB), the bureaucratic workload will not be reduced significantly. The task should be clearly allocated to a regulatory authority because this is not an ethical issue.
• The regulation states that changes in the trial master file must be trackable. How can this be done in a file which consists of 20 or more folders?
• A number of regulations mention details for the use of ‘auxiliary’ products which are drugs used in a clinical trial in addition to an investigational medicinal product. In academic trials virtually all medication may be defined as auxiliary. Off-label use should be certainly allowed. The documentation should be as limited as possible, if drugs are used in the context of clinical standard.
• The most time consuming part of clinical trial authorization is nowadays approval by an ethical review board. It is not clear how and whether this problem will be solved just by the definition of narrow timelines. One important step would be the limitation of IRB approval to ethical issues. Regulatory authorities, not IRB, should perform the assessment of qualification of centers and investigators.
• The regulation does not consider the problem of rare diseases. If this type of diseases is studied, many centers have to be activated although the majority will never include a patient. The academic research needs mechanisms for rapid activation of centers in case that a patient comes up.

Rapports

All rapports mention the need of ethical review board approval of a clinical trial. This is of interest since IRB approval has already been part of the draft regulation. Without explicit mentioning, the draft regulation contained all needs of ethical approval and this was defined as a duty of each involved country.

There are other very alarming suggestions in the different rapports which are summarized in the following.

ENVI (Environment, Public Health and Food Safety) Rapport

• The rapporteur suggests a clinical trial report, which contains beside other information the complete protocol, statistics analysis plan, and individual anonymized patient data in the form of tabulations or listings. Academic researchers will not be willing and able to publicly offer their complete study data. Beside the public interest there is also their right for intellectual and scientific property. They might plan to publish additional analyses and create a basis for their future trials. The rapporteur does not acknowledge the fact that clinical science is performed in a competitive environment. Those who do the efforts and spend funds for conducting a trial cannot be forced to provide all their results to others for undefined purposes. Furthermore, clinical trial data are extremely complex with thousands of different variables. Academic researchers will be unable to format and upload all their databases in a self explanatory and searchable format. In the end, after enormous efforts, nobody will be able to perform any reasonable analyses with this bulk of data. There is a high risk of conflicting results, which will lead to confusion instead of clarification. The suggestion as a whole will created incredible bureaucratic workload, lead to disadvantages for European research in contrast to other parts of the world and in the end will lead to no or very little new scientific information.
• The rapporteur strengthens the need that clinical trials cited in an application need to have been performed according to EU or comparable regulations. It will be impossible to assure this requirement e.g. for published historic trials which still may contain important valid data. Regulators should restrict this requirement to pivotal trials.
• The rapporteur strengthens the regulatory statement that only trials listed in a public registry (WHO primary or partnered register) can be cited in a trial application. This kind of censorship of scientific knowledge and scientific freedom cannot be accepted. Sponsors should be free to cite whatever published trial they consider necessary for the purpose of the trial. It is ethically unacceptable not to consider important published information based on regulatory arguments only. The clinical trial registration needs should be separated from the scientific rationale of a trial.
• The rapporteur adds the suggestion that clinical trial participants shall be provided with information on the results. This would lead to enormous workload for the centers. They would have to keep contact information of patients – probably even longer than the hospital needs to – in order to contact patients later on, when the final report is ready. The information need and information wish of the patient is not considered. The paragraph should be reworded in the way that patients can receive information upon request.
• In addition to the already problematic suggestion to provide complete study reports and tabulated orginal data, the rapporteur even suggests to upload incomplete date in case of trials with more than 12 months of temporary halt. This will not lead to any benefit for the safety of the patients since incomplete data can by definition not be used for a reasonable analysis.
• The rapporteur suggests that for the clinical trial application all existing evidence including systematic reviews and meta-analysis has to be discussed. It is unacceptable that one type of scientific publication is by definition considered superior to others and needs to be cited independent of quality. It has never been shown that systematic reviews have a higher benefit for patients and safety compared to other publications. This kind of censorship of scientific freedom by regulations cannot be accepted.
• The rapporteur also suggests that each application should include a complete statistical analysis plan. Again, particularly in academic trials, additional analyses which were not originally intended should be allowed as long as analysis of the primary and secondary endpoints are predefined. This scientific freedom is needed to consider new ideas and developments coming up during the conduct of a trial.
• The rapporteur demands that sponsors and investigators shall archive the content of the clinical trial master file for an indefinite period of time after concluding the clinical trial. This is unprecedented! Neither academic sponsors nor participating centers have the capacities to store 20 or more paper folders per clinical trial for indefinite periods. There is currently no practicable way to generate electronic formats of trial master files and also no technology to electronically store documents for an indefinite period. Furthermore, it is impossible to define a budget for storage costs for an indefinite time-period. It is furthermore impossible to store the content of the trial master file – even if it would be possible to generate an electronic format – in a public database because the file contains personal information on patients and physicians. This requirement is absolutely impossible to fulfill and can only lead to the result that hospitals will no longer participate in trials.

ITRE (Industry, Research and Energy) Rapport

• The rapporteur apparently does not acknowledge at all the specific needs of independent academic trials. It is very unfortunate that several problematic industry trials are cited in order to stress the need for more strict regulations whereas all the achievements from academic research seem to be not considered at all.
• A chapter on the risk of clinical trials in relation to standard care and the risks of the disease and the suggestion that regulations on these low-intervention trials should be less stringent was totally deleted. This is extremely disappointing and neglects all the efforts of academic study groups conducting industry independent publicly funded trials for treatment optimization. These trials even reduce the risk for patients but cannot be conducted any longer, if the administrative burden is not reduced.
• Similar to the ENVI rapporteur the rapporteur stresses the need to upload complete clinical trial data into a public database and the requirement that all trials cited in a clinical trial application have to be conducted according to the current EU regulations.
• In addition, the rapporteur suggests high penalties for sponsors not delivering the trial report in due time.
• In contrast to the draft regulation which allowed exceptions from immediate SAE-reporting if predefined in the protocol, the rapporteur suggests that investigators have to report all SAEs. In contrast to the draft regulation, SAEs shall be reported by the investigator to EU data base and IRB. This is even more than requested in the common practice where sponsors have to report only SUSARs. Already now – due to the overload with meaningless SUSAR reports – the alertness of investigators, sponsors, and IRBs decreases. The paper load is virtually not manageable. Any effort should be made to limit immediate reporting to reasonable extent. More detailed information can then be given in a structured safety report.
• Similar to the ENVI the rapporteur suggests that a trial master file has to be stored indefinitely.

IMCO (Internal Market and Consumer Protection) Rapport

Detailed comments and references are available on request. Please contact ELIC.

Political processes

According to the European Commission 800 million Euros per year could be saved in regulatory costs. The legislative proposal will now be discussed in the European Parliament and in the Council. The aim is that the regulation comes into effect in 2016 but it remains open which changes will be made during discussions and whether the time line will be realized. National interests will be expressed and lobby groups have already started activities against the new regulation. Therefore study groups in the European LeukemiaNet will still have to find ways to conduct international trials according to the currently active directive and the respective national regulations.

17.7.2012
Legislative proposal submitted

11.9.2012
Committee referral, European Council (health ministeries), Parliament: Committees (ENVI, IMCO, ITRE)

24.4.2013
Vote scheduled in commission

10.6.2013
Plenary sitting date

Next vote for European Parliament: June 2014

Political Decision Makers on EU level

Reports and opinions on the proposal