Chasing the train. This is the fate of Italy in terms of clinical trials. The train is the one designed by the European Regulation 536 of 2014, which establishes uniform rules to harmonize the evaluation and authorization process of a clinical study conducted in several Member States. A train that started on January 31 but had been on the track for 8 years, a time in which all member countries would have had to organize themselves to be able to participate in clinical trials from now on. Italy has not done it. Result: “already this year we will lose a quarter of the trials financed by pharmaceutical companies, which are the majority”, says Francesco Cognetti, President of the Federation of Oncologists, Cardiologists and Hematologists (FOCE). “In this way we lose the advantages that derive from experiments that will see our country excluded and that provide for an identical enrollment and centralized evaluation for all member countries. With very serious consequences for our patients, who will not be able to take advantage of the great advantages of innovation produced by research. Based on the latest available data, in 2019, 672 experiments were authorized in Italy, 516 for profit and 156 for non-profit “.
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A tragedy above all for patients. “I am here after more than 20 years from the diagnosis thanks to the fact that I entered a clinical trial”, says Felice Bombaci, national coordinator of the AIL patient groups (Italian Association against Leukemia, lymphomas and myeloma). “Research offers tangible new opportunities for healing and survival. In these 20 years I have seen my children grow up. Patients should not be deprived of the right to innovation, because it can save lives ”. An advantage for the patients, but also for the whole system. “Clinical research is an engine of economic and social development, which can offer an important contribution to the recovery of the current health crisis – explains Paolo Corradini, Vice President of FOCE and President of the Italian Society of Hematology -. There are also positive repercussions for service providers and on employment, thanks to the use of highly specialized professional profiles. And the centers where clinical trials are carried out guarantee the growth of the researchers involved. Without forgetting the great advantages for patients, who access innovative therapies even a few years before reimbursement. To this must be added the savings for the National Health Service and for the individual structures, in terms of free supply of experimental and control drugs, the costs of which are entirely borne by the sponsoring companies “. It has been estimated, in the area of oncohematology alone, a potential saving of about 400 million euros each year and, therefore, can be estimated at a few billion for the whole system.
This year’s delay will extend over the next 4-5 years, if not more. The goal is to be able to get back on the train at the end of this year because if it is true that during the first year of validity of the Regulations the sponsors have the option of deciding whether to submit the new trials following the previous standards or in agreement. with the updated ones, from 1 February 2023 all the trials will have to be submitted according to the new standards. “And the studies still in progress will have to switch to the new criteria no later than January 31, 2025, but the competition has already started three weeks ago and we are out of it. Other European countries have actually been ready for years, with the precise strategy of benefiting from the studies that countries with an organizational delay will not be able to carry out “, explains Guido Rasi, Past Executive Director of the European Medicines Agency (EMA), Full Professor of Microbiology at the University of Tor Vergata in Rome and Consultant to Commissioner Figliuolo for the Covid-19 emergency. Spain, Germany, Austria and Denmark, among others, have focused on the delay of countries such as Italy to divert the experiments on them.
The process of the new law
The so-called “Lorenzin Law” (Law 11 January 2018, n.3) delegated the Government to reorganize and reform the legislation on clinical trials and provided that, within 12 months from the date of its entry into force, it was necessary to issue one or more delegated decrees for the full implementation of the European Regulation. This was not the case. “This is why a new enabling law is now required, which will have to be approved by the two branches of Parliament and therefore by the House and Senate Commissions before reaching the Council of Ministers. A long process that must be completed within the year because in spring 2023 there will be elections and the risk is to have to start all over again ”, says Cognetti again. “Italy is at the top in the world for the results obtained in scientific research, we cannot lose this primacy – highlights Walter Ricciardi, Member of the Executive Council of the World Health Organization, President of the ‘Mission Board for Cancer’ of the European Union and scientific advisor to the Minister of Health for the Covid-19 emergency -. The obstacles still to be overcome are known: too many ethics committees, poor coordination between these bodies that often act on the basis of different protocols, excessively long authorization and start-up times for studies, enormous differences in the contracts for trials “.
The new requirements
The new regulation provides that all trials are managed through a single platform, the ‘Clinical Trial Information System’, which becomes the single access point for the submission, authorization and supervision of clinical trial applications in the European Union and in the countries of the European Economic Area (EEA). “Currently, sponsors must submit applications separately to the relevant national authorities and ethics committees of each country to obtain regulatory approval. Thanks to CTIS, sponsors will be able to apply for authorization in up to 30 EEA countries from a single application. An identical regulatory framework in each Member State guarantees the conduct of clinical trials in a unique way, with defined and certain timescales. It also makes it easier and faster to enroll patients and close their studies ”, underlines Fabrizio Pane, FOCE Treasurer and Past President of the Italian Society of Hematology. “We therefore need a delegated decree that establishes the requirements of the centers authorized to conduct clinical trials, from phase I to IV, also providing for annual monitoring and the publication of the list of authorized structures in the portal of the Italian Medicines Agency (AIFA) “.
The European Regulation also requires that the persons in charge of validating and evaluating the application have no conflicts of interest, are independent from the sponsor, from the clinical trial site and from the investigators involved as well as from the financiers, and are exempt from any undue influence. “The reorganization of the ethics committees and their relocation outside the testing center must be envisaged – continues Pane -. This issue is very important. To date, the ethics committees cannot evaluate a clinical study according to the criteria of the European Regulation, because they are not independent from the trial centers “. In Italy, multicentre and multinational trials are the most frequent, accounting for about 65% of the total. “For this reason it is urgent to adapt the ‘Italian System’ to the requirements of the European Regulation, starting precisely from the reorganization of the ethics committees, also reducing their number. Today there are about 90, far too many. It is expected that they will be reduced to forty and only 3 are those of national significance. This is a revision of the entire clinical research system of which, to date, we see no trace ”, explain Ciro Indolfi (Vice President of FOCE and President of the Italian Society of Cardiology) and Francesco Romeo (Secretary of FOCE).
The impact in oncology
In Italy, expenditure on research and development is equal to 1.2% of GDP, while the average of European countries reaches 2%, with Germany almost 3%. “Despite having few resources available, the studies conducted in Italy have changed clinical practice internationally in different types of cancer, leading to the modification of guidelines and recommendations – underline Giordano Beretta (Vice President of FOCE and President of the AIOM Foundation) and Saverio Cinieri (President of AIOM, Italian Association of Medical Oncology) -. And the Italian scientific works in the oncology field are among the most cited in the world, immediately after those of the United Kingdom. In 2020, 377,000 new cancer diagnoses were estimated in our country, about 1,000 per day. Survival 5 years after diagnosis reaches 65% in women and 59% in men. Research and innovation are fundamental because they allow new effective therapies to be made available to patients much faster, improving the chances of recovery. Italy cannot stop research due to bureaucratic obstacles ”.