The Italian Medicines Agency (AIFA) put together observational data and highlighted the need for meticulous, controlled and randomised clinical trials. Ten years ago you used to stress how we should take any available opportunity to focus on the quality of clinical research and how we should stop viewing this as just a “topic for more or less abstract reflections”. Are you satisfied with the work of these past months?
I would say- not to be over-enthusiastic- that I’m rather satisfied. The Ministerial Decree of 17 March, which stated that every clinical trial related to Covid-19 has to be approved by the AIFA and the Ethics Committee of the Spallanzani National Institute of Infectious Diseases, was a happy opportunity. The centralisation of decision-making allowed us to monitor more closely the quality of research studies and to promote trials that headed toward a randomised model while, of course, always working in compliance with regulations. I am happy with the work done in this first phase; it was extraordinary. The Scientific and Technical Committee (CTS) went from meeting four days a month to convening permanent meetings for 65 consecutive working days.
What were the results?
To this date we have very swiftly approved 30 per cent out of the almost 150 proposed and assessed trials, while learning different things on the standard of care that was being defined by the AIFA sheets at the same time. During the first phase, up until the end of March, a time of serious emergency, starting trials was a way to let patients access treatments that had a reasonable prediction of beneficial outcomes. We therefore approved mostly observational studies, that I would define as phase 2 trials and as programs to expand the prescribed use of medications. Indeed, the challenge was around randomising patients and dealing with consent and suitability, thus the issues were organisational and ethical. As we wrote in the standard of care report during the second phase- meaning in April- the AIFA did a sort of nudging work in order to incentivise randomised controlled trials, as we consider these the main path to try and understand whether a treatment works. Randomised trials were approved and started but not only because of the lessened pressure of the emergency. After approving the initial three-armed trials we established that trials should be comparative and multi-armed and that it would be better not to have too many happening at the same time as they might compete with one another, which would create problems. In addition to this we have to consider that the definition of basic optimal therapy, the standard of care, has been evolving continuously over three months, with a series of disclaimers around many treatments that had been proposed initially.
The centralisation of decision-making allowed us to monitor more closely the quality of research studies and to promote trials that headed toward a randomised model.
The dissemination of research data has always been seen as a key element of evidence-based healthcare. Is it also key for regulatory work?
It certainly is. We were very happy with the many things we saw being published: trial protocols, opinions, favourable views, some documents on the standard of care and the drug fact sheets- even for drugs that didn’t have positive efficacy data. Regarding Covid-19, after three months of monitoring and research activities we can state with reasonable certainty that the so-called real world evidence neither promoted the good use of drugs nor confirmed its own role. Without rigorous randomised trials it is not possible to know which treatment strategy is preferable. This is undoubtedly the most important lesson.
There is a lot of talk about giving responsibility back to primary healthcare. Would it be helpful to maybe give it a role in research activities as well?
Given we supported the Arco study, always in collaboration with the Spallanzani, I think that involving general practitioners in research means that they would have to take part in real research, randomised controlled trials, in order to compare all the different treatments that get proposed or utilised. Nowadays observational trials rely on large databases and although Italy also has good quality ones these were affected during the emergency because not all patients were traced. As we learned from a recent incident involving a study on patient data that had uncertain sources, which was published on the Lancet and then removed, we need to be careful when considering data banks that are not officially certified. In regards to drug efficacy, which is the big question mark for several treatments, the only drug that is being studied in a large trial is remdesivir. However, the data demonstrate moderate efficacy or a possible and modest reduction of mortality, even though the published study shows this is not statistically significant. The data on other drugs, even the most promising ones, indicate any type of benefit in terms of efficacy very cautiously.
Ten years ago you stated, “If I were the Minister of Health I would invest in the role of primary care treatments”. Is that goal still valid?
I didn’t change my mind. We worked, also as part of the AIFA, to invest in primary care treatments because I’m convinced that we need to significantly invest in those. The pandemic confirmed it as well: there is a demand for a greater ability to respond, better training and greater involvement capacity. This might also be an advisable approach for the “richer” regions, in case primary healthcare was weakened or if it’s no longer appropriate for the current times. We recently made decisions around extending the prescription of the new anticoagulants to family doctors- I prefer calling them like this, every once in a while at least. Diabetes and other chronic pathologies will be one of the domains to invest in with general practitioners. However, more needs to be done. Another difficult context is the boundary between the primary healthcare wards and the care homes for the elderly, that were a tragedy and a disgrace for Italy and other countries as well. I think that this framework needs to be reorganised. We need a new social model that is more open and inclusive rather than being centred on detention.
So, with a similar program in mind, could AIFA play an educational role?
I believe that the CTS and the Covid-19 crisis units that we promptly instituted met the expectations of doctors but also responded to the needs of patients and relatives by preparing information sheets. When the expectations around care or treatments become too high you find yourself in delicate situations where promises based on scarce data often prevail. Given the atypical nature of the Agency, both regulating and monitoring the use of medications- just think of the excellent work done by the OsMed (the Medicines Utilisation Monitoring Centre) and the ethics committees- the Agency can intensify its monitoring and research activity while going back to doing training work, guaranteeing credits and utilising the opportunities offered by technology.
Without rigorous randomised trials it is not possible to know which treatment strategy is preferable. This is undoubtedly the most important lesson.
We’re going to touch again on the topic of distance. You’ve worked for years in Geneva with the World Health Organisation (WHO), a supranational institution that some accuse of being too far from the healthcare of the countries that rely on it as a reference point. What’s your opinion on this? What do you think about the US Presidency attacking the WHO?
I think about the WHO with warm feelings because, like the Director told me when I left, “Once you’ve been at the WHO you’re always going to be in the WHO”, so I don’t just defend it but I would add that the attitude of the President of the United States really affected me. This attack represented the severe undermining of a collaboration system that we will have to deal with and, if anything, try to strengthen. The system to strengthen the WHO is actually already at hand because, if they wanted to, all the countries could make the necessary investments to help the institution function better; other than that there is no distance between the WHO and the different countries. It is not true that it looks after the poor countries because the rich ones don’t need its help. For example, the preparedness work for the flu is a classic example of how the WHO can provide help to all, starting from study and data collection models. The WHO, and perhaps the WHO alone, has a deep-rooted culture of collaborative research and randomised trials, even during emergencies. The real distancing takes place with the tendency of some rich countries that prefer to act independently. We know how problems can emerge, also in Europe, when that sense of cohesion is lost. Therefore we need “more Europe” and also “more WHO”- speaking of which, it’s a good thing that it’s mostly Europe that interacts with the WHO because it’s a sign of unity and greater ability. Distancing from this is a product of selfishness and of the conviction of being self-sufficient. The pandemic is telling us that every country is fragile- just think of Sweden admitting that they probably mismanaged the healthcare emergency- and we would all be less vulnerable if we supported the WHO more. Some of the agreements and proposals around making vaccination available to everyone are products of the WHO’s principles that Europe has also acquired in a way, not the other way around.
One last question; the Covid-19 tragedy that we are experiencing is an example of one of the central issues that the psychoanalyst Luigi Zoja discussed in his book a few years ago. Distance keeps on increasing due to the need for social distancing and the disease challenged us with the separation between “clean” and contaminated paths and with the transportation of coffins to a far destination…
In his book Zoja talks about the proximity and distance of one’s neighbour. Some of the most beautiful pages are those where he talks about the concept of hospitality and quotes the Odyssey: “All strangers and beggars come from Zeus, and even a little gift is welcome,” said Nausicaa [1]. Another reference point, to reflect on the way we experience life with this disease, comes from a radio program I recently heard on Radio Tre: Uomini e profeti (Men and prophets). Here a known Italian psychoanalyst, Manuela Fraire, explained how realising we are vulnerable or without defences and being aware of that is difficult but it’s something we have to learn to cope with. I believe that it reflected the difficulty we experienced at the beginning of the emergency, which I consider a sort of embarrassment for not being able to provide an immediate solution. Then all of a sudden we had to do something- do more- provide some drug treatments. Maybe the cure was deciding to take a step back, prescribing less aggressive treatments, staying more at home, more distancing etc.
You lived away for more than a month, first in the hospital and then in isolation, basically on the other side of the wall…
I was never sick to the point of really getting worried. When looking outside I could see a garden, an often-empty parking lot and beautiful trees, maritime pines. The decision to hospitalise me for a long period, rather than quickly discharging me, made feel very protected by doctors and nurses. The Spallanzani workers were really good and they are like that with everyone. I believe that what Beppe Ippolito said it’s true: the true patrimony of the country are the nurses, perhaps even more so than doctors, which everyone always remembers. I felt protected when I saw how strongly everyone is determined to defend the National Healthcare Service and public healthcare. In case of Covid-19 no patient thought about getting hospitalised in a private clinic…
References
[1] Zoja L. La morte del prossimo. Turin: Giulio Einaudi editore, 2009.
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