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Gilberto De Nucci

Gilberto De Nucci: The medicine radical

Between remedies and controversy: Viagra's creator criticizes the Brazilian production of medicines by government

MIGUEL BOYAYANNobody remains indifferent to the presence of pharmacologist Gilberto De Nucci. Tall, corpulent, and fast walking, De Nucci is the owner of a grave voice and goodhearted look that help him to make friends with almost the same ease that he picks up enemies. It is because this 46-year-old doctor has opinions as sturdy as they are polemical, and is not afraid of saying what he thinks. “At least two thirds of medicaments do not produce the desired effect”, he asserts. To put it more plainly, they have an action that is more psychological than pharmacological. Even so, he advocates the use of remedies: the greatest advances in medicine are due to the adoption of new drugs. De Nucci is currently developing three medicaments. The first to reach the market – possibly as early as 2005 – is lilafil, intended to treat difficulty in keeping up an erection. Produced by him for the Brazilian laboratory Cristália, lilafil’s molecule is similar to Viagra’s, and began to be tested on human beings in August. The researcher is also working on synthesizing an anti-inflammatory and a new class of antihypertensives.

If his ideas are controversial, his competence is undeniable: De Nucci is one of the country’s most productive researchers. Since 1985, he has published 217 scientific articles in international magazines. Today, he is still one of the three most influential Brazilian researchers, whose works appear amongst those most cited by other studies, according to a survey of the ISI Highly Cited database, which includes the 4,800 most influential researchers of a total of 5 million scientists. De Nucci has now registered 22 patents with the National Institute of Industrial Property and 8 with the World Intellectual Property Organization. He has also been the target of 12 legal, administrative, or ethical proceedings. According to him, he has only lost one, in the first instance, was the case started by one of the institutions where he gives lessons – the State University of Campinas (Unicamp) – for using staff from the university as volunteers in clinical studies. “Later on, I won the fight in the State of São Paulo Regional Medicine Council”, he says.

Educated at the Ribeirão Preto School of Medicine, of the University of São Paulo (USP), he went to study pharmacology in England, through a personal identification with one of his professors, the pharmacologist Sergio Henrique Ferreira. In 1986, De Nucci concluded his doctorate at the Royal College of Surgeons of England and, two months later, published in the Proceedings of the National Academy of Sciences one of his most important scientific articles, about the role of endothelin, a vasoconstrictor hormone released by the inside wall of the blood vessels. Besides teaching pharmacology at Unicamp, De Nucci gives lessons at the University of São Paulo (USP), where he helped to create the Cartesius Analytic Unit, responsible for 60% of the studies of bioequivalence carried out in the country. As if that were not enough, two years ago he opened his own research laboratory in Campinas: the Galeno, where bioequivalence tests are carried out on medicaments and the analysis of toxic substances in chicken and crustaceans intended for export.

A few months ago, you declared in an interview that 80% of the medicines did not work. Last December, one of the vice-presidents of the GlaxoSmithKline laboratories, Allen Roses, told the British newspaper The Independent that the major part of the remedies produced by his company did not act as expected in over half of the people. Could you explain this question better?
At least two thirds of medicines act like a placebo [an innocuous substance]. They do not produce any effect. Or there is no scientific evidence that they work, since it is not possible to assess their action against a series of pathologies. Imagine a person who has suffered a stroke. In this case, the effect of the medicament depends on several factors, such as the kind of stroke and the area affected. As there is no way of knowing what the behavior and the memory used to be like before the problem, it is difficult to know if the medicine is assisting the recovery. The same happens with Alzheimer’s disease. The medicine is given in the belief that the person is going to improve, but there is no certainty. After all, we do not know how this pathology arises. We know how it evolves, and to measure whether the evolution is for better or worse with the medicine is complex. There is no evidence that the medicine works against the disease. Actually, in this case, it’s not even necessary.

It isn’t necessary?
In the case of Alzheimer’s disease, there is an accumulation of certain proteins, it is enough to show that the medicament reduces this accumulation [for it to be regarded as useful]. Sometimes, it is not even known whether the problem is really important for the appearance of the disease. But, as there is no way of discovering this, it is better to put the drug onto the market and see what happens. When one does not know whether a medicine works, it’s because we do not yet have means for verifying this.

But don’t you have to know that the medicine at least does no harm, before prescribing it?
Supposedly. Clinical tests are done to find out whether the medicine, a priori, does no harm. Now this doesn’t mean to say that undesired effects will not arise, when it is administered to human beings. This risk is accepted.

Does it make sense to prescribe medicines like this?
Yes, it does. And people prescribe them even so. There’s an interesting phrase on this issue said by Sir William Osler [a Canadian author and the author of The principles and practice of medicine, of 1892, a landmark in the area of health at the beginning of the 20th century]. He says that the wish to take medicines is perhaps the main characteristic that differentiates the human being from other animals.

But there are medicines that work, the action of which extrapolates the placebo effect.
There are today medicines that really do act against given diseases. This makes everyone happy: the patient, who buys the medicine, and the doctor, because clinical studies show that the effect of the medicine is highly significant. One example is the use of aspirin in the prevention of heart attacks. Several studies show that, in the right dose, aspirin reduces almost threefold a recurrence of the problem. But it is a relative benefit, since 80% of the patients would not suffer from a further heart attack, even if they did not take aspirin.

In this situation, is it better to consume the medicine or to stop taking it?
The whole logic of the system is aimed precisely for medicines to be taken. I’m not saying that medicines are not effective. But the best clinical studies show that, for 90% of the population, medicines do not bring any benefit, or that there rarely is a benefit. This doesn’t mean that medicines are of no use, but that the percentage of patients who benefit is very small, sometimes 2% or 3%. An example: A medicine known for treating diabetes, acarbose, which is not absorbed by the organism and competes with the absorption of sugar. With the medicine, the person’s glycemia does not increase, but studies carried out in Germany – in Europe, people are more careful with this – show that people die in the same way. The medicine does not alter the evolution of the disease.

In theory, physicians accompany specific publications in their area and have to be updated, to know what is effective before giving it to the patient, don’t they?
Actually, no. Physicians are not very scientific at all. Medical assessment is subjective, in spite of people having the fantasy that physicians display a scientific attitude. History shows that they don’t.

But aren’t you a physician?
I’m a physician.

Do you mean to say that doctors make a diagnosis and prescribe merely on the basis of the results that they see in their offices?
It’s difficult to apply the scientific methods used in the laboratory in the practice of medicine. At congresses, you see a lot of conduct based on subjective criteria, the physicians saying “how I treat it, how I do it”. They are personal decisions, without any kind of scientific thinking or methodological control.

They do not take into consideration the works of evidence based medicine, reviews that show whether a certain drug serves for treating a disease?
People call it evidence based medicine. I call it evidence biased medicine. The conducts of evidence based medicine are defined following meta-analyses: you bring together the works about the positive and negative effects of a drug. But, as one knows, the probability of studies with favorable results is greater than for works with unfavorable results. This contaminates the conclusions derived from the meta-analyses, hence the expression evidence biased medicine.

This is an important issue. Abroad, there is an increasingly intense debate about the obligatoriness of pharmaceutical companies making public all their results, including the bad ones.
There’s a muddle here. Making data public doesn’t imply publicizing them in a scientific publication. The laboratories have to inform the results of all their researches, whether they are favorable or not, to the regulatory body, which then decides to authorize the sale of the medicine or not.

Isn’t it too little? Wouldn’t it be better to publish the studies in a scientific magazine? The physician who prescribes a medicine would then be able to see this data.
I assess scientific works and clinical studies, and there’s a difference between the two of them. The regulatory body does a review of the clinical study, because it is there that the raw data is. Not in the scientific article, only the tables and graphs, and this is questioned. But in people’s imagination, the pharmaceutical industry is a bad boy, it’s people who want to earn money. As if we were all to work for free…

Without wanting to demonize or to sanctify anybody, one knows that there are some highly condemnable procedures in the pharmaceutical industry, like paying trips and benefits to doctors who prescribe their medicines. In Italy, 4,000 doctors were recently prosecuted for this.
I’m not sanctifying…

Isn’t the current working model of the pharmaceutical industry inefficient? The laboratories say that developing a drug can cost US$ 800 million, because hundreds of molecules have to be created before it becomes a commercial product. Is it right to maintain this model?
It’s the capitalist model. The pharmaceutical industry aims profits, and its products have high added value. It only does not charge more because people can’t pay.

It’s the logic of the market.
Exactly. Why is the daily rate of a leading private hospital much more expensive than the rate of another one, without such a good reputation? Because the first one has its costs, its added value, period. Without going into the question of price, the fact is that there are good medicines, which help medicine advance. Incidentally, medicine only progresses with medicaments. The rest doesn’t matter much.

The clinical procedures, talking to the patient, they don’t matter?
Nonsense. It’s medicines that really make the difference. Perhaps the price is absurd, but they mean great advances. Besides these medicines, there’s an enormous range whose value is dubious, the assessment is complex, or the prescription unsuitable. But one third is effective. In actual fact, there are doubts even so. They are effective because we follow a given model of assessment. With other models, perhaps they wouldn’t have to be effective.

In Britain and in the United States, some antidepressives are being accused of inducing to suicide, and there are those who say that the pharmaceutical industry hid some data about its products. How should a public body that takes care of the quality of the medicines proceed in these cases?
The fundamental concern of the body is not that the medicine works – I think they have even lost hope of this -, but that it doesn’t do any harm. For American culture, whether a drug works is an open question. But when it is proved to be harmful, the regulatory body becomes jointly responsible, alongside the pharmaceutical industry. So there is indeed a concern with the safety of the medicine. Its effectiveness is something that the market may eventually clarify.

Why should people take medicines with a doubtful effect? Aren’t people taking more medicine than necessary?
Yes, but as I said, there is a placebo effect. This does not mean that this effect is not a good one. Look at the case of the antihistamines. If a person is stung by a mosquito and has an itch, you say: “Take the medicine straight away, or it won’t have an effect”. The itching passes before the medicament is absorbed, the medicineis lost. This is complex. There is this notion that medicine is something good, but, when the evidence is sought, few classes of drugs are effective.

Could you give some examples of really effective drugs?
When I was a medical student, duodenal ulcer surgery was frequent. There were several techniques for operating. Today, you take Tagamet (cimetidine) or Antak (ranitidine – Zantac), and the ulcer heals in three weeks. Nobody knows how to operate ulcers any more, it’s very rare. Moreover, surgery was never a medical specialty. It arose in the 19th century and should disappear in the 21st century.

Do you think that specialization in surgery has its years numbered?
Surgeries have almost ended in some specialties, since there has been a drastic reduction in the number of procedures. There are fewer and fewer surgeries in urology and in gastroenterology. Cancer surgery still exists, but may be abandoned in due course. Today, a prostate tumor is treated with heat, radiotherapy or medicaments. Except for the esthetic area, surgery is something not very sophisticated.

How much does it cost to develop a medicine in Brazil? Isn’t it cheaper than abroad?
With US$ 5 million, you can get a me-too [a copy of an existing medicine]. The me-too is a structural analog, which makes it possible to escape from patent law in Brazil and in some countries, but not in the United States. There, costs are very high in the lawsuits taken out by laboratories making an innovative medicine, claiming the similarity of an analogous drug. Not here. I’m doing this with a product from the Cristália laboratory, lilafil, which is being called the Brazilian Viagra.

What kinds of medicament could the country make with a budget like this?
Those that don’t show any complex chemistry and that are not complicated to synthesize. If getting the molecule is complex, the price will be high. Besides this, we could make medicines whose clinical assessment isn’t expensive, like the Viagra analog, where one wants to know whether the person has an erection. It’s different from a treatment for Alzheimer’s, in which patients have to be treated for a year and a series of examinations carried out.

It’s common for Brazilian researchers to identify molecules, but not to arrive at the medicament for the lack of someone to finance it. Why does this happen?
Lack of interest. I’m a pharmacologist. I was brought up in the pharmaceutical industry and I want to make medicine, which is the way I have for controlling a biological phenomenon. But the viability of doing this needs to be seen. Here, there is no chemistry for medicaments, medicines are not synthesized.

Why doesn’t this exist?
We missed the bus. We never had personnel prepared. As we didn’t have a law on patents, what advantage was there to be interested in synthesizing a medicine if it was possible to copy it. And for copying, you can’t compete in price with countries like India and China. The cost of labor in these countries is very low, and there is the so-called ecological subsidy.

Ecological subsidy?
Exactly. Look at the case of the Tietê river. Why is the river like it is, polluted? Because there is a certain level of loss that is accepted. For the Tietê to get like the Thames, in London, the industries will have to leave here, and the sewage will have to be treated. There’s a cost. In Europe, they can’t manage to synthesize one molecule of a medicine. The cost is so absurd that it’s not worthwhile. Do you think that, in Britain, they’re going to want a factory throwing out its chemical waste next door? Synthesizing medicines for Europe and the United States is done in India and in China. Cubatão (maybe the most polluted city in Brazil), for example, is the way it is because there is a subsidy: “You can produce in this place, do whatever comes into your head, and we don’t care.” It’s an option of society.

Wouldn’t it then be the case for Brazil to use China and India as well for synthesizing medicines?
Synthesizing medicines has no value. The problem is not synthesizing, but the intellectual property that is generated. It’s knowledge that has value. But I think it’s too complicated for us to catch this bus again. In Canada, 80% of the people between 18 and 25 are at university. In Brazil, this figure reaches 8%. The bus is going to pass even further away. We are much more underdeveloped today than 20 years ago.

Couldn’t Brazilian biodiversity be a source of molecules and extracts that would be the basis for new remedies?
That’s a romantic vision.

Aren’t you underestimating the country’s role and its weight? Hasn’t Brazil?s international work helped to bring down the price of some medicines against Aids?
I don’t know. If it were in football, I would be underestimating. Except for that, I don’t see anything exceptional here. Commodities’ Perhaps Brazil has the largest herd of cattle, perhaps it’s one of the biggest producers of chicken in the world.

Would it be interesting to produce an entirely national medicament, from the discovery of the molecule to the pill?
No. I think it’s stupidity. The fundamental thing is the added value, the concept, the idea of the molecule. The second most important thing in life, after your existence, what is it? Time. Who does this well? France, Italy, Hong Kong? So I’m going to produce where they do it good and fast.

But, in this aspect, the idea of the new molecules, isn’t Brazil doing well? After all, Brazilian researchers have already published several works about molecules that are effective against some diseases. That is to say, hasn’t the most difficult step, the fundamental one, already been taken?
I believe not. I’ll probably not get a job any more after this answer. There’s a certain jingoism in saying that Brazilian scientific production is 1% of the works published.

But that is the figure from the ISI (Institute of Scientific Information), which, in actual fact, estimates that 1.5% of the articles published in international periodicals are by Brazilians. You are one of the most cited Brazilian researchers, according to the ISI.
There’s a list of most cited scientists. There are three Brazilians on it: Boris Vargafgit, who has lived the whole of his life in France. The other is a colleague from Unicamp, Jorge Stolfi. Part of my production too is not from Brazil, but from when I was in England.

If you analyze it well, a major part of American science is done by foreigners.
Yes, but they are foreigners generating knowledge there. It’s a difficult issue. The leap forward that the Third World has to make is a very big one. In Brazil, the view still persists that everything has to be done here. It doesn’t work. That’s not how a medicine is made.

How should it be done?
There are two aspects: one is to develop a medicine, the other is price. One thing is wanting to develop a medicine because it’s an interesting investment from the economic point of view and deciding how to do this. The second is to make ideas viable for reaching the market and knowing how to be able to achieve this. When one manages to invest and to create a new fact, there will certainly be capital, whether from the country or from outside.

For the product to reach the market…
Ideas that are good and viable are few. On this aspect, I think that the function of the scientist who wants to get there is to run after it. If he’s selling the product he created, he has to know who can buy it.

Is there a lack of entrepreneurism in the universities?
A patent office at a university is a no-go, a shovel of lime on the public universities. I pass by them at a distance, so as not to quarrel. These offices today stimulate the drafting of patents. As less than 0.01% of patents are commercially viable, this must generate a great expense without the necessary quid pro quo. In this kind of office, who is going to negotiate with the laboratory is an economist, who has no idea of what the purpose of what was created is. It’s the scientist who wants his discovery to reach the market that has to know who to look for.

To negotiate with a large company, you have to have notions of market and marketing. Couldn’t the patent office have a role in all this?
I get the impression that our university system has become very polarized with regard to the question of what is public and what is private. They think that industry is going to steal. In an interview about the Brazilian Viagra, they asked me: “Did the university keep part of the royalties?” I said: “Zero per cent”. “How much did you get?” “I too got nothing, but I was hired as a consultant to develop the medicament.” It was the laboratory Cristália that did the synthesizing of the drug. They are negotiating its development. I earned as a professional for developing the product. Didn’t the university earn anything? It did: it had no onus and made it possible for a medicine to be created.

But didn’t you use anything of the university?
I used my time, I’m also paid by the university.

Nothing else?
I did a few experiments at the university.

The new Law on Innovation provides for professors at public universities also being able to have a relationship with private companies.
That means creating a law to remove the trammels from other laws. It’s a view of those who think that the universities are being jeopardized. We do not generate anything, that’s the big truth. And we’re afraid of creating something because they’re going to steal. That way, it’s better to close down.

Isn’t it necessary to have clear rules?
– No. You have to have results, not rules. Instead of creating laws all the time, people should let things flow. If the universities don’t have a legal mechanism for charging royalties, it doesn’t matter, because the sale of the new medicine moves the country’s economy. Something goes to the State in the form of taxes. After there are results, you learn to deal with this question.

So wouldn’t there have to be some rule at a second moment?
At a second moment. Once I made FAPESP a proposal. Why can’t we sell to private industry expensive equipment that is becoming outdated for doing research? The university’s laboratory would keep 50% of the sale and FAPESP the other 50%. But this can’t be done, because we are dealing with public assets.

Are you in favor of the existence of public laboratories for producing medicines, like Far-Manguinhos?
Far-Manguinhos [Fiocruz’s Drug Technology Institute, in Rio de Janeiro], Furp [Popular Medicine Foundation, in the state of São Paulo], all this should be closed down as quickly as possible. I think it’s absurd and have already told them so. The Bristol-Myers Squibb laboratory produces captopril in one or two places in the world. In Brazil, there are some 20 official laboratories making this medicine. In economic terms, it doesn’t work out cheap. But there won’t be medicine for free. There is a strategic error of the government: it’s not a function of government to make medicine.

Is it a problem of management?
The government’s function is to ensure the population access to medicines?

How could this happen?
There may be health policies in relation to the pharmaceutical industry. In France, the government says: “I’m going to pay so much for this medicine. If you sell at this price, I’ll buy it and offer it to the population”.

They play with purchasing power to lower the price.
In Europe, the health insurance companies pay for generic medicines for their customers. If you don’t like the generic and want the one with a brand, you pay the difference. The government is able to organize the market and to stop supplying medicines that should have already been prohibited because they cause harm to the patient. I usually say: “The doctor’s function is to do a diagnosis and to prescribe a remedy. To indicate the right treatment”. Whether the patient can buy the medicine or not has never been a medical problem. That is up to another professional.

To which professional?
To the politicians, to those who are going to manage health systems, to the hospital administrators.

And if the patient says: “It costs R$ 100 and I haven’t got any money”?
The medical function is diagnosis and treatment. It stops there.

It’s a problem of distribution of earnings and of having a system that protects the poorer people.
Yes, but it’s not the doctor’s function to protect the patients. That’s where the biggest atrocities are done.

Do you believe in homeopathy?
I have no scientific evidence that it works. But I don’t work with homeopathy. When the French biochemist Jacques Benveniste published that work in Nature [in 1988, showing that the water molecule could be capable of storing information about compounds diluted in it], I was in England. I asked James Black, the Nobel prizewinner in Medicine in 1988, what he thought of the study. Black commented that other works were showing evidence about this issue of alterations in the water molecule. He’s a Nobel laureate and he didn’t say that it was impossible. know Jacques well. He’s an excellent scientist, the discoverer, before this story of homeopathy, of an important compound: PAF-acether, a platelet-activating factor. But Jacques is a guy from the left, a communist, with political ideas contrary to the establishment.

That is, his profile displeased many.
In this respect, there’s a funny story. In Britain, Sir Cyril Burt [a psychologist who died in 1971] exerted a great influence for altering the country’s educational system. On the basis of studies with identical twins, he said that intelligence was determined by genetics. Burt won prizes and died in glory, with collaborators abroad. An American statistician saw that it was impossible to arrive at that data. He published an article and was sent packing. What he was saying was regarded as a crime, like defaming Jesus Christ. They went to listen to Burt’s collaborators. But they didn’t exist.

People believe in personalities and not in science?
They believe in what they want to believe in. After discovering that a concept doesn’t hold water, everybody demonstrates the same thing. Even if before they had proved the opposite.

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