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This introduction was intended merely to arouse the curiosity in you on the subject of the next session: " Research ethics: focus on pharmaceutical research". 

The topic of research ethics is very broad, so we thought to begin with an issue in itself very complex: the genesis of a drug.
Often in our clinical practice we ask ourselves: which of these two drugs to give to such a patient? Am I sure of the effectiveness of this drug? Will he tolerate it well? What is the most cost effective drug?
However, probably few times we ask the most basic question: "What is the criterion by which a molecule is tested? What are the springs that push a company or a researcher to study a drug for a given disease? What are the priorities?" And again: "What are (if there are!) the ethical principles that guide pharmaceutical research? Are they always followed? Which role the patient plays in medical research?"


And again: we base our current medical knowledge mainly (not only) on evidence based medicine ... but are we always sure that the scientific data described is completely reliable? Are we always confident that the result is free from bias, or it was somehow controlled, more or less consciously, by the researcher? And if in some cases this happened, do we risk building our medical practice on unreliable studies? In other words, do we trust blindly medical literature? How can we ensure that pharmaceutical research does have a common guide, ethics, that could contribute to scientific knowledge and have as its ultimate objective man’s wellbeing? 

VIDEO INTERVIEWS
Birth of pharmaceutical research
Since ancient times man has tried to understand the properties of substances and natural products by identifying their curative effects. After centuries of attempts, often accompanied by a halo of legends and superstitions, the scientific method applied to pharmacology began to take its first steps in 1600, when scientists started testing drugs on animals and performed the first controlled clinical trials, such as James Lind’s, who demonstrated the beneficial effect of citrus fruit in patients with scurvy. In the early nineteenth century William Thomas Green Morton, a Boston dentist, invented the general anesthetic. Morton discovered that ether makes the patient fall into a state of deep sleep, thus allowing the surgeon to operate without causing pain. In 1817, a pharmacist in Hannover, Friedrich Serturner isolated and identified the morphine for the first time; about 10 years later the first organic molecule is synthesized in the laboratory, and this event marks the birth of modern pharmacology and of pharmaceutical industries.


Birth of the first regulatory bodies
With the beginning of the twentieth century, it becomes increasingly clear the need to establish oversight bodies to fight against dangerous or ineffective drugs, and to test all pharmaceutical products that the industry began to produce and market, until that time, without official supervision.
In the United States the Food and Drug Administration (FDA) was founded in 1906, and still today regulates the sale of drugs and foods. In Europe, France and Switzerland are the first Countries to have any regulation in this regard.
After the aberrant experiments conducted in Nazi concentration camps, the international community, for the first time in history, decided to write a document with strict limits on human experimentation. It was 1947. The top world experts wrote what has since been called the Nuremberg Code. It originates from the papers of the case that took place in that city against the Nazi doctors who carried out experiments in the death camps. The Code draws a line between lawful trial and torture. The trial is lawful when the person voluntarily gives his consent to undergo an experiment, after being informed of:
- The purpose for which the experiment is carried out;
- The duration of the experiment;
- The limits that the therapy could have;
- The possible consequences he may face.
The Code states that "the voluntary consent of the subject is absolutely necessary."
The second article states that "The experiment should be such as to provide useful results for the good of society, and not otherwise obtainable by other means or methods of study; the nature of the experiment shall be neither random nor without purpose." One wonders if today experiments are all geared to the good of society or to other interests.
Today the main document that regulates the ethics of trials in humans is the Declaration of Helsinki, established in 1964. The document establishes the rights of human beings involved in drug testing.
If the Nuremberg Declaration sets out basic principles for the protection of individuals involved in experiments, and therefore is a kind of "constitution" of the matter, the Helsinki Declaration enters into technical details.
However, the patient’s consent as an absolute requirement no to be replaced by any other form, and the need to have more precise regulations about experimentation on humans, is an achievement still under development and not uniform across Countries. In Italy, a part from the international declarations, the rules of Good Clinical Practice are in force, setting out criteria and principles for conducting clinical trials. Patients have the right to express their adherence to the study by signing a document, the so-called "informed consent" only after having received all the necessary information. The patient is also entitled to confidentiality on data collected and the right to know who owns his clinical data. Each patient may decide to give or withhold his consent to participate without impacting the right to be treated. Furthermore, he is not obliged to give explanations in case of refusal or abandonment of the project. In any event, he is entitled to receive the best currently available therapy.
The rights of those who participate in clinical trials should be guaranteed by the presence of ethics committees. Each university or research hospital has got one. They usually include 12-15 members: two clinicians, a biostatistician, a pharmacologist, an expert on legal matters, a family practitioner or a NHS doctor, a bioethicist, a nurse and a lay member (representative of patients' associations). There are also representatives of the institution where the study is conducted and other observers that from time to time may be involved for special needs, acting as outside experts.
Before starting a trial with a new drug or treatment on humans, an approval by an ethics committee is needed. Currently there are approximately 300 registered ethics committees.
Ethics committees should consider:
• the ethics of the study and the protocol rigor including any new additions the study will bring about;
• the need and the opportunity of the trial in view of the documents provided at the beginning of the study, the manner in which it is conducted, the procedures for obtaining the "informed consent";
• the feasibility of the study;
• the standards of Good Clinical Practice;
• the ethical issues that relate to the patient: the type and quality of information, the way patient’s confidentiality and protection will be assured.

Results of questionnaire to researchers on ethics committee

MAPA

How pharmaceutical research in recent years is changing
In no other area like that of drugs the relationship between product quality and quality of life, and economic development and citizens’ welfare, is so tight.
The pharmaceutical companies support for more than 90% pharmaceutical research; this means that on the one hand they play a key role in the development, testing of new drugs and the promotion of studies on the pathophysiology and treatment of diseases; on the other hand, they can affect in a negative way scientific research if the financial interests overcome the need to safeguard the common good. In recent decades the pharmaceutical industry has gained unprecedented control over the evaluation of its own products. Drug companies fund a lot of clinical research on drugs and there is some evidence that they alter the results of the research they sponsor in order to prove that the drugs they produce are better and safer than others’. The problem, therefore, is not so much the sponsorship itself, but the way it is carried out. Before 1980, industries funded academic institutions giving researchers full responsibility on the funded project. The researchers designed the study, analyzed and interpreted the data, wrote the paper and decided how and where to publish the results. Generally, neither the researchers nor the institution where they worked had other financial connections with the pharmaceutical company that had sponsored the study. In recent years, instead, the financing companies are intimately involved in every aspect of the research on their products. They often draw their studies, perform analysis, write papers and decide whether, when and on which journal to publish the work. In some multicenter trials, Authors may not even have access to their own data. The Pharmaceutical Research and Manufactures of America has justified this behaviour by saying that "as owners of the database of the study, the sponsors have the discretion to determine who can have access to that particular database." In some extreme cases, therefore, researchers are nothing more than “working arms”, intended only for supporting the patient and collecting data in accordance with the decision taken by the pharmaceutical company.
These phenomena have now been widely described in the literature and are more and more known. It is, however, good to remember that they do not represent the totality of cases.
In my short work experience, I have done research in the "old" way. In fact, in the laboratory I am involved in a project sponsored by NovoNordisk, that aims at investigating the effects of insulin on precursors of adipocytes in subcutaneous and omental adipose tissue. The project was designed by my professor and his closest associates and is conducted in our laboratory. The experiments were designed and created entirely by us, we have carried out the analysis, we are writing the paper and we have decided the journal where to publish it. In these two years we have never suffered any kind of interference by the pharmaceutical company.
To add on, researchers often have other financial connections with the sponsors of their research. They often are paid as experts or speakers at medical conferences, and sometimes they have shares in the companies themselves. A recent review showed that about two-thirds of academic medical institutions have an interest (equity interest) in the companies that sponsor their own research, and a study on medical schools departments has shown that in about 2/3 of cases their revenues got some income from pharmaceutical companies, and that in about 3/5 of cases, the professors themselves had some personal income.
Each pharmaceutical company has its own guidelines for avoiding conflicts of interest, but they are generally quite forgiving and easily by-passed.
An example? Recently, a high-ranking Republican in the Senate Finance Committee, said that Dr A. Schatzberg, director of the department of psychiatry at Stanford University and president-elect of the American Psychiatric Association, controlled more than $ 6 million in shares in Corcept Therapeutics, a company he co-founded and that was developing mifepristone for treating psychotic depression. At the same time Dr Schatzberg was the principal investigator of a grant from the National Institute of Mental Health on the study of mifepristone in depression. In a statement issued on June 25, 2008 Stanford University claimed to have given up its shares in Corcept, in accordance with its institutional rules on conflict of interest, but, at the same time, there was no objection to the position of Dr Shatzberg. The statement said further that, although Dr Schatzberg was the principal investigator of a grant funded by the National Institute of Mental Health, he did not have any responsibility in any of the aspects of the conduct of the publicly funded research on mifepristone. This statement raises many questions about what exactly it means to be the principal investigator of a grant and co-author of a paper. How did it go? Following the scandal caused by Sen Charles Grassley, on the 31st July 2009, Stanford University notified that Dr Schatzberg was temporarily replaced as principal investigator of the grant in order to eliminate any misunderstanding (3).
Funding research and production of scientific knowledge has become a key marketing strategy for the industry. A significant proportion of research activities, as well as the distribution and dissemination of biomedical knowledge, has been brought under the control of private commercial interests.
Pharmaceutical research is conditioned by the need to fight specific diseases and to scientifically legitimize the use of new drugs, in a scientific and appropriate manner, by demonstrating their efficacy for a specific condition. For this need, and in order to influence sales, the pharmaceutical industry has developed many strategies, now defined as disease-mongering, or “disease marketing”.
In a 2006 study, Payer has identified ten techniques to manipulate the results of scientific research (4).
We cannot dwell on them all, but we will mention only some, with relevant examples.

1st example: PFIZER AND VIAGRA

Viagra is a classic example of disease mongering: stimulated by economic interests represented by pharmaceutical companies, a drug developed for people with a real medical problem was sold to a much larger, perfectly healthy, population. The campaign, funded by Pfizer, had as primary goal to make people more aware of the problem of erectile dysfunction, thus, at least initially, Viagra had a single indication, namely the treatment of a disease. Subsequently, the pharmaceutical industry in question has shifted its attention to all consumers, thus enlarging the market ... and the result is what we all know. What we ask is, if scarce resources are used for medicines or procedures that are useful but not essential, how can other treatments be funded in an appropriate manner? We are also going to see how many diseases do not receive adequate funding just because they are of no interest to the West or because they involve a small portion of the population (5).

2nd example: "Pandemic" of influenza H1N1
The second case of disease-mongering is just as famous and, I would say, thorny. It was denounced by Wodarg Wolfgang, the German president of the Health Committee of the Council of Europe. He accused drug companies of having influenced the decisions of the World Health Organization to declare the pandemic, last year, of the H1N1 virus (6). Wodarg, physician and epidemiologist, said that the multinational drug companies had accumulated "huge profits" without any financial risk, while governments around the world drained their meagre health budgets spending millions in the purchase of vaccines against an infection that was not very aggressive. Wodarg passed a resolution asking the Council of Europe to inquiry into the role of pharmaceutical companies. Last June, the Council of Europe expressed its opinion that "The alarm about pandemic influenza A/H1N1 was a waste of public money and an unjustified alarmism about the risks run by European citizens". The document harshly criticised the management of the pandemic by WHO, but also by EU agencies and national governments. The Committee highlighted the serious lack of transparency in the process that led to the declaration of the pandemic. In particular, it pointed the finger at the WHO and EU agencies that provided the necessary information to parliamentarians to address doubts about the conflict of interest of some experts who collaborated with WHO and other institutions but also with the pharmaceutical companies.
In an article on the topic of pandemic H1N1 virus, according to the authors, to Fiona Godlee, editor of the journal, and to experts from the British Bureau of Investigative Journalism, the scientists that in 2004 drew up the key guidelines for WHO, that advises governments to stockpile drugs in case of pandemic influenza, had previously been paid for other jobs, by some pharmaceutical companies producing the drugs in question. The three scientists had in fact been consultants and researchers for Roche and GlaxoSmithKline, manufacturers of drugs, Tamiflu and Relenza respectively, against the A influenza (7).
The economic interest leads to the sponsorship of studies and scientific articles in order to spread knowledge that would lead to the sale of specific drugs. To achieve this, companies often spend more on quantity of publications rather than on their quality. There is also a tendency to emphasize those studies that have been successful, rather than those showing that the sponsored drug was not more effective nor safer than others already in the market.

3rd example: Gabapentin
Clinical trials protocol requires to specify the primary and secondary objectives of the study. Although it may be legitimate a change of the primary objectives during the study, a good research practice requires that the procedure by which such decisions are made, the time and the reasons for changing are clearly documented in a statistical analysis plan and that these changes are described in the published reports of the trial. Any changes made to the primary objectives after completion of the statistic test is a reporting bias, especially when this is done to document apparently positive results when the analysis of primary outcomes did not give good results. Although it has been reported that reporting bias occurs regardless of the source of funding, they seem to be much more frequent in studies funded by pharmaceutical companies. Here's the example of gabapentin (Neurontin, Pfizer), whose clinical trial, that the company referred to in order to support its use for the prophylaxis of migraine, for bipolar disorder, for neuropathic nociceptive pain, was examined by Vedula and others (8). Outcomes described in the published work were compared with those described in the internal research documents of the pharmaceutical company involved in financing. More than half of the studies included in the analysis was not published in full. In 7 of the 9 trials that were published in full, it was reported a statistically significant primary outcome and for more than half of these the primary outcome specified in the published report differed from that originally described in the protocol. Frequently there is also a difference between the secondary outcomes published in the article and those in the original protocol. Therefore, in those trials in which the results were not statistically significant (p ≥ 0.05) for the primary outcome, or were not published in full, or have been published with a change in their primary outcome, Vedula showed that all the changes between what is specified in the protocol, what was known before the publication (as presented in internal reports of the pharmaceutical company) and what was presented to the public, have finally resulted in bringing to the medical literature the effectiveness of gabapentin for indications that were not approved. Of particular alarm is the finding that the primary outcome (ie, the main measure of effectiveness of the drug in these indications) has often been reported inaccurately. The same Vedula said that his study suffered from several limitations, including the possibility of not having access to all "raw" data of the trials studied, and having considered only few studies referring to a single drug and a single pharmaceutical company.
However, other studies conducted by different authors for different drugs, showed the same bias and of course, the existence of the ambiguous practice of publishing data does not meet ethical standards for clinical research and raises serious doubts about the ability to maintain the integrity of scientific knowledge.
So far we have only discussed the ethical issues related to research funded by pharmaceutical companies; however, it would certainly be simplistic and unfair to attribute to them all responsibilities. The first responsibility of acting ethically goes no doubt to the researcher that is personally involved in the research. In the USA, Brian Martisson, Melissa Andersson and Raymond de Vries, ethics specialists, have asked a number of researchers about the fairness of their research, irrespective of age, whose work was funded by the National Institutes of Health, a public research institution. Among the 3,247 who responded, many said they had, to some extent, manipulated their research work. At least one third admitted to have violated certain ethical standards in clinical trials or to have 'covered' colleagues who were using false data, or to have proposed incorrect interpretations of the data. Only a very small percentage, 0.3%, confessed having completely falsified a study or having copied a work from others. A massive 15% said they had changed the design, methodology or results because of the pressure by commercial sponsors. Another 15% revealed to have changed the results because instinctively they did not judge as truthful. More than 27% said they did not keep records of research projects. In the USA a saying runs in science: "publish or perish". The researcher who doesn’t publish loses his visibility and opportunities for sponsorships. The purpose of the publications, as it is also evident from the results of our questionnaire, is often to gain prestige in the scientific community and funding for their studies. The ethics takes a back seat.

Results of questionnaires for biomedical area researchers
How can we remedy this "oversight" in relation to ethical issues? A first possible remedy is to assume critically all the information that we collect (from journals, as well as from speakers at a conference or from specialists of a pharmaceutical product) and begin to examine each contribution starting from their sources.
Three authors, M.A. Weingarten, Paul M, L. Leibovici, have asked themselves how to find a method to establish the ethics of clinical trials and studies presented in systematic reviews. In fact, though the Nuremberg case and the Declaration of Helsinki have established some ethical standards to be met, many clinical trials do not adhere to these standards or do not report if researchers have adhered to (for example, they do not mention whether informed consents were acquired). We will not dwell here on the way authors suggest to check the ethics of a trial (the main points are summarized in this slide and you can find out yourself on the BMJ published in 2004) (9), but rather why it is important to include ethical considerations among the evaluation parameters for trials in the reviews.
The first reason is to increase awareness in the scientific community of the need for high ethical standards in research on humans. This awareness would encourage reviewers to identify unethical studies and to doubt about the morality of using the results of those studies. A second assumption is based on demonstrating that information about the ethical quality overlap significantly with core information such as validity, reliability and the ability to generalize the results of clinical research. In a review of 767 well-controlled and randomized trials published between 1993 and 1995 on NEJM, Lancet, BMJ, JAMA, it was noted that trials with high methodological quality were also those most likely to provide information about their ethical aspects. One might therefore conclude that the results of trials ethically sound are also the most scientifically reliable (10).
Finally, with Prof. Santi’s help, we want to get into a broader, global perspective and consider the gap between health needs and the dictates of capitalism in a global context. The huge investment of resources in "highly profitable" drugs results in less attention to the development of drugs for people with less "purchasing power" (I refer in particular to the peoples of developing Countries and to patients with rare diseases). From a strict medical point of view, the needs of a child suffering from malaria in South-Saharan Africa should have priority over an Italian middle-aged who suffers from hair loss; through the prism of capitalism, however, the “bald” man has a purchase value greater than the African boy. Jurgen Drews, medical director of one of the major pharmaceutical companies, is an expert on relations between ethics of scientific research and market profit. He has stated that in recent years an obsessive focus on profits and the increased costs of new products launch, have led pharmaceutical companies to direct their research efforts primarily towards medicines called "me-too remedies”, that is drugs for pervasive diseases such as hypercholesterolemia and hypertension, for which, however, there are already many potential treatments. Drews propose a number of solutions to overcome these outstanding medical emergencies, including greater collaboration between intergovernmental and non-governmental industrial partners. An extraordinary example of this type of effort was launched by the Institute for OneWorldHealth, led by Dr. Victoria and funded by the Bill and Melinda Gates Foundation. The Institute for OneWorldHealth accepts donations from the industries and the voluntary services of scientists to develop drugs that may be useful in the Southern hemisphere. In return, companies can achieve reductions in taxes and gain positive public relations. Still, it must be remembered that, owing to the increased inputs regarding the need for more ethical research, many pharmaceutical companies have tried to devote part of their profits into research on diseases in developing countries, as well as on rare diseases.
We did a little research and hereunder are just a few examples:
- Merck Sharp and Dohme: river blindness (onchocerciasis)
- Sigma-tau: malaria
- NovoNordisk: haemophilia, Word Diabetes Foundation (dedication to improving knowledge and treatment of diabetes in developing countries).
Exemplary is the case of Merck and the river blindness. This is a terrible disease that affects about 80 million people in the poorest parts of Africa, the Middle East and Latin America, resulting in uncontrollable itching and, between the major complications, blindness. In 1970 Dr. Campbell, a scientist at Merck, began to carry out research to develop a drug for river blindness. Merck won a prize for having donated substantial resources to develop the drug, without having very good prospects of a return. The invermectine, the drug developed by Merck to fight river blindness, revealed afterwards power and effectiveness against a wide variety of pests, allowing Merck to have both, a non-profit market and an economic return. Probably all of us today should remember the words of George W. Merck, the founder of the pharmaceutical company, who said in 1959: "We try never to forget that medicine is for the people. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear. The better we have remembered it, the larger they have been.”
This is not to deny the importance of studies that evaluate the effectiveness of drugs, which remain fundamental. However, the doctors in clinical practice, when prescribing, are guided by the information on the effects and safety of the substances; thus the challenge is ensuring the patient and the physician that economic benefits do not clash with ethics and scientific methodology, essential in order to obtain results free from conflict of interest.

Gianluca Conversa, Maria Paola Barbaro


References
1) Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003;289(4):454-465.
2) Campbell EG, Weissman JS, Ehringhaus S, et al. Institutional academic-industry relationships. JAMA. 2007;298(15):1779-1786.
3) University statement on Senate Finance Committee investigation on conflicts of interest in medical research: June 25, 2008. Stanford University. http://ucomm.stanford.edu/news/062508conflict_of_interest.pdf. Accessed July 2, 2008.
4) Payer L. Box The major disease-mongering tactics identified by Lynn Payer. Apud Tiefer L Female sexual dysfunction: a case study of disease mongering and activist resistance. PloS Medicine. 2006.
5) Lexchin J. Bigger and better: how pfizer redefined erectile dysfunction. PloS Med. 2006.
6) Disease mongering, come si inventa una malattia per vendere un farmaco. L'inchiestaDi Benedetta Sangirardi, http://www.affaritaliani.it/cronache/disease_mongering-invenzionemalattia51009.html
7) TGCOM mondo.
8) Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med. 2009 Nov 12;361(20):1963-71.
9) Michael A Weingarten, Mical Paul, Leonard Leibovici Assessing ethics of trials in systematic reviews, BMJ 2004.
10) Ruiz-Canela M, Irala-Estevez J, Martinez-Gonzalez MA, Gomez-Gracia E, Fernandez-Crehuet J. Methodological quality and reporting of ethical requirements in clinical trials. J Med Ethics 2001;27:172-6

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