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The market of human experimentation

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Abstract

How should experiments on humans be regulated and controlled? Is it possible to create an equilibrium between the optimal protection of patients’ rights and all the other interests involved? This paper analyzes the problem from a Law and Economics point of view and tries to develop a theoretical model that would provide a way to achieve that equilibrium, both in terms of effectiveness and efficiency, a model in which the interaction between different parties can lead to a market where information is exchanged for innovation. This paper is based on work that has been done up to now by other sciences, like medicine and bioethics, treating the issue with an alternative approach in order to propose an oversight system able to give an answer to this unsolved problem. This work is mainly aimed at defining the rules of the market in Europe, including its actors and their interactions using both a normative and a positive approach. Both the behavior of rational people and that of bounded ones are analyzed, as well as the strategies that can be applied against the latter by stronger parties. Finally, the public stakeholder’s role in preventing this from happening is analyzed.

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Notes

  1. A clear instance could be the Vipeholm experiment (Sweden, 1945–1955) where, in order to learn more about dental health, the effect of carbohydrates on dental caries was tested on mental patients. See Seeman (2006–2007).

  2. Also known as Independent Ethics Committee (IEC) or Ethical Review Board (ERB).

  3. Regarding the above mentioned generational conflict, Calabresi (1969) argues that IRB is an expression of the value of research that involves human subjects, suggesting that it is necessary to achieve “…an adequate balancing of present against future lives and still sufficiently indirect and self-enforcing as to avoid clear and purposive choices to kill individuals for the collective good…”.

  4. Emanuel et al. (2000) suggest that IRB should check and guarantee “…the presence of scientific validity into the protocol and favorable risk benefit ratio, so as value enhancements of health or knowledge…”, moreover, thinking about patients, it is necessary to ensure “…fair subject selection, informed consent as well as the respect for enrolled patients…”.

  5. Coleman (2004) states that there is a great deal of evidence that Institutional Review Boards “…have exercised primary oversight responsibility for human subject research for the past three decades, but they continue to be overburdened, underfunded, and often incapable of reviewing complex research protocols effectively…”.

  6. Even if a great deal of attention has been paid over the years on informed consent and its process, the therapeutic misconception is still a thorny issue. See the work of Appelbaum et al. (1982); or Sankar (2004).

  7. Sankar, supra note 6. She defines frame as “…the background expectations that we bring to an interaction, or that motivate an account or a narrative…”. Moreover, she suggests that “…framing is the way we impose those expectations or promote one account over others. At its simplest level, framing uses inclusion and exclusion to juxtapose and arrange elements in order to signal or impose a particular account or frame…”.

  8. Calabresi, supra note 3. He argues “…some doctors will be too concerned with the individual patient and thereby sacrifice too many future lives by cutting off an experiment too soon. Others will be too concerned with the unassailability of their results and, therefore, continue an experiment beyond the point at which society's interest in future lives is met…”.

  9. The paper of Arrow (1963) suggests the existence of a market, which is characterized by risk and uncertainty in medical treatments supplied by the medial-care industry, as well as a demand for services in which sick people are affected by a mechanism of trust and confidence in the choice of a physician.

  10. In the USA after proved safety and effectiveness, this authorization is given by the FDA (Food and Drug Administration), while in the European Union there are several state authorities, each of which is responsible for the pharmaceutical drugs introduced on the national market.

  11. The testing process can be divided essentially into three phases: Phase I (designed to determine the pharmacokinetic and pharmacological aspect, involving healthy volunteers); Phase II (effectiveness of the drug for a particular ailment, in a small sample of patients); Phase III (additional data about effectiveness and safety). See Tufts University, the Tufts Center for the Study of Drug Development, “How New Drugs Move through the Development and Approval Process” (http://csdd.tufts.edu).

  12. Malani (2006) affirms “…a medical treatment is said to have a placebo effect if a patient’s response to treatment depends positively on his or her expectations about the value of that treatment. In other words, placebo effects cause more optimistic patients to respond better to treatment than less optimistic patients…”.

  13. An instance could be Médecins Sans Frontières, “…an international, independent, medical humanitarian organization that delivers emergency aid to people affected by armed conflict, epidemics, healthcare exclusion and natural or man-made disasters…”. See MSF report 2008.

  14. The clinical assumption should be thought of as a war of attrition to defeat the disease. For instance, currently there is no cure for AIDS, but there is a retroviral treatment to contain the action of the HIV virus known as highly active antiretroviral therapy (HAART). If a HIV positive patient can survive for years today, it is the consequence of little steps made through years of human experimentation, a path that, 1 day, will lead to an effective cure.

  15. Dickert et al. (2002).

  16. Grady (2001) affirms that even if it is of widespread concern “…that money is potentially coercive or could cause undue inducement…”, an appropriate amount of “… money to reimburse research participants for their expenses and compensate them in some way for their time and effort may be a demonstration of respect and appreciation for these generous individuals…” instead of coercion.

  17. Taking physicians’ behavior into account, there is also another consideration, that is to say the alternative role of the scientific community. A high fee could be the consequence of the absence of value of scientific publications within the community in which the physicians work and live.

  18. See: Clinical trial compensation guidelines (The Association of the British Pharmaceutical Industry, 1994). The document suggests exactly this idea of risk sharing between parties, that is to say “…participation in the trial is then based on an expectation that the benefit/risk ratio associated with participation may be better than that associated with alternative treatment. It is, therefore, reasonable that the patient accepts the high risk and should not expect compensation for the occurrence of the adverse reaction of which he or she was told…”.

  19. The paper of Moses et al. (2005) uses data to prove budget allocation taking into account the main voices involved (Table 3, “US Pharmaceutical Research and Development by Function, 1994–2003”). Without loss of generality, this work proposes that the Research phase is denoted by “prehuman and preclinical” factors, whereas the Development phase is denoted by “Phase I–III”, “Phase IV” and “Approval and regulatory” factors.

  20. The paper of Levin et al. (1987) suggests the idea that “…a patent confers, in theory, perfect appropriability…” but, in practice, “…many patents can be circumvented…”. Starting from their analysis, this paper considers the policy maker’s role within the clinical research, focusing on the time factor of the protection system.

  21. See: L’industrie du médicament en France, réalités économiques (Edition 2008—LEEM).

  22. Notice that this anxiety is caused by the information gap between parties, thus uncertainty in the available options and real medical knowledge. Otherwise, without this gap, the role of the physician is superfluous and the sick person could find a cure by himself.

  23. Grady, see supra note 16. This phenomenon is well known and discussed in biomedical ethics. Poor current knowledge is considered as an undue influence that can affect the research subjects’ choice of participating in a trial.

  24. RU-486 was designed by Roussel Uclaf, a French pharmaceutical company that was the owner of the patent, whereas it was marketed and distributed by Exelgyn Laboratories under the trademark “Mifegyne”. For more about the development of the drug, see Christin-Maitre et al. (2000).

  25. The European Union’s directives on human experimentation and patients protection system are 2005/28/EC and 2001/20/EC, that are transposed in Italy with Decreto Ministeriale del 06/11/2007 and Decreto Legislativo n. 211 del 24/06/2003, while in France with Loi 2004-806 du 09 août 2004.

  26. The EFGCP Report on The Procedure for the Ethical Review of Protocols for Clinical Research Projects in Europe (Update: March 2008). See also http://www.recherche-biomedicale.sante.gouv.fr/pro/comites/coordonnees.htm (France) and http://oss-sper-clin.agenziafarmaco.it/consultazione_ce_pub.htm (Italy).

  27. In order to give an idea of transaction costs let us imagine how the same hypothetical study would be handled by the French system as opposed to the Italian one. In France the system is shaped around seven regional areas with several IRB responsible of each region and all of its research centers. In Italy the situation is really different. First the approval of the IRB coordinator is necessary. Then each satellite IRB must accept or refuse the study. The average time the coordinator of an Italian Institutional Review Board takes to come to a decision is 35 days while the satellite takes 50 days. Considering also that authorization from the institution where the trial is conducted takes time, this means that it will take at least 4 months before a potential patient will be enrolled. See AIFA, La sperimentazione clinica dei medicinali in Italia, 8° Rapporto Nazionale, 2009. Taking an open market into account, this could easily denote a national values representative of the oversight system and so countries’ competitiveness.

  28. Grady, see supra note 16. In addition to this there are other inappropriate and excessive influences that can affect patients’ choices. The paper affirms that “…these influences include: the promise of treatment, albeit investigational, for the desperately ill who have exhausted other treatment options; access to care or medications or other treatment for those who cannot afford these on their own or have no or inadequate healthcare coverage; the advice from a trusted physician or healthcare provider that the study is the best or only hope…”.

  29. An example could be a very common drug such as aspirin, also known as acetylsalicylic acid. It is commonly used as an analgesic and antipyretic. But, thanks to an anti platelet effect, it is also used to prevent heart attacks, strokes and blood clots. Initially only one effect was recognized but, one century later, an additional one was discovered by using that drug.

  30. Arrow, see supra note 9. Analyzing the absence of an ideal insurance against the informational gap between patient and physician, he suggests that is necessary to have of “…some guarantee that at least the physician is using his knowledge to the best advantage. This leads to the setting up of a relationship of trust and confidence”.

  31. The transmission model should follow three main phases: the patient’s medical history and current state; the availability of options, based on both established medical treatment and the experimental one; finally, if it presents itself, the discussion about patient’s doubts and possible issues.

  32. Sankar, see supra note 6. She has proved that investigators who discuss the options available avoid explaining some aspects such as expected benefits and the difference between clinical research and medical treatment or explain them incorrectly, leading to therapeutic misconception.

  33. See supra note 24. An instance of this shortcut could be the thought that an institution, like a hospital cannot morally propose something that can damage you.

  34. Faden et al. (1986) authors suggest that during an informed consent session physicians should highlight both probabilities, that is to say both survival rates and mortality rates. Moreover, in order to overcome patients’ biases, or at least mitigate them, they recommend using these probabilities in a clear and understandable way.

  35. EMEA (2001).

  36. Jolls et al. (1998) affirm that “…probabilities will often be affected by how “available” other instances of the harm in question are…”.

  37. Malani, supra note 12. By comparing clinical trials with different probabilities to be assigned to the control group or the treatment group, he shows that “…patients in the high probability trial will believe that they are more likely to receive treatment…”, and thus “…the treatment (control) group of the higher-probability trial should perform better than the treatment (control) group of the lower-probability trial…”.

  38. Competitive enrollment means that if there is an X total number of research subjects, they will be distributed among the research centers according to how quickly they enroll patients. Each center does not know how global enrollment proceeds or the patient’s assignment (double blinded). The one who knows everything, and decides on the assignment, is the trial manager, who can manipulate the procedure if she wishes.

  39. Coleman, supra note 5. He suggests that IRB adopt a decision-making mechanism to review human experimentation.

  40. In this work the role of pharmaceutical research was underlined in order to show how economic interests could affect physicians’ behavior when they enroll patients in a trial, even if it were applied in some unprofitable fields, such as hematology, where it would be the main type of research done.

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Ippoliti, R. The market of human experimentation. Eur J Law Econ 35, 61–85 (2013). https://doi.org/10.1007/s10657-010-9190-y

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