Ethical issues on experiments in anima nobile on hepatitis

POINT OF VIEW

Ethical issues on experiments in anima nobile on hepatitis

Rosangela Gaze^I; Diana Maul de Carvalho^II; Luiz Fernando Rangel Tura^III; Carolina Carvalho Serres da Silva^IV

^IMSc in Collective Health; Instituto de Estudos de Saúde Coletiva, Universidade Federal do Rio de Janeiro (UFRJ); Researcher, History, Health and Society Laboratory, UFRJ, Rio de Janeiro, RJ, Brazil

^IIPhD in Sciences, ENSP/Fiocruz; Associate Professor, Department of Preventive Medicine, and History, Health and Society Laboratory, UFRJ, Rio de Janeiro, RJ, Brazil

^IIIPhD in Medicine (DIP), UFRJ; Associate Professor, Department of Preventive Medicine, and History, Health and Society Laboratory, UFRJ, Rio de Janeiro, RJ, Brazil

^IVMedical Student, UFRJ, Rio de Janeiro, RJ, Brazil

^{Correspondence to}

Introduction

Scientific debate on hepatitis at the beginning of the 20^th century focused mainly on the aetiology of the "icterus catharralis"¹. After the 2^nd World War discussion centered on a probable infectious agent. Since the 1960s, after the identification by Baruch Blumberg of the Australia antigen², other agents of viral hepatitis (VH) have been identified. Transaminases and hepatic biopsy in the 1950s, and serological diagnosis, gave additional visibility to the VH and contributed to the growing efforts on research of passive and active immunization of the 1970/1980s. From 1990 on, the hepatitis C pandemic helped to focus scientific and economic interests in the production of drugs. Research methods and goals changed but phase three experiments - clinical trials - still require interventions in people.

The history of diseases provides many examples of research in human beings, volunteers or not. In the case of hepatitis, resistance of the scientific community to accept its infective etiology¹, in part due to the difficulty of developing an experimental animal model³, may have stimulated even more experiments in human populations. While the aetiology of hepatitis was being discussed, leptospirosis and yellow fever - s whose predominant clinical presentation (icterus and fever) include them in the same key for differential diagnosis - already had clearly defined aetiology, animal models for research, and diagnostic tests⁴. Although recognized as "campaign jaundice"⁵ since 1915, it was only during World War II, when 200.000 American soldiers and five million German militaries and civilians were struck by it, that emerged "a great impetus to the understanding and prevention of the "⁶.

In the 1960s, human blood, feces, and secretions from the sick were inoculated in volunteers to try to understand transmission and propose prevention of the hepatitis. Nowadays, experiments in anima nobile require compliance to ethical requirements and the informed consent is sine qua non to their implement⁷.

We discuss contradictory aspects of the informed consent in classical human experiments on hepatitis in the first half of the 20^th century in view of the design of clinical trials today.

We bring to discussion particular aspects of the experiments in anima nobile on hepatitis through a selection of classic studies pointing to contradictory ethical aspects including the informed consent. Many authors have shown the advances in legislation on ethical issues concerning research in human subjects^8,9. Research on AIDS has been, on the last two decades, at the center of debates that emphasize the concepts of vulnerability and difference or diversity as attributes of social groups and individuals, that should be of special concern as ethical issues of research protocols¹⁰. Studies on hepatitis seem to point to similar issues although they were not frequently the object of debate in the old days. These questions are discussed considering sociocultural and time diversities, focusing the multiple dimensions that derive from technology and scientific uncertainties.

The informed consent

Although the informed consent, included in the CNS Resolution 196/1996 as free and informed consent, is relatively new⁷ recognition of its relevance was presented at the turn of the 20^th century¹¹. The Parliament of Prussia in 1898 asked for government action, motivated by controversies concerning the research on syphilis prevention that required inoculation of serum from patients in prostitutes, who became ill. The Rudolf Virchow's report concluded that no physician was allowed to inject infective serum in a volunteer without previous consent¹¹.

Krugman and Giles¹², authors of the studies on hepatitis at Willowbrook State School (WSS) between 1956 and 1970, begin their research at the same year of the elaboration of the Project for the Code on Ethics in Experiments on Human Subjects that was presented at the General Assembly of the World Medical Association in 1961. The authors refer that the studies at WSS were in accordance with the Project that allowed research with legally incompetent subjects once the informed consent of their legal representatives was obtained^12,13. In 1964 this Project was revised into what became known as the Declaration of Helsinki and presented a more restrictive version concerning the legally incapable although maintaining the possibility of their participation as subjects of research¹⁴. Similarly, the Brazilian CNS Resolution 196/96 (item IV.3)⁷ also admits research involving children and adolescents with restricted mental capabilities or mental and subjects with impaired capabilities to provide consent, requiring that the protocol provide clear justification for this choice of research subjects and that informed consent is provided by legal representatives, and information is provided to the subjects to the limits of their capabilities.

Vollmann and Winau¹¹ point out that even before the Nuremberg Code in 1947¹⁵ - that established that only the legally capable should be able to volunteer as subjects of research experiments - regulations derived from public debate and from the Prussian Parliament in the 1900 were more restrictive and provided that "minors and incompetent subjects were generally excluded from non-therapeutic research, as they could not give valid informed consent."

Nevertheless, as pointed out by Kotow¹⁶, it was the Belmont Report in 1978 that developed in its full complexity the principles of autonomy, beneficence, non-maleficence, justice and equity regarding the research in human subjects¹⁷. This report came to light six years after the closing of the hepatitis research unit at WSS in 1972¹⁸. Publication of the results of the WSS studies provided the ground for a broad debate on ethics in research^6,18-20, and some of the arguments for and against these protocols seem to have been recently rekindled in the debate on ethics in AIDS research protocols in Africa. Garrafa and Prado¹⁰ show the relevance of revisiting the past as they expose the many social and economic issues that may be involved in proposals of ethical relativity.

The argument of high endemicity

Nowadays, electing volunteers for research requires a methodology that guarantees the control of selection biases and of ethical principles. The choice of sex professionals could be justified by the perspective of development of therapies and preventive measures for s with higher incidence/ prevalence in that population. In 1970, Krugman e Giles¹² justified an experimental study that had lasted 14 years, with the argument of high endemicity of hepatitis in an institution for special children (Willowbrook State School). In 2011, the European & Developing Countries Clinical Trials Partnership (EDCTP) - non-governmental organization founded on 2003 - considering Sub-Saharan Africa as the most affected region in the world regarding these infections, impairing its development and leading to extreme poverty, took as a mission "to accelerate the development of new or improved drugs, vaccines and microbicides against HIV/AIDS, malaria and tuberculosis, with a focus on phase II and III clinical trials in Sub-Saharan Africa"²¹. HIV, malaria and tuberculosis were selected for the discussion of the argument of high endemicity because these s present nowadays scientific challenges and social mobilization for their control that seem similar to the situation of hepatitis when the WSS experiments were underway. What are the implications of using diverse ethical criteria in experiments in anima nobile? To study the progression of HIV infection can we inject live malaria parasites in HIV patients in China, even if this protocol has been rejected in the USA? Lurie and Wolfe²² ask these questions, and answer that "these are not simply hypothetical worst-case scenarios"; this research has "already been performed".

Kotow⁹, discussing the informed consent on clinical trials, presents the question of vulnerability of populations of some countries that corroborate such studies suggesting that their position as underdeveloped countries may generate almost colonial relations that may limit their capacity to adequately defend the interests of their population.

Carvalheiro²³ points out that the inclusion of developing countries in studies of HIV vaccine developments seem to be justified not only by the genetic variability of HIV but also to elude the vigilance of regulatory agencies, so often inexistent or careless of such questions in the Third World. What are the differences between the questions raised by Carvalheiro²³ and the Willowbrook study¹²? In the first case, the autonomy of the subjects can be limited by not so well understood research protocols and the unquestionable scientific authority of the principal investigators. In the second case, the autonomy of the subjects was transferred to the parents or legal guardians that were informed that the children could be benefited by immunity against the disease.

Krugman and Giles¹² took extreme care to justify the human experiment and the process of obtaining informed consent. For instance they argued that since the susceptible children would be invariably infected when interned at WSS, artificial induction of hepatitis could have a therapeutic effect. They also comment that only the children whose parents had given written informed consent were included in the study and that the technique to obtain the consent had evolved with time. With the strategy of group meetings involving families and a multidisciplinary team (social psychiatry specialist, physician, nurse and attendants) they obtained more agreements.

However, we should pose a question - to avoid anachronism in the judgment of the procedures of the past²⁴ - as to the possible influence of the list of renowned institutions that approved the research protocol on the agreement of the parents. How many parents of special children, for so long segregated, in the USA or anywhere, in the 1950s (or today), would be able to decide freely the consent to a study informed to be prophylactic and sanctioned by so many well-known scientific institutions?

To answer this we recall the critics of that time such as Goldby²⁰. In his letter to The Lancet, he emphasizes that the "duty of a paediatrician in a situation such as exists at Willowbrook State School is to attempt to improve that situation, not to turn it to his advantage for experimental purposes, however lofty the aims." The Editor seems to ratify this opinion commenting on the affirmative that the study was therapeutical: "It is hard to accept that view, even when applied to a school where a very high proportion of children will, in existing conditions, be infected anyway" ²⁰. These comments suggest that the institution was not considered as a model and that many parents could be leaving their children there for lack of options. It shows the possibility of a situation of extreme vulnerability of these families of children with special needs back in the 1950/1960, even in the USA.

We can imagine similar situations in populations whose only possible access to medication may be linked to the consent to participate in clinical trials. It seems to have occurred in the AIDS Clinical Trials Group Study 076 (ACTG 076) when, after years of proven efficacy and widespread use of the antiviral zidovudine for prevention of perinatal transmission of HIV in the USA, pregnant women in other countries still had no access to such medication²².

Clinical trials and partially known results

Although Saul Krugman passed into history as a pioneer of hepatitis B vaccination6, many of the more than 700 subjects of the Willowbrook Studies were not immunized¹². They became chronically infected, as observed by the researchers, although they had no means at that time to further understand their findings: "The extremely long-term, if not permanent, persistence of Au/SH observed in nine of the 18 children in whom it was found suggests that it is not a very efficient antigen in terms of antibody stimulation or that the antibodies that it induces are incomplete"²⁵.

Observing these experiments with todays knowledge, it seems hardly justifiable to inject or ask the subjects to swallow solutions of feces from icteric patients²⁶. But, in 1945 it was not possible to predict all the consequences of this procedure. Even today, possible adverse effects of new drugs are very hard to be fully predicted before they are licensed to use and we are familiar with the many instances of the need for drug recall such as pointed out in the classical study by Beecher²⁷. The frequency of human experiments on hepatitis was criticized in 1952 by Fraga Filho²⁸ who considered that the number of human experiments on etiology of hepatitis with similar results no longer needed further trials. Tables 1 and 2, reproduced from his doctoral thesis, show the evidence for his argument. Here are registered the number of volunteers, the authors, and the period of the study.

MacCallum²⁹ published a similar review for serum hepatitis presenting eight experimental studies in anima nobile, that took place from 1944 to 1946, with the innoculation of 548 people, 184 (33,6%) of them presenting icterus. The followed the reception of measles convalescent serum and yellow fever vaccine that contained human serum. The author remarks that "[...] as a result of the use of blood products on a massive scale during the period 1939-1945, a sufficient number of different 'outbreaks' of homologous serum hepatitis occurred [...]" and that, as the "[...] could not transmitted to laboratory animals experimental studies have been carried out in man". Apparently without perception of any contradiction, he also describes methods of inactivation of the icterogenic agent and points that it is desirable to have a routine method for serum treatment that would inactivate this agent without destroying the desirable serum properties.

The perception of the uncertainty of scientific knowledge makes us aware of the need to constantly question and adequate the meanings and uses of the informed consent³⁰. The fragility of the informed consent and the autonomy of volunteers and researchers themselves, stand out when we reflect about scientific research from a historical perspective.

Koch's postulates and scientific uncertainty

In the beginning of the 20^th century, biomedical research of infectious diseases causality was ruled by the Koch's postulates and it was in this scenario where most experimental studies on hepatitis were developed.

The hypothesis of an infectious nature of icterus catharralis presented difficulties for lack of animal models or in vitro data, as required by the postulates, and human experiments were done to check the hypothesis. In a 1945 article, co-written by Albert Sabin, we read: "and by using man as the experimental animal some of the properties of the agent of infectious hepatitis have been determined"³¹.

Not only the difficulties of the animal model but also the search for irrefutable evidence stimulated studies on human volunteers, often disregarding the unnecessary risks the volunteers could be standing^3,4.

In 1967, Deinhardt et al. registered that marmosets were susceptible to human hepatitis and could be appropriate animal models. But, avoiding criticism, the authors emphasized that although they had demonstrated the transmission of human hepatitis to those primates through the elevation of transaminases and compatible liver lesions they could not confirm it through the elevation of antibodies. That ratified the need for caution in the interpretation of the results and justified further human experiments: "It is yet to be proved that the agent inducing hepatitis in marmosets is indeed the agent of human viral hepatitis by the reintroduction of the agent after several marmoset passages into man"³².

Koch's postulates are insufficient for the standards of today. As was seen later, the non-reproduction of hepatitis in experiments with animals³² was overcome by electron microscopes and molecular biology that made possible the identification of HAV and HCV.

A growing tendency to see epidemiological studies as a hierarchy of methods, conferring greater scientific value to experimental randomized studies and less value to observational studies must also be subject to discussion.

Informing volunteers on possible hazards and damages to health as a result from experiments is a delicate task since there is always a margin of uncertainty for the researcher himself. To act ethically we must consider the principle of precaution for it is not always possible to evaluate risks as precisely as we would like to.

This principle in relation to prevention of hepatitis has been recently discussed by Harvey J. Alter³³, co-discoverer of the Australia antigen and receiver of the Lasker Award for the study that led to the discovery of HCV and the development of screening tests that reduced transfusion hepatitis to almost zero³⁴. Koch and Evans postulates are insufficient for today's standards. The non-reproduction of hepatitis in vitro was overcome by electron microscopes and molecular biology that made possible the identification of HAV and HCV. The lack of application of the principle of precaution, or protection as referred by Schramm et al.⁸, may be contributing to the transfusional transmission of hepatitis in scientific research and in biomedical procedures, due to the lack of substitution of old methods by newer and safer technology, as determined by CNS Resolution 196/96⁷: "the principal investigator must stop the protocol immediately when any risk or damage to the health of the research subjects, not exposed in the informed consent and consequent to research procedures, is detected" and "as soon as the advantage of a procedure over another is detected, the protocol must be suspended and the best procedure must be offered to all research subjects".

Keeping pace with scientific changes the legislation on the ethics of research must be reviewed to consider the uncertainty implied on the information given to volunteers and the possibilities of hazard^30,35. Moreover, it is not enough that the legislation be regularly reviewed, but the investigator must exercise his responsibility by being ahead of the legislation when the preservation of the health and well being of the research subjects may be at issue.

Resistance to reformulation of scientific concepts

The history of adverse effects of yellow fever vaccination of American soldiers in World War II offers a unique opportunity to discuss how the resistance to reconsider concepts and to change processes of production of pharmaceutical products may cause irreversible damage to health and retard the implementation of precautionary measures of control^36,1,33.

Since the 1930s, Findlay et al.⁴ had shown evidence of association between yellow fever vaccination and hepatitis and proposed that the vaccine be produced without the use of human serum. But it was only during World War II - when there were 28,585 cases of jaundice in American and other troops, with 62 deaths; and the American government and the scientific community became the targets of a hot press debate - that changes in the process of vaccine production were introduced³⁶.

Other examples of this scientific resistance are the long intervals between the recognition of transfusional transmission of HBV and HCV and the implementation of preventive measures: 30 and 15 years respectively. According to Alter³³: "This statement is being made not to cast retrospective blame, but to take a lesson from history and to illustrate the value of having a protective preemptive mechanism in place before the next agent strikes."

Conclusions

This brief historical view of the informed consent, focused on the case of hepatitis, points to its unequivocal role in the assurance of the autonomy of research subjects. But, it also leads us to ask if it is sufficient to preserve these subjects from hazards. The answer seems to be no.

We have shown factors that can interfere with free and informed consent of research volunteers. The complexity involved in the acceptance or refusal to be the subject of research must be considered by Ethics Committees and adequate means must be developed to further advance the protection of research subjects. An important component for the preservation of the social value of scientific research is strict adherence to the legislation that aims to protect society.

Informed consent aims to protect and preserve the health of the research subjects and cannot be reduced to an instrument for the preservation of the integrity of research protocols. The responsibility of the researcher and the institution cannot be restricted to these protocols, to preserve the credibility of both. The researcher also needs to be informed and to feel free to interrupt the research when he suspects that it may be causing harm to the subjects.

Acknowledgement

Guilherme Santoro Lopes, PhD, gave fundamental suggestions to the discussion and for further research.

Study conducted at Universidade Federal do Rio de Janeiro (UFRJ), Medical School, History, Health and Society Laboratory, Rio de Janeiro, RJ, Brazil

• 1. Schmid R. History of viral hepatitis: a tale of dogmas e misinterpretations. J Gastroenterol Hepatol 2001;16(7):718-22.
• 2. Blumberg BS, Alter HJ, Visnich S. A new antigen in leukemia sera. JAMA 1965;191(7):541-6.
• 3. Dienstag JL. Non-A, non-B hepatitis. II. Experimental transmission, putative virus agents and markers, and prevention. Gastroenterology 1983;85(3):743-68.
• 4. Findlay GM, MacCallum FO, Murgatroyd F. Observations bearing on the aetiology of infective hepatitis (so-called epidemic catarrhal jaundice). Trans R Soc Trop Med Hyg 1939;32(5):575-86.
• 5. Melnick JL. History and epidemiology of hepatitis A virus. J Infect Dis 1995;171(Suppl 1):S2-8.
• 6. Sherlock S. Landmarks in viral hepatitis. JAMA 1984;252(3):402-6.
• ⁷
  Brasil. Ministério da Saúde. Conselho Nacional de Saúde. Resolução CNS nº 196 de 10/10/1996. Diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. [cited 2011 May 13]. Available from: http://conselho.saude.gov.br/resolucoes/1996/Reso196.doc
• 8. Schramm FR, Palácios M, Rego S. O modelo bioético principialista para a análise da moralidade da pesquisa científica envolvendo seres humanos ainda é satisfatório? Ciência Saúde Coletiva 2008;13(2):361-70.
• 9. Kotow M. Bioética de riesgos biomédicos. Rev Bioética 2010;18(1):15-30.
• 10. Garrafa V, Prado MM. Mudanças na declaração de Helsinki: fundamentalismo econômico, imperialismo ético e controle social. Cad Saúde Pública 2001;17(6):1489-96.
• 11. Vollmann J, Winau R. Informed consent in human experimentation before the Nuremberg Code. Br Med J 1996;313(7070):1445-7.
• 12. Krugman S, Giles JP. Viral hepatitis: new light on an old . JAMA 1970;212(6):1019-29.
• 13. WMA - World Medical Association. Draft code of ethics on human experimentation, World Medical Association. Canad Med Assoc 1963;89(18):958. [cited 2011 May 13]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1921848/pdf/canmedaj01020-0049.pdf
• 14. WMA - World Medical Association. Human experimentation. code of ethics of the World Medical Association. Declaration of Helsinki (Recommendations Guiding Doctors in Clinical Research). Canad Med Assoc J 1964;91(11):619. [cited 2011 May 13]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1927433/pdf/canmedaj01065-0048.pdf?tool=pmcentrez
• ¹⁵
  NIH - National Institutes of Health. Regulations and Ethical Guidelines. Nuremberg Code. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law nº 10, v. 2, p. 181-2. Washington (DC): U.S. Government Printing Office; 1949. [cited 2011 May 13]. Available from: http://Ohsr.Od.Nih.Gov/Guidelines/Nuremberg.Html
• 16. Kotow M. História da ética em pesquisa com seres humanos. RECIIS Rev Eletr Com Inf Inov Saúde 2008;2(Supl 1):S7-S18.
• ¹⁷
  Belmont Report. The Belmont Report Ethical Principles and Guidelines for the protection of human subjects of research. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Washington (DC): DHEW Publications (OS) 78-0012; 1978. [cited 2011 May 13]. Available from: http://ohsr.od.nih.gov/guidelines/belmont.html
• 18. Ingelfinger FJ. [Editorials]. Ethics of experiments on children. N Engl J Med 1973; 288(15):791-2.
• 19. JAMA [Editorials]. A Shedding of Light. JAMA 1970;212(6):1057-8.
• 20. Goldby S. Experiments at The Willowbrook State School. Lancet 1971;1(7702):749. [Letters to the Editor]
• 21. EDCTP. European & Developing Countries Clinical Trials Partnership. 2011. [cited 2011 May 14]. Available from: http://www.edctp.org/Home.162.0.html
• 22. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med 1997;337(12):853-6.
• 23. Carvalheiro JR. O crucial debate da ciência no limiar do século 21. Ciênc Saúde Coletiva 2002;7(1):17-41.
• 24. Goldim JR. O Caso Tuskegee: quando a ciência se torna eticamente inadequada. Núcleo Interinstitucional de Bioética - HCPA/UFRGS. 1999. [cited 2011 May 14]. Available from: http://www.ufrgs.br/bioetica/tueke2.htm
• 25. Giles JP, McCollum RW, Berndtson LW Jr, Krugman S. Viral Hepatitis: relation of Australia/ SH antigen to the willowbrook MS-2 strain. N Engl J Med 1969;281(3):119-22.
• 26. Mac Callum FO. Transmission of arsenotherapy jaundice by blood: failure with faeces and naso-pharyngeal washings. Lancet 1945;245(6342):342.
• 27. Beecher HK. Ethics and clinical research. N Engl J Med 1966;274(24):1354-60.
• 28. Fraga Filho C. Hepatite por vírus [Thesis for university lecturer's exam]. Rio de Janeiro: Faculdade de Medicina da Universidade do Brasil; 1952.
• 29. MacCallum FO. Homologous serum hepatitis. Proc R Soc Med 1946;39(10):655-7.
• 30. Lipworth W. Managing scientific uncertainty in health legislation. Intern Med J 2007;37(2):119-23.
• 31. Paul JR, Havens WP Jr, Sabin AB, Philip CB. Transmission experiments in serum jaundice and infectious hepatitis. JAMA 1945;128(13):911-5.
• 32. Deinhardt F, Holmes AW, Capps RB, Popper H. Studies on the transmission of human viral hepatitis to marmoset monkeys. I. transmission of , serial passages, and descriptions of liver lesions. J Exp Med 1967;125(4):673-87.
• 33. Alter HJ. Pathogen reduction: a precautionary principle paradigm. Transfus Med Rev 2008;22(2):97-102
• 34. NIH - National Institutes of Health. Clinical Center: important events in CC History. Bethesda: The NIH Almanac; 2010. [cited 2010 Jun 18]. Available from: http://www.nih.gov/about/almanac/organization/CC.htm
• 35. Gaze R, Carvalho DM, Yoshida CFT, Tura LFR. Estudos de soroprevalência das hepatites virais: reflexões éticas acerca da prática de investigação. Rev Assoc Med Bras 2006;52(3):162-9.
• 36. Jaundice following yellow fever vaccination. Editorial. JAMA 1942;119(14):1110.

Publication Dates

• Publication in this collection
  14 Oct 2011
• Date of issue
  Oct 2011