Sci Eng Ethics (2015) 21:1049–1064 DOI 10.1007/s11948-014-9579-z ORIGINAL PAPER

Deliberate Microbial Infection Research Reveals Limitations to Current Safety Protections of Healthy Human Subjects David L. Evers • Carol B. Fowler • Jeffrey T. Mason Rebecca K. Mimnall



Received: 29 March 2014 / Accepted: 31 July 2014 / Published online: 24 August 2014  Springer Science+Business Media Dordrecht (outside the USA) 2014

Abstract Here we identify approximately 40,000 healthy human volunteers who were intentionally exposed to infectious pathogens in clinical research studies dating from late World War II to the early 2000s. Microbial challenge experiments continue today under contemporary human subject research requirements. In fact, we estimated 4,000 additional volunteers who were experimentally infected between 2010 and the present day. We examine the risks and benefits of these experiments and present areas for improvement in protections of participants with respect to safety. These are the absence of maximum limits to risk and the potential for institutional review boards to include questionable benefits to subjects and society when weighing the risks and benefits of research protocols. The lack of a duty of medical care by physician– investigators to research subjects is likewise of concern. The transparency of microbial challenge experiments and the safety concerns raised in this work may stimulate further dialogue on the risks to participants of human experimentation. Keywords Intentional infection  Deliberate infection  Healthy human subject research  Microbial challenge experiments  Maximum risk  Duty of care  Exaggerated benefits Introduction Intentional infection experiments on healthy human subjects are designed to temporarily harm volunteers by infecting them with pathogens in a manner that is as D. L. Evers (&)  C. B. Fowler  J. T. Mason Veterans Affairs Maryland Health Care System, Research Service, 10 North Greene Street, Baltimore, MD 21201, USA e-mail: [email protected] R. K. Mimnall Office of Research and Development, Veterans Health Administration, Washington, DC, USA

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humane as possible. The newly unhealthy, sometimes subclinical volunteers are dosed with infection-mitigating treatments or none and the course of disease is monitored by investigators. Subject recovery is anticipated prior to the completion of experiments. The general study design of exposing subjects to risks without intending direct health benefits extends beyond microbial challenge experiments to the placebo arms of clinical research, pesticide exposure safety studies, and some phase I biologic or drug safety trials. The principles of respect for persons, beneficence, and justice guide much of today’s human subjects of research protections. Protections of the well-being of research participants include informed consent, research oversight by institutional review boards (IRB) or their equivalent, and frequently accepted ethical standards (Emanuel et al. 2000). Even when all of these protections are satisfied, the ethics of microbial challenge studies can remain questionable. For example, outrage at the abuses of the 1946–1948 US Public Health Service (PHS) experiments in Guatemala (Presidential Commission 2011) was not uniformly directed. The affront to the academic and professional community was the contemporaneous failure, or lack of human subject research protections. The public, however, was offended by the experimental design in and of itself; the indignity of systematic infection of healthy volunteers (Lynch 2012). These Guatemala studies were criticized by the directors of the Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) as unethical, due in part to the deliberate infection of individuals with pathogens that could cause serious illnesses: chancroid, gonorrhea, and syphilis (Frieden and Collins 2010). IRBs are said to spend a great deal of effort on informed consent documentation but too little time reviewing risks and benefits (Weijer 2000). These priorities are consistent with today’s praise of the 1900–1901 Walter Reed studies on yellow fever (Reed 1902) and criticism of the 1955–1970 Willowbrook hepatitis experiments (Krugman 1986). Their merits may be traced to how each study handled informed consent and diminished autonomy. The subjects of the yellow fever studies were consenting adults while the Willowbrook subjects were institutionalized children. Alternatively, if merit was based upon the risks faced by the subjects, then the hepatitis studies would likely be praised and the yellow fever studies criticized. The hepatitis strains used were not only attenuated but also introduced to subjects who were refractory to symptomatic hepatitis. We could find no evidence of study-related deaths among 700–750 Willowbrook subjects. However, following violent illness, 3 of 24 volunteers died in Reed’s yellow fever experiments (Chaves-Carballo 2013). This suggests that volunteer safety may be of lesser importance than other human subject research controls. Some believe that great results justify great risks. This resonates with ‘the end justifies the means,’ a rationale that is likely incompatible with respect for persons. It also anticipates the outcome of experiments when all that is known are great risks. Unknown or mediocre results are unlikely to justify great risks. If the purpose of human subject research protections is to protect the mental and physical safety of participants, then careful examination of risk and safety are warranted. Insofar as microbial challenge studies appear to be an extreme case of risky research

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interventions that fail to benefit participants, they provide a forum to examine some limitations to current protections of volunteer safety.

Methods For Table 1, we queried the search term ‘‘infection AND volunteer’’ in the US National Center for Biotechnology Information’s PubMed to obtain a list of initial publications in English from peer-reviewed journals. Papers that cited the initial publications and papers that were cited by the initial publications were included in the final data set. No controls were applied against biased or incomplete data. We included publications that identified at least 100 healthy human subjects experimentally infected with pathogens, including experimental live attenuated vaccine candidates. Two human subject research standards were evaluated for each study: informed consent and research oversight. For Table 2, we queried the search term ‘‘x AND challenge’’ at the US National Library of Medicine‘s clinicaltrials.gov (Zarin et al. 2014) where x was BCG, dengue, gonococcus, helminth, influenza, malaria, norovirus, meningococcus, pneumococcus, respiratory syncytial virus, rhinovirus, salmonella, and tularemia. We included those trials that experimentally infected healthy human subjects with pathogens, including experimental live attenuated vaccine candidates, and occurred after year 2009.

Intentional Infection Experiments on Humans are Commonplace and Contemporary While preparing this work we found it difficult to discuss microbial challenge studies with our colleagues, family, and friends. They frequently if not uniformly responded to the subject matter with disbelief followed by outrage. Similar anecdotal experiences were reported by Lynch (2012). Many persons assumed that intentional infection research on humans was either illegal or no longer being performed, performed on a small number of persons, or limited to locations outside of the UK or US. This section is intended to convince the reader that intentional infection experiments on healthy humans have a rich history in the mid-late 20th century that continues to the present day. Intentional Infection Experiments on Humans are Commonplace There is little information, and perhaps little attention to the frequency of microbial challenge experiments and the number of healthy volunteers: The [Academy of Medical Sciences, London] Working Group was unaware of any reliable quantitative estimate of the number of adverse events related to participation in microbial challenge studies overall or, indeed, a collective

123

123

4,000

358

700–750

1950–1959

1954–1973

1955–1970

Plasmodium

S. flexneri

Influenza virus

111

267

100 s

107

[250

1988

1993–2007

1994–2003

1999–2004

2003–2004

N. gonorrhoeae

H.ducreyi

C. jejuni

Plasmodium

118

Enterotoxic E. coli

[1,300

1971–2009

Influenza virus

Various

1986–2012

443

1970–2012

S. typhi

Various

C. burnetii

Hepatitis A, B

Various

Respiratory viruses

Influenza virus

1985–1992

1,280

6,500

1965–2005

1,600

1,000 s

1962–1974

[18,000

1946–1989

1948–1988

120

Rhinovirus, et al.

1,308

1946–1948

800

H.ducreyi, N. gonorrhoeae, T. pallidum

C800

1959–1960

Hepatitis B

[744

1943–1945

1944–1946

1961–1964

N. gonorrhoeae

241

1943–1944

Plasmodium

Dengue

Influenza virus

[670

[200

1902–2013

1941–1944

Agent

No. healthy human Subjects

Date (year)

Dysentery

Endemic & traveler’s diarrhea

Endemic & traveler’s diarrhea

n.a.

Typhoid fever

n.a.

Q fever

Hepatitis

n.a.

n.a.

Common cold

chancroid, gonorrhea, and syphilis

Malaria

Hepatitis

Gonorrhea

Influenza

Dengue hemorrhagic fever

Disease

Table 1 Studies where healthy human subjects were deliberately infected with microbial pathogens

n.d.

Y

Y

Y

Y

n.d.

Y

Volunteers

n.d.

n.d.

Volunteers

n.d.

n.d.

Y

n.d.

n.d.

Volunteers

Volunteers

N

Volunteers

n.d.

Volunteers

Volunteers

n.d.

Informed consent

n.d.

IRB

IRB

IRB

Y

n.d.

IRB

n.d.

n.d.

n.d.

Y/IRB

n.d.

n.d.

Y

n.d.

n.d.

Partial

Y

Y

Y

n.d.

Y

Y

n.d.

Research oversight

Oxford et al. (2005)

Katz et al. (2004)

Hobbs et al. (2011)

Janowicz et al. (2009)

Black et al. (1988)

Epstein (2013)

Preston Church et al. (1997)

Porter et al. (2011)

Kalil et al. (2012)

Carrat et al. (2008)

Levine et al. (2001)

Knight (1964)

Benson et al. (1963)

Krugman (1986)

Pittman et al. (2005)

Knight (1964)

Oxford (2013)

Tyrrell (1992)

Presidential Commission (2011)

Shuster (1997)

MacCallum (1946)

Presidential Commission (2011)

Henle and Henle (1946)

Thomas (2013)

Reference

1052 D. L. Evers et al.

99–109

2009–2013

C. jejuni

Agent

Disease

Y

Informed consent Y/IRB

Research oversight

Kirkpatrick et al. (2013)

Reference

No. number, n.d. no data/not disclosed, n.a. not applicable, Y yes, N no, IRB institutional review board. Volunteers refers to studies that called subjects ‘volunteers’ but no informed consent was mentioned

[41,116

No. healthy human Subjects

Date (year)

Table 1 continued

Current Safety Protections of Healthy Human Subjects 1053

123

123

5

Common cold

Food poisoning

Rhinovirus

Salmonella 4,011

75

UK

Germany, UK, US

UK

UK

Australia, Colombia, Germany, Kenya, Netherlands, Senegal, Spain, Switzerland, Tanzania, UK, US

US

n.a.

Belgium, UK, US

n.a.

n.a.

US

Locations

1/1

0/0

4/4

0/2

0/3

0/4

0/1

11/44

16/30

1/1

0/7

n.a.

0/11

n.a.

n.a.

0/2

Curative treatment reported

2/2

n.a.

3/9

n.a.

n.a.

1/1

Placebo/no. efficacy studies

d, h

f, h, i

d, h

d

a, b, d, h, i

c, g, h

n.a.

c, d, h, i

n.a.

n.a.

i

Purpose (note)

No. number, n.a. not applicable, a–g as described by Kotloff (2003): a proof of microbial pathogenicity, b definition of protective antigen, c identifying factors that influence disease acquisition and severity, d assessment of vaccine efficacy, e demonstration of infection-derived immunity, f identification of protective immune responses, g refinement of vaccine formulation, schedule, and delivery, h–i as described here: h development/refinement of challenge method/strain; i assessment of experimental live attenuated vaccine safety

Data is presented as reported to clinicaltrials.gov (Zarin et al. 2014)

179

191

295

90

1,855

451

0

842

0

0

108

No. subjects

2

3

1

pneumonia

44

Respiratory illnesses

Plasmodium

0

7

Respiratory syncytial virus (RSV)

Malaria

Norovirus

11

0

0

2

No. studies

Pneumococcus

Meningitis, etc.

Gastroenteritis

Meningococcus

Schistosomiasis, etc.

Gonorrhea

gonococcus

Influenza

Tularemia

F. tularensis

Influenza virus

Dengue hemorrhagic fever

Dengue

Helminths

Disease

Pathogen

Table 2 Research studies conducted 2010 to present, where healthy human subjects were deliberately infected with microbial pathogens

1054 D. L. Evers et al.

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record of all those who participate, either in the UK or other countries such as the US. (Academy of Medical Sciences 2005) We responded to this observation by briefly counting the subjects in deliberate infection studies from World War II to the present, using the literature found at PubMed (see Methods). Nearly all of these publications were reviews that described multiple related studies (Table 1). We identified some 40,000 healthy human subjects of intentional infection experiments from approximately World War II to the early 2000s. The data in Table 1 is likely to underestimate the number of studies and participants. Far from ethically impossible, deliberate microbial infection experimentation on healthy human volunteers is legal, continues to be performed in the UK and US, and involves many thousands of participants. The lack of standardization and frequency of omissions in the data (Table 1) was consistent with that reported by Kalil et al. (2012). This may have been responsible for our inability to confirm the expectation of improvements in both informed consent and research oversight after the human subject research reforms that followed the early 1970s. Neither did the data verify the expectation that the total number of historical participants and studies were significantly greater than those of contemporary studies. Relatively mild ailments such as the common cold, diarrhea, and sexually transmitted diseases were more frequently performed than those from more virulent organisms such as hepatitis, influenza, and Plasmodium. Potentially severe etiological agents, such as Coxiella burnetii, Francisella tularensis and Venezuelan Equine Encephalitis virus were even fewer in number. These three infectious agents are classified as Select Agents due to their potential to pose a severe threat to public health and safety.1 Intentional Infection Experiments on Humans are Contemporary The printed meeting agenda of a 2013 conference on Controlled Human Infection Studies in the Development of Vaccines and Therapeutics included current microbial challenge studies with BCG (a vaccine strain of tuberculosis), dengue, gonococcus, helminths, influenza, malaria, meningococcus, norovirus, pneumococcus, respiratory syncytial virus, rhinovirus, Salmonella, and tularemia (Pollard et al. 2012). Since years often pass between scientific meetings, publications, and review articles, we turned to clinicaltrials.gov (Zarin et al. 2014) for data on microbial challenge experiments from the year 2010 to the present. We identified some 4000 healthy human subjects of intentional infection experiments from 2010 to the summer of 2014 (Table 2). We suspect this is an underestimate for two reasons: we queried a limited number of etiological agents and clinicaltrials.gov is not an exhaustive database. If we were to approximate the data in Table 1 to 40,000 subjects in 70 years and the data in Table 2 to 4,000 subjects in 5 years, then there would be no decrease, but rather a greater than 40 % increase in the number of participants per year from the intervals 1

US Select Agents are defined in Title 7 Code of Federal Regulations part 331 (7CFR331), 9CFR121, and 42CFR73; the ‘Select Agent and toxins regulations’.

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between 1941 to 2010 and 2010 to the present. We cannot consider this a rigorous analysis, but it does suggest that, contrary to our expectation, contemporary studies were greater in number than those associated with eras of human subject research abuse and subsequent reforms. All of the studies from 2010–2014 reported carefully documented informed consent and were approved by an IRB or their equivalent. Many efficacy studies employed placebo arms where one group of volunteers received infectionmitigating treatments and a second received none prior to exposing both groups to the same pathogen. Comparator test article treatments might have been just as informative as well as more humane than placebo controls. For example, there are two classes of marketed drugs and multiple licensed vaccines that are effective against influenza, yet placebo controls were still employed. This suggests the possibility of repetition because some 1,280 healthy subjects were infected, with wild-type virus but no antiviral prophylaxis or treatment, between 1965 and 2005 (Carrat et al. 2008; Table 1). Little data was provided on curative treatments for participants after the experimental phases of these studies. The stated purpose of the studies varied, but generally fit the seven categories (see legend to Table 2) of motivations described by Kotloff (2003), excepting a frequent category only peripherally mentioned by Kotloff (2003): deliberate infection to optimize a future challenge method, a design that might be more difficult to justify based upon its benefits to society. Investigators, sponsors and funding agencies invariably justify deliberate infection research with a sobering description of public health threats from the pathogens in question. If an infectious agent is important enough to merit the allocation of scarce resources, then the disease it causes is unlikely to be a minor, every day, or harmless event. Why such prevalent and important pathogens lack clinically significant frequencies and intensities to enable natural infection studies is a mystery to us. Yet carefully controlled studies are conducted on healthy volunteers with microorganisms such as influenza (Table 2). Something like 140 million American consumers will queue and often pay out of their pocket for influenza vaccines (flu shots) this season (Centers for Disease Control 2014). They are presumably trying to avoid the real danger of natural infection.

Risks to Healthy Human Subjects IRBs are responsible for independent assessment of the risks and benefits of submitted research protocols. Where regulated by the US HHS and FDA regulations,2 this includes the two criteria of: first, risks to subjects are minimized and reasonable, and second, benefits to society outweigh risks to subjects. Approval of protocols requires that both criteria are met. The lack of orthodoxy in IRB 2

The ‘HHS regulations’ are administered under the HHS Assistant Secretary for Health by the Office for Human Research Protections (OHRP) under 45CFR46, part A of which constitutes the US federal Common Rule. The FDA is an agency division of the HHS and ‘FDA regulations’ refers to the clinical research regulations codified in 21CFR50, 21CFR56, 21CFR312 and 21CFR812. The CDC, NIH and FDA are divisions of the PHS but OHRP is not.

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decisions is a frequent topic of commentary and research. For example, at least one IRB denied a particular protocol as too risky for approval yet other IRBs expedited the same study because it presented only minimal risk (Abbott and Grady 2011). Rather than the mistake of approving protocols that pose unreasonable risks to subjects, the infractions cited in FDA warning letters to IRB tend to focus upon infractions of membership requirements and standard operating procedures (Bramstedt and Kassimatis 2004; Gogtay et al. 2011). Dual-track, net risks, comparator, and other analyses provide frameworks for understanding and performing risk versus benefit determinations. Dual-track analysis assigns each protocol to beneficial or non-beneficial intent. Non-beneficial research risks are acceptable if the first and second criteria above are met (Council for International Organizations of Medical Sciences 2002; Weijer and Miller 2004). The beneficial versus non-beneficial distinction was criticized to the extent that it was removed from the 2000 and following versions of the Declaration of Helsinki (World Medical Association 2013). It is likewise absent from the US HHS and FDA regulations. The net risks test compares the risks and benefits of each protocol intervention to those of available alternatives. An intervention poses a net risk when it is riskier than its alternatives. Interventions with net risk are acceptable if the first and second criteria above are met. The risks from all interventions are added and the protocol is acceptable if their sum appears reasonable to IRBs (Wendler and Miller 2007). Comparator analysis evaluates research risks to participants against comparable voluntary public service activities that are socially acceptable (London 2006). For example, were research risks comparable to those associated with donating a kidney, and donating a kidney was a socially acceptable act, then those research risks are acceptable (Rid et al. 2010). IRB decision-making remains reasonably independent and is likely to resist change. However, it might be practical for well thought out updates and clarifications to existing controls to reduce experimental risks to healthy human subjects. Below we describe three such issues for further consideration. Upper Limits to Risks The word risk has a variety of meanings in human subject research. Here we focus upon minimal, minimized, and maximum risk. Minimal risk may be defined as no greater likelihood of insult or injury than that encountered in daily life or in a routine medical or psychological examination (Council of Europe 2012; FDA and HHS regulations), or alternatively, at most, a very slight and temporary detrimental impact on the health of the research participant (Council of Europe 2005). Not minimal risk, but rather minimized risk is required for IRB approval of human experimentation. Minimized risk amounts to scientifically valid experimental design and the avoidance of unnecessary risks to subjects (HHS and FDA Regulations). This is subjective and minimization of risk is likely the most difficult of these three risks to regulate. This may reflect a legitimate need to accommodate the wide variety of protocols that are presented to IRBs, but it may also be the very opposite of the rule of law, the guiding principle where justice is blind and all are accountable to the same controls. IRB evaluation of protocols would likely be fairer,

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faster, and more uniform if IRB criteria for content and approval were more predictable. At the other end of the spectrum is maximum risk to subjects. We are unaware of any enforceable upper limits to the physical, psychological, social, and economic risks that may be borne by healthy human subjects of research. Since a reasonable balance of risks and benefits is required for human subject research, with sufficient societal need, no limits can be placed upon the harm endured by the participants. This suggests the potential for a good deal more harm than mere denial of civil rights. Many would find this unacceptable. Upper limits on acceptable risk are in the interest of participant safety and likely to be well received by an informed public. Some proposed definitions of maximum risk are presented in Table 3. Since a wide range of definitions are advocated (Miller and Joffe 2009), a consensus is unlikely to be reached quickly. Further, enforceability may conflict with international sovereignty. We propose that upper limits to risk could be based upon the principles of the United Nations Universal Declaration of Human Rights (1948). If we continue to ignore this issue or to choose not to decide, then we have chosen the absence of maximum risk. This invites abuse and embarrassment that can be avoided. Questionable Benefits to Subjects and Society It is possible that exaggerated benefits to either subjects or society might justify increased risk to healthy participants. Benefits are widely advertised by name when recruiting healthy volunteers because ‘it is frequently difficult to recruit participants who are not offered an incentive to participate’ (Goldenberg et al. 2007). Subjects of human experimentation may receive a variety of incentives and rewards that could be considered direct health benefits. These include baseline physical exams, free medical care, treatment for the very ailments introduced by the research, incidental findings, and assurances that study-related injuries will be treated without charge. Some benefits are more credible than others. Volunteers may also receive public transportation vouchers, temporary room and board, gaining firsthand knowledge of an infectious disease, material goods, receiving personal attention, college course credit, and a break from the daily routine if not a bona fide vacation. Monetary compensation was formerly considered a benefit in the US (Macklin 1989). In the US it is now called a recruitment incentive and is excluded from IRB deliberations of the individual benefits that offset risks to subjects (Office for Human Research Protections 1993; Food and Drug Administration 2010). The volunteer’s personal satisfaction of altruistic service to humanity was similarly disallowed (Office for Human Research Protections 1993). Since these remunerations to participants became nominally forbidden from IRB risk–benefit determinations with minimal fanfare, it may be practical to place today’s least credible benefits off-limits. Benefits to society are likewise certain to be hawked. It is in the interest of the physician–investigator, institution, and sponsor/funding source to emphasize and publicize the real and potential benefits of their research. Budgets, careers, drug and medical device approvals, funding, and prestige, etc. are at stake. Every specialist

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Table 3 Proposed upper limits of risk to human subjects of biomedical research ‘Risk to subjects should be limited to…’

Reference

Infectious agents that are self-limiting or susceptible to therapies that reverse symptoms and clear the infectiona

Miller and Grady (2001)

Those incurred by a standard medical examination

Council for International Organizations of Medical Sciences (2002)

No more than those encountered in a phase I drug study

Academy of Medical Sciences (2005)

Minimal risk and minimal burden

Council of Europe Additional Protocol (2005)

No greater than those associated with comparator activities, such as volunteer firefighting or providing emergency medical services

London 2006

No more than a 1 % chance that healthy human volunteers will experience serious harm, such as death, permanent disability, or severe illness or injury

Resnik 2012

No limits

Shaw 2014

a

Specific to intentional infection studies on healthy human volunteers

imagines their own work to be of the highest importance and is superlatively frustrated by any impediments (von Hayek 2007). They can be expected to complain that ‘important research’ is being held up by IRB review and other hurdles. There is also some certainty that those who profess to benefit society are unlikely to do so (Beecher 1959). We make these remarks without cynicism. It is easy to convince yourself that what is good for you is good for society (Friedman and Friedman 1990). Duty of Care to Healthy Volunteers A duty of care is the obligation to provide a standard of reasonable care while performing acts that could foreseeably harm others. International aspects of this topic have been substantially covered elsewhere (Lie et al. 2004). Many regulations and advisory bodies explicitly favor the rights, safety, and well-being of research participants over those of the public. The language typically amounts to: The interests of the trial subject are first priority and must not be subordinated to the interests of science or society (Council of Europe 2012; World Medical Association 2013; International Conference on Harmonization 1996; Shuster 1997). This ‘do no harm’ principle suggests the guarantee of a duty of care toward healthy human subjects. Yet the same documents allow, if not advocate research performed solely for the benefit of science, fully aware that this may expose volunteers to harm. Thus the above guarantees may inaccurately describe actual policy or alternatively, they may fail to distinguish healthy volunteers from ill patients. Where there is a dichotomy between patients and research subjects, healthcare may be expected to be provided to the former while there is no such obligation to the later (Joffe and Miller 2008). This could be in conflict with the principle of respect for persons. Alternatively, a partial entrustment model favors a limited duty

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of care that is consistent with physician responsibilities to healthy research subjects that are less than their responsibilities to patients (Richardson and Belsky 2004). Primary responsibility would be likely to be assigned to the physician–investigator (Beecher 1959; World Medical Association 2013). Others concur: Where medical skills are involved the relationship between subject and experimenter seems to be the same as that between patient and physician, so that ethical considerations apply to the former relationship as to the latter. This is the subject’s real protection. (Roxburgh 1963) In the traditional doctor–patient relationship, the patient passively follows the physician’s plan due to trust that their physician will safeguard their best interests. This trust is generally well-placed. However, a ‘physician knows best’ model of the doctor–patient or doctor–subject relationship is often criticized as unjustified paternalism that compromises informed consent. Although volunteers frequently overestimate the likelihood of direct benefits and continue to believe that their ailments will be top priority to clinicians, the contemporary investigator–research subject relationship generally replaces trust in the physician with informed consent (Lemmons and Elliott 2001). Some even argue that informed consent should be the decisive consideration for human subject research oversight (Edwards et al. 2004). The principle of ‘those who consent cannot claim injury’ transfers responsibility to minimize experimental risks from the physician–investigator, institution, sponsor/funding source, and IRB to the volunteer. Informed consent may even reduce professional liability and favor blaming the victims for adverse experimental effects. Paternalism carries responsibilities that ‘free will’ lacks. Physicians are negligent when their conduct falls below the prevailing standards of medical practice. Medical practice standards extend to healthy volunteers insofar as a duty of care exists (Jansson 2003). In the US, institutions and sponsors are not required to provide care or payment for research injuries. Legal precedent for duty of care in healthy human subject research is currently limited to a 2001 Maryland court case where the blood levels of lead increased in child subjects of a Johns Hopkins University study on lead abatement. The court ruled that the researchers and institution owed a duty of care to the subjects (Mastroianni and Kahn 2002). This suggests the possibility that duty of care arises from not only the principles of benevolence and respect for persons, but also that of justice (Lemmons and Elliott 2001).

Conclusion Microbial challenge studies have been performed and continue to be performed in a manner that is contemporary and relevant. Our cursory search revealed some 40000 healthy human volunteers from approximately World War II to 2009 and 4000 from 2010 to the present. Some find these experiments unjustifiable because they present undue risk to participants as well as insufficient benefits to society (Annas 1991). If a favorable balance of both risks and benefits to individual volunteers was required,

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independent of those to society, then risks to healthy subjects would likely be reduced at the probable price of ending all healthy human research. Yet others argue that informed and consenting subjects should have the right to participate in high risk research (Shaw 2014). There may well be a conflict between autonomy and safety. We ask readers to consider whether they would rather discourage their friends and loved ones from participating in deliberate infection experiments at any level of risk, or to indifferently leave informed and consenting persons to what may well be their own folly. Highly respected infectious disease specialists published a paper titled ‘Would you volunteer to be quarantined and infected with influenza virus?’ (Oxford et al. 2005). Their advice and discussion of this question were noticeably absent in print. We have presented issues that may hinder the safety of healthy human subjects of research. They include: 1. 2. 3. 4.

The lack of upper limits to risks in healthy human subject research. Potential justification of increased risks to subjects due to questionable benefits to subjects or society. The ambiguous duty of medical care for research subjects. (Tentatively proposed:) A comprehensive yet narrow focus on the protection of informed consent.

We will be greatly honored if this work facilitates further exploration into the risks of healthy human experimentation and practical strategies for their further mitigation. Conflict of interest The authors are employees of the US government.

References Abbott, L., & Grady, C. (2011). A systematic review of the empirical literature evaluating IRBs: What we know and what we still need to learn. Journal of Empirical Research on Human Research Ethics, 6, 3–19. Academy of Medical Sciences. (2005). Microbial challenge studies of human volunteers. http://www. acmedsci.ac.uk/viewFile/publicationDownloads/1127728424.pdf. Accessed 16 March 2014. Annas, G. J. (1991). Mengele’s birthmark: The Nuremberg Code in United States courts. Journal of Contemporary Health Law and Policy, 7(1), 7–45. Beecher, H. K. (1959). Experimentation in man. Journal of the American Medical Association, 169, 461–478. Benson, W. W., Brock, D. W., & Mather, J. (1963). Serologic analysis of a penitentiary group using raw milk from a Q fever infected herd. Public Health Reports, 78, 707–710. Black, R. E., Levine, M. M., Clements, M. L., Hughes, T. P., & Blaser, M. J. (1988). Experimental Campylobacter jejuni infection in humans. Journal of Infectious Diseases, 157, 472–479. Bramstedt, K. A., & Kassimatis, K. (2004). A study of warning letters issued to institutional review boards by the United States Food and Drug Administration. Clinical and Investigative Medicine, 27(6), 316–323. Carrat, F., Vergu, E., Ferguson, N. M., Lemaitre, M., Cauchemez, S., Leach, S., et al. (2008). Time lines of infection and disease in human influenza: a review of volunteer challenge studies. American Journal of Epidemiology, 167, 775–785. Centers for Disease Control and Prevention. (2014). Key facts about seasonal flu vaccine. http://www.cdc. gov/flu/protect/keyfacts.htm. Accessed 27 June 2014.

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1062

D. L. Evers et al.

Chaves-Carballo, E. (2013). Clara Maass, yellow fever and human experimentation. Military Medicine, 178(5), 557–562. Council for International Organizations of Medical Sciences. (2002). International ethical guidelines for biomedical research involving human subjects. http://www.cioms.ch/publications/guidelines/ guidelines_nov_2002_blurb.htm. Accessed 27 June 2014. Council of Europe. (2005). Additional Protocol to the Convention on Human Rights and Biomedicine, concerning biomedical research. http://conventions.coe.int/Treaty/en/Treaties/Html/195.htm. Accessed 27 June 2014. Council of Europe Steering Committee on Bioethics. (2012). Guide for research ethics committee members. http://www.coe.int/t/dg3/healthbioethic/activities/02_biomedical_research_en/guide/ Guide_EN.pdf. Accessed 10 June 2014. Edwards, S. J. L., Kirchin, S., & Huxtable, R. (2004). Research ethics committees and paternalism. Journal of Medical Ethics, 30, 88–91. Emanuel, E., Wendler, D., & Grady, C. (2000). What makes clinical research ethical? Journal of the American Medical Association, 283(20), 2701–2711. Epstein, J. E. (2013). Taking a bite out of malaria: Controlled human malaria infection by needle and syringe. American Journal of Tropical Medicine and Hygiene, 88, 3–4. Food and Drug Administration. (2010). Payment to research subjects information sheet, guidance for institutional review boards and clinical investigators. http://www.fda.gov/regulatoryinformation/ guidances/ucm126429.htm. Accessed 16 March 2014. Frieden, T. R., & Collins, F. J. (2010). Intentional infection of vulnerable populations in 1946–1948: another tragic history lesson. Journal of the American Medical Association, 304(18), 2063–2064. Friedman, M. & Friedman, R. D. (1990) Free to choose: A personal statement. Harcourt Inc. Gogtay, N. J., Doshi, B. M., Kannan, S., & Thatte, U. (2011). A study of warning letters issued to clinical investigators and institutional review boards by the United States Food and Drug Administration. Indian Journal of Medical Ethics, 8(4), 211–214. Goldenberg, L. R., Owens, E. F, Jr, & Pickar, J. G. (2007). Recruitment of research volunteers: methods, interest, and incentives. Journal of Chiropractic Education, 21(1), 28–31. Henle, W., & Henle, G. (1946). Experimental exposure of human subjects to viruses of influenza. Journal of Immunology, 52, 145–165. Hobbs, M. M., Sparling, P. F., Cohen, M. S., Shafer, W. M., Deal, C. D., & Jerse, A. E. (2011) Experimental gonococcal infection in male volunteers: Cumulative experience with neisseria gonorrhoeae strains FA1090 and MS11mkC. Frontiers in Microbiology, 2. doi:10.3389/fmicb.2011. 00123. International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. (1996). Guideline for good clinical practice E6(R1). http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf. Accessed 27 June 2014. Janowicz, D. M., Ofner, S., Katz, B. P., & Spinola, S. M. (2009). Experimental infection of human volunteers with Haemophilus ducreyi: Fifteen years of clinical data and experience. Journal of Infectious Diseases, 199, 1671–1679. Jansson, R. L. (2003). Researcher liability for negligence in human subject research: Informed consent and researcher malpractice actions. Washington Law Review, 78, 229–263. Joffe, S., & Miller, F. G. (2008). Bench to bedside: mapping the moral terrain of clinical research. Hastings Center Report, 38(2), 30–42. Kalil, J. A., Halperin, S. A., & Langley, J. M. (2012). Human challenge studies: A review of adequacy of reporting methods and results. Future Microbiology, 7, 481–495. Katz, D. E., Coster, T. S., Wolf, M. K., Trespalacios, F. C., Cohen, D., Robins, G., et al. (2004). Two studies evaluating the safety and immunogenicity of a live, attenuated Shigella flexneri 2a vaccine (SC602) and excretion of vaccine organisms in North American volunteers. Infection and Immunity, 72(2), 923–930. Kirkpatrick, B. D., Lyon, C. E., Porter, C. K., Maue, A. C., Guerry, P., Pierce, K. K., et al. (2013). Lack of homologous protection against Campylobacter jejuni CG8421 in a human challenge model. Clinical Infectious Diseases, 57, 1106–1113. Knight, V. (1964). The use of volunteers in medical virology. Progress in Medical Virology, 6, 1–26. Kotloff, K. L. (2003). Human challenge studies with infectious agents. Journal of Investigative Medicine, 51(supp. 1), S6–S11.

123

Current Safety Protections of Healthy Human Subjects

1063

Krugman, S. (1986). The Willowbrook hepatitis studies revisited: ethical aspects. Reviews of Infectious Diseases, 8, 157–162. Lemmons, T., & Elliott, C. (2001). Justice for the professional guinea pig. American Journal of Bioethics, 1(2), 51–53. Levine, M. M., Tacket, C. O., & Sztein, M. B. (2001). Host-Salmonella interaction: Human trials. Microbes and Infection, 3, 1271–1279. Lie, R. K., Emanuel, E., Grady, C., & Wendler, D. (2004). The standard of care debate: The Declaration of Helsinki versus the international consensus opinion. Journal of Medical Ethics, 30, 190–193. London, A. J. (2006). Reasonable risks in clinical research: a critique and a proposal for the Integrative Approach. Statistics in Medicine, 25(17), 2869–2885. Lynch, H. F. (2012). The rights and wrongs of intentional exposure research: Contextualizing the Guatemala STD inoculation study. Journal of Medical Ethics, 38, 513–515. MacCallum, F. O. (1946). Homologous serum hepatitis. Proceedings of the Royal Society of Medicine, 39, 655–657. Macklin, R. (1989). The paradoxical case of payment as benefit to research subjects. IRB, 11(6), 1–3. Mastroianni, A. C., & Kahn, J. P. (2002). Risk and responsibility: Ethics, Grimes v Kennedy Krieger, and public health research involving children. American Journal of Public Health, 92, 1073–1076. Miller, F. G., & Grady, C. (2001). The ethical challenge of infection-inducing challenge experiments. Clinical Infectious Diseases, 33, 1028–1033. Miller, F. G., & Joffe, S. (2009). Limits to research risks. Journal of Medical Ethics, 35(7), 445–449. Office for Human Subjects Research Protection. (1993). Institutional review board guidebook. http:// www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm. Accessed 26 March 2014. Oxford, J. S. (2013). Towards a universal influenza vaccine: volunteer virus challenge studies in quarantine to speed the development and subsequent licensing. British Journal of Clinical Pharmacology, 76, 210–216. Oxford, J. S., Gelder, C., & Lambkin, R. (2005). Would you volunteer to be quarantined and infected with influenza virus? Expert Review of Anti-Infective Therapy, 3(1), 1–2. Pittman, P. R., Norris, S. L., Coonan, K. M., & McKee, K. T, Jr. (2005). An assessment of health status among medical research volunteers who served in the Project Whitecoat program at Fort Detrick, Maryland. Military Medicine, 170, 183–187. Pollard, A. J., Savulescu, J., Oxford, J., Hill, A. V., Levine, M. M., Lewis, D. J., et al. (2012). Human microbial challenge: The ultimate animal model. The Lancet Infectious Diseases, 12, 903–905. Porter, C. K., Riddle, M. S., Tribble, D. R., Louis Bougeois, A., McKenzie, R., Isidean, S. D., et al. (2011). A systematic review of experimental infections with enterotoxigenic Escherichia coli (ETEC). Vaccine, 29, 5869–5885. Presidential Commission for the Study of Bioethical Issues. (2011). ‘‘Ethically impossible’’ STD research in Guatemala from 1946 to 1948. http://bioethics.gov/sites/default/files/Ethically-Impossible_ PCSBI.pdf. Accessed 26 March 2014. Preston Church, L. W., Le, T. P., Bryan, J. P., Gordon, D. M., Edelman, R., Fries, L., et al. (1997). Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge. Journal of Infectious Diseases, 175, 915–920. Reed, W. (1902). Recent Researches Concerning the Etiology, Propagation, and Prevention of Yellow Fever, by the United States Army Commission. Journal of Hygiene (London), 2, 101–119. Resnik, D. B. (2012). Limits on risks for healthy volunteers in biomedical research. Theoretical Medicine and Bioethics, 33(2), 137–149. Richardson, H. S., & Belsky, L. (2004). The ancillary-care responsibilities of medical researchers: an ethical framework for thinking about the clinical care that researchers owe their subjects. Hastings Center Report, 34(1), 25–33. Rid, A., Emanuel, E. J., & Wendler, D. (2010). Evaluating the risks of clinical research. Journal of the American Medical Association, 304(13), 1472–1479. Roxburgh, H. L. (1963). Experiments on human subjects. Medicine Science and the Law, 3, 132–140. Shaw, D. (2014). The right to participate in high-risk research. Lancet, 383(9921), 1009–1011. Shuster, E. (1997). Fifty years later: The significance of the Nuremberg Code. New England Journal of Medicine, 337(20), 1436–1440. Thomas, S. J. (2013). Dengue human infection model: Re-establishing a tool for understanding dengue immunology and advancing vaccine development. Human Vaccines and Immunobeneficials, 9, 1587–1590. Tyrrell, D. A. (1992). A view from the Common Cold Unit. Antiviral Research, 18, 105–125.

123

1064

D. L. Evers et al.

United Nations. (1948). The universal declaration of human rights. http://www.un.org/en/documents/ udhr/. Accessed 27 June 2014. von Hayek, F. A. (2007) In B. Caldwell (Ed.), The road to serfdom. London: University of Chicago Press. Weijer, C. (2000). Ethical analysis of risk. Journal of Law Medicine and Ethics, 28, 344–361. Weijer, C., & Miller, P. B. (2004). When are research risks reasonable in relation to anticipated benefits? Nature Medicine, 10(6), 570–573. Wendler, D., & Miller, F. G. (2007). Assessing research risks systematically: The net risks test. Journal of Medical Ethics, 33, 481–486. World Medical Association. (2013). World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. Journal of the American Medical Association, 310(20), 2191–2194. Zarin, D. A., Tse, T., & Menikoff, J. (2014). Federal human research oversight of clinical trials in the United States. Journal of the American Medical Association, 311(9), 960–961.

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Deliberate Microbial Infection Research Reveals Limitations to Current Safety Protections of Healthy Human Subjects.

Here we identify approximately 40,000 healthy human volunteers who were intentionally exposed to infectious pathogens in clinical research studies dat...
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