Re: Did the FDA break its own rules in approving the antibiotic Recarbrio?
Dear Editor
Doshi and Ross point out questionable social value and scientific validity in studies of antibiotics.[1-3] The study design was incapable of addressing whether the drug combination improved efficacy for patients compared to the older drug alone. The principal investigator acknowledged the drug would be targeted in practice to patient types other than those enrolled. This highlights an ethical problem with exposing study participants to harm without any potential benefit to themselves and using participants simply as a means to an end to gain market approval. Despite these ethical concerns, this situation was framed as “just the way things are” and “the pathway through the FDA” to bring more drugs to market.[1]
Research shows these issues are common in antibiotic studies.[4,5] How are ethical/institutional review boards (IRBs) and regulatory agencies allowing these studies to proceed, given the violation of international basic ethical principles articulated over 50 years?
The public recoiled in disbelief when ethical abuses in the Tuskegee syphilis study, the Willowbrook hepatitis study, and the Pfizer meningitis trials in Nigeria were brought to light. The common theme - patients were enrolled in research exposing them to harm for no benefit to themselves. These episodes led to meaningful reforms to prevent unethical exploitation of research volunteers. Major reforms included establishing IRBs charged with preventing unethical conduct of research and enactment of the Kefauver-Harris amendments to FDA legislation to assure new drugs are demonstrated to be safe and effective.
Yet these safeguards still routinely fail the public. As this investigation shows, new drugs are approved in the absence of demonstrated improved efficacy due to invalid study design. In antibiotic development misuse of so-called “non-inferiority (NI) trials” are common.[4,5] The goal of this poorly-named hypothesis is evaluating whether new drugs are no worse than (not “just as effective as”) existing effective drugs by some amount chosen by drug companies and regulators.[6,7] NI is ethical in evaluating new drugs when there is trade-off of small losses of efficacy for non-efficacy benefits like decreased adverse effects. NI does not evaluate whether new drugs have improved efficacy, which should be the research question in addressing antibiotic-resistant disease. In acute life-threatening diseases, NI violates the Declaration of Helsinki which states participants should not be exposed to any drug less effective than the best available when irreparable harm can result.[8] Exposing volunteers to harm for no benefit also violates the principles of justice and beneficence in the Belmont Report.[9]
Furthermore, research shows volunteers are not informed in consent that worse efficacy of the new drug is hypothesized in NI, violating the principle of respect for persons.[9,10] According to the Common Rule consent forms need to include clear, easy to understand language describing key information helpful to potential participants in understanding why they might or might not participate in trials.[11]
In the US, the record is clear. IRBs routinely fail to protect volunteers from unethical research. Volunteers cannot trust trials are asking questions worth answering or that the research design is capable of generating reliable answers. Consequently, they cannot trust there are reasonable balances between risks and benefits. Nor can they trust they will be given vital information required as a part of informed consent. Furthermore, the FDA is not fulfilling its mission to advance public health and bring only safe and effective drugs to market. These failures should prevented through new policies that increase transparency and hold all accountable. IRBs should also be proactive in taking their job to protect the public seriously particularly with respect to monitoring the quality of design, the adequacy of consent, and the need for any given clinical research study.
References:
1. Doshi P. Did the FDA break its own rules in approving the antibiotic Recarbrio? BMJ. May 15 2023;381:p1048. doi:10.1136/bmj.p1048
2. Ross DB. The decline of science at the FDA has become unmanageable. BMJ. May 15 2023;381:p1061. doi:10.1136/bmj.p1061
3. Freedman B. Scientific value and validity as ethical requirements for research: a proposed explication. IRB. Nov-Dec 1987;9(6):7-10.
4. Mitra-Majumdar M, Powers JH, Brown BL, Kesselheim AS. Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs. BMJ Med. 2022;1(1):e000227. doi:10.1136/bmjmed-2022-000227
5. Yahav D, Tau N, Shepshelovich D. Assessment of Data Supporting the Efficacy of New Antibiotics for Treating Infections Caused by Multidrug-resistant Bacteria. Clin Infect Dis. Jun 01 2021;72(11):1968-1974. doi:10.1093/cid/ciaa457
6. Mauri L, D'Agostino RB. Challenges in the Design and Interpretation of Noninferiority Trials. N Engl J Med. Oct 2017;377(14):1357-1367. doi:10.1056/NEJMra1510063
7. Acuna SA, Chesney TR, Baxter NN. Incorporating Patient Preferences in Noninferiority Trials. JAMA. Jun 2019;doi:10.1001/jama.2019.7059
8. World Medical Association. Declaration of Helsinki. http://www.wma.net/en/30publications/10policies/b3/
9. US Department of Health and Human Services. Ethical Principles and Guidelines for the Protection of Human
Subjects of Research: the Belmont Report. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html
10. Doshi P, Hur P, Jones M, et al. Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011. JAMA Intern Med. Oct 2017;177(10):1-8. doi:10.1001/jamainternmed.2017.3820
11. US Department of Health and Human Services. The Common Rule. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/in....
Competing interests:
Dr Powers is a consultant on clinical study design over the last three years for: AdaptivePhage, Arrevus, Atheln, Bavaria, Nordic, Capricor, Cellularity, Eicos, Evofem, Eyecheck, Gilead, GSK, Mustang, OPKO, Otsuka, Resolve, Romark,SpineBioPPharma, UTIlity. Dr Wilkes and Dr Yarborough have no conflicts of interest to declare.
Rapid Response:
Re: Did the FDA break its own rules in approving the antibiotic Recarbrio?
Dear Editor
Doshi and Ross point out questionable social value and scientific validity in studies of antibiotics.[1-3] The study design was incapable of addressing whether the drug combination improved efficacy for patients compared to the older drug alone. The principal investigator acknowledged the drug would be targeted in practice to patient types other than those enrolled. This highlights an ethical problem with exposing study participants to harm without any potential benefit to themselves and using participants simply as a means to an end to gain market approval. Despite these ethical concerns, this situation was framed as “just the way things are” and “the pathway through the FDA” to bring more drugs to market.[1]
Research shows these issues are common in antibiotic studies.[4,5] How are ethical/institutional review boards (IRBs) and regulatory agencies allowing these studies to proceed, given the violation of international basic ethical principles articulated over 50 years?
The public recoiled in disbelief when ethical abuses in the Tuskegee syphilis study, the Willowbrook hepatitis study, and the Pfizer meningitis trials in Nigeria were brought to light. The common theme - patients were enrolled in research exposing them to harm for no benefit to themselves. These episodes led to meaningful reforms to prevent unethical exploitation of research volunteers. Major reforms included establishing IRBs charged with preventing unethical conduct of research and enactment of the Kefauver-Harris amendments to FDA legislation to assure new drugs are demonstrated to be safe and effective.
Yet these safeguards still routinely fail the public. As this investigation shows, new drugs are approved in the absence of demonstrated improved efficacy due to invalid study design. In antibiotic development misuse of so-called “non-inferiority (NI) trials” are common.[4,5] The goal of this poorly-named hypothesis is evaluating whether new drugs are no worse than (not “just as effective as”) existing effective drugs by some amount chosen by drug companies and regulators.[6,7] NI is ethical in evaluating new drugs when there is trade-off of small losses of efficacy for non-efficacy benefits like decreased adverse effects. NI does not evaluate whether new drugs have improved efficacy, which should be the research question in addressing antibiotic-resistant disease. In acute life-threatening diseases, NI violates the Declaration of Helsinki which states participants should not be exposed to any drug less effective than the best available when irreparable harm can result.[8] Exposing volunteers to harm for no benefit also violates the principles of justice and beneficence in the Belmont Report.[9]
Furthermore, research shows volunteers are not informed in consent that worse efficacy of the new drug is hypothesized in NI, violating the principle of respect for persons.[9,10] According to the Common Rule consent forms need to include clear, easy to understand language describing key information helpful to potential participants in understanding why they might or might not participate in trials.[11]
In the US, the record is clear. IRBs routinely fail to protect volunteers from unethical research. Volunteers cannot trust trials are asking questions worth answering or that the research design is capable of generating reliable answers. Consequently, they cannot trust there are reasonable balances between risks and benefits. Nor can they trust they will be given vital information required as a part of informed consent. Furthermore, the FDA is not fulfilling its mission to advance public health and bring only safe and effective drugs to market. These failures should prevented through new policies that increase transparency and hold all accountable. IRBs should also be proactive in taking their job to protect the public seriously particularly with respect to monitoring the quality of design, the adequacy of consent, and the need for any given clinical research study.
References:
1. Doshi P. Did the FDA break its own rules in approving the antibiotic Recarbrio? BMJ. May 15 2023;381:p1048. doi:10.1136/bmj.p1048
2. Ross DB. The decline of science at the FDA has become unmanageable. BMJ. May 15 2023;381:p1061. doi:10.1136/bmj.p1061
3. Freedman B. Scientific value and validity as ethical requirements for research: a proposed explication. IRB. Nov-Dec 1987;9(6):7-10.
4. Mitra-Majumdar M, Powers JH, Brown BL, Kesselheim AS. Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs. BMJ Med. 2022;1(1):e000227. doi:10.1136/bmjmed-2022-000227
5. Yahav D, Tau N, Shepshelovich D. Assessment of Data Supporting the Efficacy of New Antibiotics for Treating Infections Caused by Multidrug-resistant Bacteria. Clin Infect Dis. Jun 01 2021;72(11):1968-1974. doi:10.1093/cid/ciaa457
6. Mauri L, D'Agostino RB. Challenges in the Design and Interpretation of Noninferiority Trials. N Engl J Med. Oct 2017;377(14):1357-1367. doi:10.1056/NEJMra1510063
7. Acuna SA, Chesney TR, Baxter NN. Incorporating Patient Preferences in Noninferiority Trials. JAMA. Jun 2019;doi:10.1001/jama.2019.7059
8. World Medical Association. Declaration of Helsinki. http://www.wma.net/en/30publications/10policies/b3/
9. US Department of Health and Human Services. Ethical Principles and Guidelines for the Protection of Human
Subjects of Research: the Belmont Report. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html
10. Doshi P, Hur P, Jones M, et al. Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011. JAMA Intern Med. Oct 2017;177(10):1-8. doi:10.1001/jamainternmed.2017.3820
11. US Department of Health and Human Services. The Common Rule. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/in....
Competing interests: Dr Powers is a consultant on clinical study design over the last three years for: AdaptivePhage, Arrevus, Atheln, Bavaria, Nordic, Capricor, Cellularity, Eicos, Evofem, Eyecheck, Gilead, GSK, Mustang, OPKO, Otsuka, Resolve, Romark,SpineBioPPharma, UTIlity. Dr Wilkes and Dr Yarborough have no conflicts of interest to declare.