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Drug and Vaccine Access in the Ebola Epidemic: Advising Caution in Compassionate UseDrug and Vaccine Access in the Ebola Epidemic FREE

Andrew Hantel, MD; and Christopher Olusola Olopade, MD, MPH
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 14 October 2014.


From the University of Chicago, Chicago, Illinois.

Acknowledgment: The authors thank Daniel Sulmasy, MD, PhD, and Nathaniel Steiger, MD, for their editorial work.

Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2002.

Requests for Single Reprints: Andrew Hantel, MD, University of Chicago, 5841 South Maryland Avenue, MC 7082, Chicago, IL 60637.

Current Author Addresses: Dr. Hantel: University of Chicago, 5841 South Maryland Avenue, MC 7082, Chicago, IL 60637.

Dr. Olopade: University of Chicago, 5841 South Maryland Avenue, MC 2121, Chicago, IL 60637.

Author Contributions: Conception and design: A. Hantel.

Analysis and interpretation of the data: C.O. Olopade.

Drafting of the article: A. Hantel, C.O. Olopade.

Critical revision of the article for important intellectual content: A. Hantel.

Final approval of the article: A. Hantel, C.O. Olopade.

Collection and assembly of data: C.O. Olopade.


Ann Intern Med. 2015;162(2):141-142. doi:10.7326/M14-2002
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An advisory panel to the World Health Organization (WHO) recently released a statement concluding that it is ethical to use experimental medications and vaccines that have not been formally approved—or even tested in humans—to treat persons with Ebola virus disease in the current West African outbreak (1). This epidemic has killed more than 2100 persons and has an estimated mortality of 55% to 70% (23). Thus far, 6 patients have been treated with ZMapp, an investigational, combination monoclonal antibody developed by Mapp Biopharmaceutical. Since receiving treatment, 4 of these patients have improved and 2 have died (3).

The WHO panel has affirmed the ethical validity of using unapproved medications and has made a concerted attempt to balance the potential benefits of treatment with unknown risks. The panel's position, although specific to the current epidemic, aligns with the expanded access regulations of the U.S. Food and Drug Administration, colloquially known as “compassionate use.” These regulations, along with the “animal rule” that governs medications only tested in animal models, are already in place to allow access to unapproved medications in conditions without alternative treatments and include a mandate to monitor and collect data during use (45). Even before the Ebola crisis, the application of these policies came with logistical and ethical controversy (6). In the current epidemic setting, the WHO panel mandates 3 ethical norms that raise unique and possibly insurmountable difficulties to providing expanded access: fairness in scarcity, informed consent and respect for the patient, and physician nonmaleficence. In addition, the “celebrity status” of investigational drugs distracts from an at least equally compelling need for standard supportive critical care that is essential in treating Ebola.

Triage in scarce, established treatments is often possible when the natural history of the disease, medication effects, and status of the patient are taken into account. Yet, with experimental treatments, few of these factors can be determined vis-à-vis the effect of the drug—one loses the ability to discern the patients likely to benefit. With this inability to properly triage, the consequences of misuse may be 3-fold: poorer outcomes for the “treated” severely ill population, missed opportunities for realistically treatable patients, and a possible induction of resistance that bears worse outcomes for future patients. The multinational setting of the epidemic magnifies these unknown inequalities. The proprietary nature of unregistered medications amplifies the strain between private supply and public demand. Possible secondary gains demand regulation that can never be attained within the epidemic time frame. These potential difficulties in transitional accountability bring to mind Pfizer's meningococcal meningitis trial, in which 200 Nigerian children were administered dose-reduced ceftriaxone or an unregistered medication, trovafloxacin, without informed consent. This led to a $75 million settlement, international outrage, and 11 deaths, all of which underscore physicians' responsibilities in human research (7).

Compounding issues raised by scarcity in experimental treatment is the inability of persons in an epidemic to give meaningful informed consent (7). This is multiplied by the likelihood that treating physicians could unknowingly cause harm. Participants consent to early-stage trials—which are done primarily for toxicity and dosing assessment rather than treatment—under the pretext that the trial is a rigorous, stepwise process to benefit future persons (8). When this paradigm is applied to the epidemic context, problems arise. Data collection is difficult in expanded access and may be impossible during an epidemic (7). Any data obtained to assess benefit or toxicity could have innumerable biases and misappropriations, making their application under current research standards impossible. The value of informed consent is also diminished because it lacks the pretext of risk acceptance to benefit others. In addition, physicians' ability to meaningfully inform vulnerable populations is overestimated. The belief that informed consent is understood by patients naive to advanced health care, especially in an epidemic, is cavalier (7). It belies participants' perceived risk and physicians' duty to abide by primum non nocere.

These difficulties in the application of expanded access are joined by the misguided attention and funding garnered by unregistered medications and vaccines. Novel treatments can add little to the underfunded areas that are bereft of standard critical care. Combined with public health efforts to stem disease transmission and provide public education, implementing routine hemodynamic support must be the focus of all involved organizations. Without early initiation of supportive care, Ebola can quickly lead to cardiovascular collapse and multiorgan failure (2). Consequently, an influx of health care personnel adequately supplied with intravenous fluids, catheters, safety needles, and personal protective equipment is the intercession most likely to curb the epidemic.

These interventions must be appropriately directed toward patient treatment and disease containment. Liberia, Guinea, and Sierra Leone have overwhelming infection rates and physician–patient ratios as low as 1 to 100 000 (3, 9). Case-fatality rates and health care personnel infections are highest and transmission is easiest in areas with overwhelming disease burden and population density (3, 9). Because thousands more cases are expected, we advocate for focusing experienced personnel and supplies at urban centers within these countries. Priority in these areas should be given to infected health care personnel whose ability to provide future treatment is critical (1). Next, supportive care should be directed at those with few comorbid conditions and early disease manifestations due to higher rates of recovery and lower rates of transmission to personnel (9). This strategy ethically stratifies care for affected patients while providing the best chance for epidemic containment.

Moving forward, the medical community must focus on implementing the current standard of care fairly and with maximum benefit while maintaining principled experimentation to provide a better future standard. As more novel medications and vaccines are considered for use, we advocate for a transparent and collaborative effort among all parties supplying and requesting treatments. Confirmation of informed consent by local experts should be required before experimentation, as advised by Nigeria's medical ethics panel (10). Data and safety monitoring and experimentation protocols, with plans for adequate drug supply to allow sufficiently powered research, must be prospectively provided. And in the end, the application of these policies must come second to providing proven therapy with supportive critical care.

References

World Health Organization.  Ethical considerations for use of unregistered interventions for Ebola viral disease: report of an advisory panel to WHO. Geneva: World Health Organization; 2014. Accessed at http://apps.who.int/iris/bitstream/10665/130997/1/WHO_HIS_KER_GHE_14.1_eng.pdf on 17 August 2014.
 
Gallagher J.  Ebola: Experimental drug ZMapp is ‘100% effective' in animal trials. BBC News. 29 August 2014. Accessed at www.bbc.com/news/health-28980153 on 26 September 2014.
 
Gallagher J.  Ebola: How bad can it get? BBC News. 5 September 2014. Accessed at www.bbc.com/news/health-29060239 on 26 September 2014.
 
U.S. Department of Health and Human Services.  Guidance for Industry: Expanded Access to Investigational Drugs for Treatment Use—Qs & As. Washington, DC: U.S. Department of Health and Human Services; 2013. Accessed at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf on 26 September 2014.
 
Sullivan NJ, Martin JE, Graham BS, Nabel GJ. Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule. Nat Rev Microbiol. 2009; 7:393-400.
PubMed
CrossRef
 
Dennis B, Cha AE.  ‘Right to Try' laws spur debate over dying patients' access to experimental drugs. The Washington Post. 16 May 2014. Accessed at www.washingtonpost.com/national/health-science/right-to-try-laws-spur-debate-over-dying-patients-access-to-experimental-drugs/2014/05/16/820e08c8-dcfa-11e3-b745-87d39690c5c0_story.html on 26 September 2014.
 
Annas GJ. Globalized clinical trials and informed consent. N Engl J Med. 2009; 360:2050-3.
PubMed
CrossRef
 
Faden RR, Beauchamp TL, Kass NE. Informed consent, comparative effectiveness, and learning health care. N Engl J Med. 2014; 370:766-8.
PubMed
CrossRef
 
World Health Organization.  Ebola situation in Liberia: non-conventional interventions needed. Geneva: World Health Organization; 2014. Accessed at www.who.int/entity/mediacentre/news/ebola/8-september-2014/en/index.htm on 26 September 2014.
 
Adebamowo C.  Statement on the use of innovative or non-validated medical treatment in Nigeria. Abuja, Nigeria: National Health Research Ethics Committee of Nigeria, Federal Ministry of Health; 2014. Accessed at http://nhrec.net/nhrec/statement-on-the-use-of-innovative-or-non-validated-medical-treatment-in-nigeria on 26 September 2014.
 

Figures

Tables

References

World Health Organization.  Ethical considerations for use of unregistered interventions for Ebola viral disease: report of an advisory panel to WHO. Geneva: World Health Organization; 2014. Accessed at http://apps.who.int/iris/bitstream/10665/130997/1/WHO_HIS_KER_GHE_14.1_eng.pdf on 17 August 2014.
 
Gallagher J.  Ebola: Experimental drug ZMapp is ‘100% effective' in animal trials. BBC News. 29 August 2014. Accessed at www.bbc.com/news/health-28980153 on 26 September 2014.
 
Gallagher J.  Ebola: How bad can it get? BBC News. 5 September 2014. Accessed at www.bbc.com/news/health-29060239 on 26 September 2014.
 
U.S. Department of Health and Human Services.  Guidance for Industry: Expanded Access to Investigational Drugs for Treatment Use—Qs & As. Washington, DC: U.S. Department of Health and Human Services; 2013. Accessed at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf on 26 September 2014.
 
Sullivan NJ, Martin JE, Graham BS, Nabel GJ. Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule. Nat Rev Microbiol. 2009; 7:393-400.
PubMed
CrossRef
 
Dennis B, Cha AE.  ‘Right to Try' laws spur debate over dying patients' access to experimental drugs. The Washington Post. 16 May 2014. Accessed at www.washingtonpost.com/national/health-science/right-to-try-laws-spur-debate-over-dying-patients-access-to-experimental-drugs/2014/05/16/820e08c8-dcfa-11e3-b745-87d39690c5c0_story.html on 26 September 2014.
 
Annas GJ. Globalized clinical trials and informed consent. N Engl J Med. 2009; 360:2050-3.
PubMed
CrossRef
 
Faden RR, Beauchamp TL, Kass NE. Informed consent, comparative effectiveness, and learning health care. N Engl J Med. 2014; 370:766-8.
PubMed
CrossRef
 
World Health Organization.  Ebola situation in Liberia: non-conventional interventions needed. Geneva: World Health Organization; 2014. Accessed at www.who.int/entity/mediacentre/news/ebola/8-september-2014/en/index.htm on 26 September 2014.
 
Adebamowo C.  Statement on the use of innovative or non-validated medical treatment in Nigeria. Abuja, Nigeria: National Health Research Ethics Committee of Nigeria, Federal Ministry of Health; 2014. Accessed at http://nhrec.net/nhrec/statement-on-the-use-of-innovative-or-non-validated-medical-treatment-in-nigeria on 26 September 2014.
 

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Ebola Virus Disease: Paving Inroads Into Drastic Diseases.
Posted on October 14, 2014
Stephen B. Strum, MD, FACP
International Strategic Cancer Alliance
Conflict of Interest: None Declared
Experience is a great teacher but man seldom learns from "history". In my own medical career as a cancer researcher and clinician spanning 51 years, I have personally seen impressive responses, involving complete and durable remissions, by combining diligent research into the peer-reviewed literature coupled with elements of intuition, daring, visionary thinking, collaboration with colleagues, open and honest communication and most of all, the prime directive: caring about the patient. I would be glad to share details of these medical inroads in another context.

When it comes to ebola virus disease (EVD), there is a dire need to bring together all the characteristics cited in the above paragraph in a Task Force or Manhattan Project spirit if we are to make swift and meaningful advances. Learning from history of what has been published and organizing, and most importantly sharing that information is key. I concur with much of the editorial by Hantel and Olopade. Supportive care of the patient with EVD must be center stage in any treatment approach. But I do not agree with a conservative approach when it comes to drastic diseases like ebola virus disease (EVD), which, if unchecked, may dwarf the death rates of the 1918 influenza pandemic.

Integrative care is a microcosm of what all of biology declares-- the oneness of our universe and the need to at the very least see ourselves as a global people with needs to work together in a sincerely integrative fashion. We must live up to our designation as homo sapiens (sentient man) and work internationally as scientists and healthcare workers, whose prime directive is resolution of all major threats to humankind. We are blatantly failing at this in the 21st century, in virtually every aspect of human interaction. EVD, in my opinion, is trumpeting the need, no actually it is signaling the demand for oneness on our pale blue dot. We need to bring EVD under control by working in concert i.e., in harmony. Yes, Carl Sagan, this is our uni-verse, our one story.
Cross-sectional bioinformatics analysis on proteins associated to the Ebola virus
Posted on October 19, 2014
Carlos Polanco, Jorge Alberto Castañón-González
Universidad Nacional Autónoma de México,Universidad Anáhuac
Conflict of Interest: None Declared
To the Editor:

We read the interesting Hantel and colleagues’ article (1) related to the adopted strategies taken by the international community to face the Ebola Virus Disease outbreak. They lead us to share some thoughts on cross-sectional bioinformatics studies around the proteins associated to this virus.

The multinational work in Bioinformatics has produced multiple specialized protein databases that contain thousands of proteins. It has taken years to gather and refine the information contained in these databases so we can perform with reasonable confidence prospective cross-sectional studies that will provide useful information oriented to the design of future drugs against the Ebola Virus.

What is the “protein distance” (range of variation of a group of proteins with some physic-chemical properties, and then compare those ranges with the variations of the amino acids forming that set of studied proteins) between Ebola Virus proteins, and those proteins associated with other viruses? Is it the same distance observed between their physical-chemical properties?

With a computer program (2), that essentially features a single physico-chemical property; the electronegativity (3,4) measured in the polar interactions of amino acids that form the linear sequence of a protein, we identified the action of several groups of antimicrobial-antiviral peptides.

The outbreak of Ebola Virus Disease is on, the spread of the disease and the loss of human lives are already counting (5), so the generation of drugs aimed to treat this devastating disease or any other must explore all the possibilities at hand.

1. Hantel A, Olusola Olopade C. Drug and Vaccine Access in the Ebola Epidemic: Advising Caution in Compassionate Use. Ann Intern Med. Published online 14 October 2014 doi:10.7326/M14-2002

2. Pauling L. The Nature of the Chemical Bond and the Structure of Molecules and Crystals: An Introduction to Modern Structural Chemistry. Cornell University Press, ISBN:9780801403330, USA. 1960. pp. 644.

3. Polanco C, Samaniego JL, Buhse T, Mosqueira FG, Negron-Mendoza A Ramos-Bernal S, Castañón-González JA. Characterization of Selective Antibacterial Peptides by Polarity Index. International Journal of Peptides 2012,58502, doi:10.1155 /2012/585027

4. Howard SJ, Hopwood S, Davies SC. (Letter Polanco C, Castañón-González JA, Samaniego-Mendoza JL. Buhse T. 2014) Antimicrobial Resistance: A Global Challenge. Sci. Transl. Med doi: 10.1126/ scitranslmed.3009315

5. Butler D, Morello L. Ebola by the numbers: The size, spread and cost of an outbreak. Nature 514, 284–285. doi: 10.1038/514284a
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