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Annotated Bibliography

Core Articles:

“It is essential that steps be taken immediately to remedy the current shortage of drugs – not only in anesthesia and critical care but also in therapeutic areas, such as oncology and infectious diseases. Such steps might include legislation requiring manufacturers to provide adequate notification to federal and provincial authorities of any impending shortage, so that stockpiling and contingency planning can occur. Penalties should be levied if such steps do not occur. In the event of an unpredictable disaster or interruption in supply, there should be contingency supplies available for drugs deemed essential. While pharmaceutical companies have the right to determine which products they develop and manufacture, there are certain critical drugs that may not be profitable (e.g., morphine, ephedrine, norepinephrine) but are essential for the health of Canadians. Policy remedies to ensure an uninterrupted supply of all essential medications are easily imagined.”

“Drug shortages are emerging as a major public health threat. Grave concern has been expressed by the medical community and government officials, and the crisis has been highlighted in recent media stories. Nevertheless, little has been written to date in the legal literature about the drug shortage crisis, and this timely article begins to fill this gap. It provides a thorough analysis of the origins and implications of the drug shortage problem and formulates a multi-layered approach to addressing it. The article argues that drug shortages result from a combination of market failures and regulatory constraints. It proposes a blend of legislative, regulatory, and private-sector interventions that should deter undesirable conduct on the part of manufacturers and provide appropriate incentives to combat the drug shortage phenomenon.”

“Drug supply shortages are common in health systems due to manufacturing and other delays. Frequently, shortages are successfully addressed through conservation and redistribution efforts, with limited impact on patient care. However, when Sandoz Canada Inc. announced in February 2012 that it was reducing production of a number of generic injectable drugs at its Quebec facility, the scope and magnitude of the drug supply shortage were unprecedented in Canada. The potential for an extreme scarcity of some drugs raised ethical concerns about patient care, including the need to limit access to some health services. In this article, the authors describe the development and implementation of an ethical framework to promote equitable access to drugs and healthcare services in the context of a drug supply shortage within and across health systems.”

“There are numerous causes for the escalating drug shortage crisis, but in our view, none are as powerful as simple economics. The most straightforward solution is to change the way generic sterile injectables are reimbursed. As suggested earlier, if the generic drug price is kept at 5% to 10% of the brand drug price, and/or the ASP plus 6% reimbursement is modified to an ASP plus 10% to 20%, the profit margin will remain reasonable, and generic drug companies will have adequate incentive to continue to supply the drug. There may be other approaches to financial incentives that would achieve the same end, and such suggestions would be welcome. Although some experts worry about increasing the cost of care, it should be noted that: first, increasing generic drug prices, which account for 2% of the total cost of chemotherapy drugs, will have a minimal effect on the total cost of cancer care; second, the continuing drug shortages may be costing as much as $200 to $300 million per year; third, money can be saved if oncologists have access to reasonably priced generic drugs; fourth, increased costs attributable to the gray market will be eliminated; and fifth, medical errors caused by changing to untested practices will be reduced.”

“Over the past several years, patients and caregivers have faced an increasing number of drug shortages, predominantly of generic injectable agents. The reasons for these shortages are complex. Narrow profit margins for generic drugs have limited the incentive to produce them. Other reasons include the limited number of manufacturers, increased worldwide demand, shortages of raw materials, production problems, aging production plants, stockpiling, and long timelines for approval. Patient care may suffer significantly as a result: alternative drugs must be prescribed, but the replacement may be less efficacious, more toxic, prohibitively expensive, or all of the above, and safety may be compromised if providers are unfamiliar with administering the substitute.”

This article summarizes the steps that the FDA and the oncology community have taken together to address the problems of medication shortages.   Also, it goes on to explain that there are many remaining challenges regarding this issue, including: growth in demand while manufacturing remains stable, production delays, discontinuation of older drugs, etc.

“Ethanol lock therapy (ELT) has been shown to reduce the incidence of catheter-related blood stream infections (CRBSI) in intestinal failure (IF) patients. Dosing and frequency remains undefined. Scrutiny of pharmaceutical facilities by the Food and Drug Administration led to the voluntary shutdown of the sole supplier of ethanol, resulting in a nationwide shortage. To conserve supply, we reduced ELT frequency from a daily regimen. We examined the impact that reduction in ELT frequency had on CRBSI in pediatric IF patients.”

“Although President Obama issued an executive order last October directing federal agencies to deal with the ongoing drug shortage and to look into the price gouging taking place in the so-called gray market (seeJ. Natl. Cancer Inst. online Jan. 23, 2012), frustration continues to build among oncology professionals trying to meet patients’ needs. Meanwhile, little coordination seems to exist among federal agencies.”

“The number of critical medication shortages in the United States has reached an unprecedented level, requiring decisions about allocating limited drug supplies. Ad hoc decisions are susceptible to arbitrary judgments, revealing preformed biases for or against groups of people. Health care institutions lack standardized protocols for rationing scarce drugs. We describe the principles on which an ethically justifiable policy of medication allocation during critical shortages was created at our hospital. Based on supportable scientific evidence and with all clinically similar patients treated as similarly deserving of consideration, drugs were distributed according to a hierarchy of clinical need and predicted efficacy. We explain the ethical rationale for the procedures we adopted, how the policy was implemented at a large academic medical center, and more than 1 year of experience with a number of different medications. Our experience has demonstrated the feasibility and utility of formulating a rational and ethically sound policy for scarce resource allocation in an academic teaching hospital that could be used in a variety of health care settings. The method has proven to be reliable, workable, and acceptable to clinicians, staff, and patients.”

“Although most public concern about sporadic shortages of generic drugs focuses on effects on patients and clinicians in community practice, the shortages are also delaying progress in many clinical trials, especially in oncology. At least 22 drugs on the FDA’s drug shortage list last winter were cancer drugs, and an estimated half of the 400 NCI-funded trials actively recruiting patients had at least one drug on the list, according to the Coalition of Cancer Cooperative Groups.”

“For the first time in the United States, some essential chemotherapy drugs are in short supply. Most are generic drugs that have been used for years in childhood leukemia and curable cancers — vincristine, methotrexate, leucovorin, cytarabine, doxorubicin, bleomycin, and paclitaxel. The shortages have caused serious concerns about safety, cost, and availability of lifesaving treatments. In a survey from the Institute for Safe Medication Practices, 25% of clinicians indicated that an error had occurred at their site because of drug shortages. Many of these errors were attributed to inexperience with alternative products — for instance, incorrect administration of levoleucovorin (Fusilev) when used as a substitute for leucovorin or use of a 1000-mg vial of cytarabine instead of the usual 500-mg one, resulting in an overdose. Most cancer centers quadruple-check drugs for accuracy, and we’re unaware of any documented death of a patient with cancer such as the nine deaths in Alabama attributable to the use of locally compounded liquid nutrition because the sterile product was not available. However, it is only a matter of time.”

“While the oncology community has been focusing much of its attention on the remarkable activity and enviable science related to the discovery of targeted drugs, the importance of standard cytotoxic therapeutics has suddenly become apparent, owing to shortages of the common workhorses of cancer treatment — methotrexate, leucovorin, 5-fluorouracil, cytosine arabinoside, vincristine, etoposide, the anthracyclines, paclitaxel, cisplatin, and others. The list of generic drugs in short supply across all medical specialties is astounding and includes antibiotics, anesthetic agents, antihypertensive medications, and common electrolyte solutions and vitamins. These shortages, which primarily affect injectable generic drugs, have forced physicians to prioritize patients, improvise standard regimens (substituting capecitabine for 5-fluorouracil, for example, in adjuvant therapy for colorectal cancer), and at times, choose unproven treatment options for patients with curable disease. The National Cancer Institute has watched with increasing concern as common drugs have disappeared from the shelves of cancer-center pharmacies, threatening the completion of research protocols.”

“A nationwide shortage of many cancer drugs shows signs of easing, at least temporarily, according to officials at the U.S. Food and Drug Administration. But sudden shifts in drug availability remain a concern, placing cancer patients at continuing risk for harm, doctors say.”

“The issue of drug availability appears to be getting worse and will continue to compromise the delivery and cost of health care. All stakeholders must collaborate so the best decisions are made on behalf of patients and all people involved are informed.”

“The increasing frequency of drug shortages creates complex challenges for health care providers and facilities. Drug shortages have a profound impact on patient safety, clinical outcomes, quality control, health care facility management, and other important factors. Although it is impossible to predict or prepare for every drug shortage, careful planning can prevent the consequent problems from turning into a crisis. Establishing clear procedures and guidelines for managing drug shortages is essential. Proper information-gathering, extensive collaboration, and timely communication strategies are critical elements of an effective drug shortage management plan.”

“We evaluate eight simple allocation principles that can be classified into four categories: treating people equally, favouring the worst-off, maximising total benefits, and promoting and rewarding social usefulness. No single principle is sufficient to incorporate all morally relevant considerations and therefore individual principles must be combined into multiprinciple allocation systems. We evaluate three systems: the United Network for Organ Sharing points systems, quality-adjusted life-years, and disability-adjusted life-years. We recommend an alternative system-the complete lives system-which prioritises younger people who have not yet lived a complete life, and also incorporates prognosis, save the most lives, lottery, and instrumental value principles.”

Articles Related to Drug Shortages:

“Periodic and unexpected shortages of drugs, biologics, and even medical devices have become commonplace in the United States. When shortages occur, hospitals and clinics need to decide how to ration their available stock. When such situations arise, institutions can choose from several different allocation schemes, such as first-come, first-served, a lottery, or a more rational and calculated approach. While the first two approaches sound reasonable at first glance, there are a number of problems associated with them, including the inability to make fine, individual patient-centered decisions. They also do not discriminate between what kinds of patients and what types of uses may be more deserving or reasonable than others. In this article I outline an ethically acceptable procedure for rationing drugs during a shortage in which demand outstrips supply.”

Transcript of interview conducted of members of the ASHP on formulary management including drug shortage management (towards the end of the article).  The team explains that they use a variety of strategies to combat the problem of drug shortages including: rationing, alternatives, use restrictions and therapeutic interchange.

“Drug shortages present a serious dilemma for healthcare organizations. To successfully manage drug shortage situations, organizations need to have a standardized, rational process in place. This article discusses the clinical, ethical, and legal processes behind the development of a strategy to manage limited supplies of a intravenous immunoglobulin (IVlG). Although the example is specific, the approach presented can be applied by other healthcare organizations to address other impending drug shortage situations.”

Scarcity of Organs/Transplant:

Study on the committees that decide whether or not to list patients for  liver transplantation.  Because replacement livers are not easy to come by this is also a study in the allocation of scarce resources.  The study found that although the listing procedure varies from hospital to hospital there are some underlying similarities, namely the use of inductive reasoning.  Patients were excluded from the list for various psychosocial and medical reasons.   Furthermore, “The difficult decisions made by liver transplant committees are reasonably consistent and well-intentioned, but the process might be improved by having more explicit written policies and clarifying roles.”

UK study on the availability of organs for transplant purposes.  The article discusses the, “potential for a conflict between public and clinical priorities with legal requirements and this may lead to challenge in the courts.”  The study recommends that allocation policies for organs be as transparent and well defined as possible and always defer to evidence over assumption.

“A new Israeli law has been instituted to give those who sign donor cards allocation priority if they are ever in need of an organ transplant themselves.”… “Prioritization of organ allocation to donors comes with a significant moral and ethical debate, and since its implementation in January 2010 there has been much controversy surrounding the new policy. This article provides a description of the new Israeli plan, specifically focusing on the practical, moral, and ethical debates surrounding the new system.”

“The aim of the Life Years from Transplantation (LYFT) proposal is to allocate kidneys to patients who obtain the greatest survival benefit from transplantation, which would lengthen the lives of kidney transplant recipients but restrict the ability of older Americans to obtain a transplant. The debate around the LYFT proposal reveals the ethical and policy challenges of identifying which patients should receive a treatment based on the results of cost-effectiveness and other HTA studies. This article argues that attempts to use HTA for healthcare rationing are likely to disadvantage older patients.”

“Community preferences for organ allocation hinge on a complex balance of efficiency, social valuation, morality, fairness, and equity principles. Being a community-held resource, effective ways to identify and incorporate community preferences into allocation algorithms for solid organ transplantation are warranted.”

A study that is composed of a review of community preferences regarding organ allocation and the underlying issues that surround it. The study concludes that multiple factors are at play including: social valuation, morality, fairness, and equity principles.  Because the organs are a resource that the whole community uses, community preferences are valid regarding this issue.

“Congress charged the National Academy of Sciences, Institute of Medicine to perform an independent study of the original [organ transplantation] system and proposed rule changes. In an analysis of approximately 68,000 transplant waiting list records, the committee developed several conclusions and recommendations largely specific to liver transplantation policies. The purpose of this paper is to describe both the results of the study and the statistical foundations of the mixed-effects multinomial logistic regression model that led to the committee’s conclusions.”

“This paper results on the use of a multi-criterion decision-making system (MCDM) analyzing a group process in an attempt to better define hospital policy. In a pilot program at The Hospital for Sick Children, Toronto, a series of small scale focus groups was constituted to examine criteria defining organ transplant eligibility.”

Scarcity of Resources:

Study on, “optimal scarce resource-rationing principle in the emergency response domain, considering the trade-off between lifesaving efficiency and ethical issues.”  The “least serious” principle performs best but is not without ethical problems.  We must consider the CBA (cost benefit analysis) between efficiency of process and ethical issues.

“Pandemic influenza may exacerbate existing scarcity of life-saving medical resources. As a result, decision-makers may be faced with making tough choices about who will receive care and who will have to wait or go without.”….” Our findings underscore the importance of public consultation in pandemic planning for sustaining public trust in a public health emergency.”  Furthermore, “Policymakers may benefit from a better understanding the public’s empirical and ethical ‘starting points’ in developing effective pandemic plans.”

This article investigates “the views of students, support staff and academic staff at the University of Alberta in Edmonton, Canada on the allocation of scarce resources during an influenza pandemic to discover if there were any shared values.”

“This paper briefly explores the ethics-related challenges associated with the development of modern critical care triage protocols and provides descriptions of some ‘enhanced fairness’ features which were developed through the use of an inclusive deliberative engagement process by a Canadian provincial Department of Health.”

This paper concludes that ethical consultation in questions of scarcity would “facilitate the achievement of several practical goals.”  Namely: it would encourage efficiency, encourage awareness, encouragement of reflection and justification, improvement in external and internal transparency, prevent misuse.

“This paper presents a decision-making model for clinicians that is based upon the bioethical principles of beneficence and justice. The model begins with the basic assumptions of triage and progresses into a useful algorithm based upon utilitarian principles. The model is intended to be used as a guide for clinicians in making decisions about the allocation of scarce resources in a just manner and to serve as an impetus for institutions to create or adapt plans to address resource allocation issues should the need arise.”

“We analyze the ethical principles that could guide allocation and propose an allocation strategy that incorporates and balances multiple morally relevant considerations…” These considerations include: number of lives saved, number of years saved for each life, and prioritizing patients with the lowest chance of survival.   Furthermore: “we also argue that these principles are relevant to all patients and therefore should be applied to all patients, rather than selectively…”

“This article applies developing concepts of mass critical care (MCC) to children. In public health emergencies (PHEs), MCC would improve population outcomes by providing lifesaving interventions while delaying less urgent care. If needs exceed resources despite MCC, then rationing would allocate interventions to those most likely to survive with care. Gaps between estimated needs and actual hospital resources are worse for children than adults.”… “To ration MCC to children most likely to survive, the Pediatric Index of Mortality 2 score meets the criteria for validated pediatric mortality predictions. Policymakers must define population outcome goals in regard to lives saved versus life-years saved.”

In the case of an influenza pandemic medical resources will become scarce.  This paper discusses two general principles for the allocation of these resources: utility and equity.  This report also explains how these two principles will not always line up exactly with each other, but where the “points of convergence” are.  These points of convergence include: saving the most lives, prioritizing children, giving priority to life-saving responders.  Furthermore the paper, “tentatively argue[s] that constraints on people’s freedom, as necessary for an effective public health approach, may support giving somewhat more weight to saving the most lives, than to concerns of equity.”

“In healthcare, a tension sometimes arises between the injunction to do as much good as possible with scarce resources and the injunction to rescue identifiable individuals in immediate peril, regardless of cost (the “Rule of Rescue”)…. In this paper we explore the appropriate role of the Rule of Rescue in public resource allocation decisions by health technology funding advisory bodies such as the National Institute for Health and Clinical Excellence. We consider practical approaches to operationalising the Rule of Rescue from Australia and the UK before examining the relevance of individual moral imperatives to public policy making. We conclude that whilst public policy makers in a humane society should facilitate exceptional departures from a cost effectiveness norm in clinical decisions about identified individuals, it is not so obvious that they should, as a matter of national public policy, exempt any one group of unidentified individuals within society from the rules of opportunity cost at the expense of all others.”

“Whereas the annual influenza season in the United States is fairly predictable, the influenza vaccine supply is variable, leaving providers vulnerable to supply and demand fluctuations each season. During the 2004-2005 influenza vaccine shortage, Oregon invoked Oregon Revised Statute 433-030 to target vaccine supplies to protect persons at highest risk for complications from influenza. This case study describes Oregon’s efforts to ration vaccine at the point of administration by limiting the number of individuals eligible for vaccination. An evaluation of this process found that providers responded positively to the mandatory prioritization of vaccine recipients; however, limitations in assessing and affecting redistribution of privately held vaccine supplies and challenges in enforcement of the plan were revealed.”

“Comparatively little attention has been paid to examining the institutional conditions within which priority setting decisions are made. We review a case study of priority setting in hospital operational planning in Toronto, which had been designed by executive leaders to be broadly inclusive of senior and middle-level clinical and administrative leaders. We report three power differences that arose as limiting factors on the inclusiveness of the priority setting process. We argue that these findings have significant theoretical implications for the accountability for reasonableness framework and propose a fifth condition, the “empowerment condition”, which states that there should be efforts to minimise power differences in the decision-making context and to optimise effective opportunities for participation in priority setting.”

“The impact of drug shortages on patient care, the resources used to manage drug shortages, and the cost associated with drug shortages were studied.”… “A national survey indicated that drug shortages are having a significant impact on patient care activities and finances in hospitals.”

Misc.

“Although access to medicines is a vital feature of the right to the highest attainable standard of health (“right to health”), almost two billion people lack access to essential medicines, leading to immense avoidable suffering. While the human rights responsibility to provide access to medicines lies mainly with States, pharmaceutical companies also have human rights responsibilities in relation to access to medicines. This article provides an introduction to these responsibilities. It briefly outlines the new UN Guiding Principles on Business and Human Rights and places the human rights responsibilities of pharmaceutical companies in this context. The authors draw from the work of the first UN Special Rapporteur on the right to the highest attainable standard of health, in particular the Human Rights Guidelines for Pharmaceutical Companies in Relation to Access to Medicines that he presented to the UN General Assembly in 2008, and his UN report on GlaxoSmithKline (GSK).”

This paper addresses three main issues concerning the ethical distribution of resources: justice, how to deal with arbitrary dispersal of resources, and how do we determine the order in which claimants are helped.  “My conclusion is that not ignoring prior receipt of the same medical resource, and prioritizing those who have not previously had access to the medical resource in question, may be perceived as fairer and more equitable by society.”

“This review gives a systematic overview on physicians’ perspectives on influences, strategies, and consequences of health-care rationing…. Retrieved studies focused on themes that fell under three major headings: (i) conditions and influences of BSR, (ii) strategies of BSR, and (iii) consequences of BSR”

Government and Professional Organizations:

“This document represents the Working Guidelines to be operationalized in decision-making going forward. However, this is a living document. Feedback will continue to be received and discussed, and changes receiving consensus agreement from the Provincial Planning Group will be incorporated into the Working Guidelines. While the focus of this document is on the question of allocation criteria, it should be seen as a resource of last resort. The ethics of responding to drug shortages begins with efforts of collaboration, communication and planning to avoid the need for this kind of allocation.”

“The current class-wide shortages in the industry appears to be a consequence of a substantial expansion in the scope and volume of products produced by the industry that has occurred over a short period of time, without a corresponding expansion in manufacturing capacity.  While several manufacturers are currently expanding capacity, most of this capacity will not become available for several years.  The expansion in product scope and quantity, in turn, stems from both an increase in the overall volume of chemotherapy drugs used and an unusually high rate of patent expirations in this sector that began in 2008 and has continued through 2010.  While the generic industry is highly competitive in the long run, the supply of products is constrained in the short-run, because it takes several years for new firms to enter or for existing firms to add capacity.  In the short run, existing firms make strategic decisions about how to deploy production capacity among products, based on their conjectures about what choices their competitors will make.”

“Drug and other medical product shortages have the potential to adversely affect patient care by delaying treatment or forcing the use of second-choice products. Some recent shortages have involved drugs for life-threatening conditions and, in some cases, the product in shortage has been the only product for the patient’s condition. This is a significant public health problem, one that deserves the concerted attention of government and industry.”

Drug Shortage Committee was formed to address the issues of drug shortages and to develop an, “assertive action plan that reflects the recommendations and intent of stakeholders to work together to stop patient harm and disruptions in patient care caused by drug shortages.”

General study commissioned by the CDC on the ethical concerns that would be raised during a potential influenza pandemic, with special consideration applied to vaccines, antiviral drug distribution, and community mitigation interventions.

A report on the working group convened Massachusetts Department of Public Health and the Harvard School of Public Health Center for Public Health Preparedness.  The group contained ethicists, lawyers, clinicians and state public health officials.   The group considered the issues of: antiviral medication, prioritization of critical care, and state seizures of private assets. The group identified 4 goals and 7 principles to help guide further discussion of this topic.

Paper studying the shortage of drugs in hospitals and health systems.  Paper concludes that proper planning although potentially impractical can help prepare health care systems for unexpected shortages. Paper outlines several different facets of successful planning strategy including: information gathering, teamwork to assess options and communication with all interested parties.

News:

NPR article that profiles children with Lymphoma who cannot obtain access to necessary drugs.

Article details the recent ruling by a federal court that will allow a patient to proceed with a lawsuit against a pharmaceutical company in which she charged that the company, “breached its responsibility to supply patients with a needed medicine.”

Article detailing how a shortage of drugs used to prevent IV-related infections in children led to a ten-fold increase of infections at a Michigan hospital.

“Probably to their great disappointment, President Obama’s critics cannot blame this rationing on death panels or health care reform. Rather, it is caused by a severe shortage of important cancer drugs.”

“This month, a shortage of another cancer drug, cytarabine, a crucial drug for many leukemia patients, including children, drew an outcry from oncologists around the country who warned that hospitals were being forced to ration the drug and delay some patients’ treatments or give them less effective therapies. “It’s a nightmare,” says Hagop Kantarjian, chair of the leukemia department at MD Anderson Cancer Center in Houston, Texas. Kantarjian penned a commentary in The Washington Post last week after querying 8000 colleagues about the shortage via newsletter and receiving “about 200 e-mails with horror stories,” he says. By week’s end, the crisis, which began last fall and worsened this year, eased as vials of cytarabine became available.”

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