Ethical Dilemmas in Rare Diseases
Scientists continue to make research advancements by creating specialized and highly effective therapies for many diseases and disorders, moving the population toward a better quality of life. It was fourteen years ago that Gail Attara, our president and chief executive officer, wrote about the advent of biologic medicines for Crohn’s disease and ulcerative colitis and foreshadowed the many biologics in development for other conditions that have no adequate treatment available.1 Now, tens of thousands can access these life changing treatments and these numbers will only grow as more innovative therapies come to Canada. However, there are some changes to drug pricing regulations that might seriously affect what medications come to Canada, which we will discuss below.
As medicines improve and address gaps in care, it is crucial to remember that opportunities arrive at a cost. Concerns with healthcare expenses dominate conversations among decision-makers and public payers (i.e., government drug plans), particularly how to best afford and deliver innovative therapies to people who need them the most while balancing a public budget. Decisions on which medicines to approve for coverage affect everyone living with a disease, especially those who have a rare condition. These patients are often grappling with complex decisions regarding their prognosis, the lack of treatment options, and exorbitant drug costs.
What is a rare disease?
There are more than 7,000 known rare diseases and yet only about 250 treatments are available to address several of these conditions.2 The definition of a rare disease or disorder differs around the world. In 2006, Health Canada developed a draft definition,3 which stated that a rare disease or disorder is a condition that affects fewer than 5 in every 10,000 persons, or 0.05%. Canada is behind other countries in developing a framework that recognizes the unique challenges within the regulations and coverage of medications for rare diseases, also known as orphan drugs.
There are rare gastrointestinal (GI) and liver conditions and other rare conditions manifest GI symptoms, such as diarrhea, bloating, nausea, and vomiting. With a lack of screening methods for many rare conditions, a misdiagnosis can lead to delays in proper treatment and worsening of the disease. For instance, congenital sucrase-isomaltase deficiency (CSID) is a rare genetic disorder that occurs when the body is unable to produce the sucrase-isomaltase enzyme necessary for the proper metabolism of sugar in fruits (sucrose) and in grains (maltose). By not being able to able to absorb these sugars, they experience abdominal pain, bloating, excess flatulence, and diarrhea. These symptoms resemble those found in other GI conditions, making diagnosis challenging. Research suggests that while CSID occurs in only 0.02% of North Americans of European descent, it is prevalent in 5% of the indigenous populations of North America and Greenland.4
Ethics and Healthcare Costs
Managing healthcare costs is important, but ethical considerations are as well. Researchers from the Czech Republic, Malaysia, and Japan state that the ethical perspective was missing for rare diseases and disorders.5 They conducted a literature review to determine what ethical questions arise when considering healthcare policy for rare conditions and orphan drugs. They also considered what ethical principles decision-makers should employ to address these questions.
They narrowed their assessment to 21 articles from an initial 4,139. From these, they identified five ethical questions surrounding issues with:
- the best approach to funding research and reimbursement of orphan drugs, especially when there are limits on financial resources
- the implications of inequities in care resulting from compassionate access and accelerated approval for drugs for rare diseases
- different definitions of rare conditions
- achieving international collaborations between groups and countries
- the right authority for the approval of research and clinical trials and whether an ethics committee would best oversee this
None of the papers took a definitive stance on how to resolve these issues. The authors suggest that we need a global effort to address all these concerns. They contend that the main barrier to implementing this approach is a worldwide lack of interest in international collaborations. The absence of a global consensus on ethical values, as well as political, societal, cultural tensions, and alignment on interests and priorities among nations fuels the disinterest. Countries also vary in resources and capabilities and there are important questions to address in assigning responsibilities among developed and developing countries. Nations also need to prioritize a myriad of challenges that their citizens are experiencing, including the fact that some rare conditions are unique to specific populations found only in some geographical areas or genetic populations. Note that the list of ethical questions and theories are not exhaustive and that the authors observed English journal articles only.
Global Efforts and Challenges
While the authors of the above-mentioned study list reasonable concerns as to why international collaboration is not a feasible approach, real-world examples challenge this claim. Academics, researchers, scientists, regulators, pharmaceutical manufacturers, and patient groups are continuously pursuing collaborations across borders via international conferences, focus groups, and other initiatives. In fact, patient organizations lead a number of these efforts.6
There are obstacles and risks involved throughout the research and manufacturing process of orphan drugs. Clinical trials can only attract a few participants, ranging from as little as two per study to hundreds of participants at a time, but many often reside in great geographic distances from one another and from a research centre. In some cases, the drugs are custom designed to a person’s genome. In contrast, clinical trials for medicines to treat common conditions can exceed tens of thousands of participants. Clinical trial data for rare diseases are typically few. This, along with other research limitations, may lead to a higher probability of receiving a negative recommendation from decision-makers when they consider whether to provide public coverage for an orphan drug.
Other uncertainties remain with regulatory approval and monitoring of drug effectiveness among populations using the therapy. Sometimes a medicine does not meet a particular country’s orphan drug definition and faces barriers to receiving regulatory approval,2 so the global market for the drug shrinks.
Finally, governments tend to designate the majority of drug budgets to cover treatments for diseases that affect larger populations, therefore, applying the theory of utilitarianism where the morally good action is the one that produces the best outcome for the greatest number of people.5 This is a devastating, sometimes deadly, outcome for a person with a rare disease or disorder.
Alternative Solutions
While there may be no agreement in the literature on how to best address ethical dilemmas in the rare diseases and orphan drug space, we can gain insights from the leadership of patient organizations and advocates.
The unfortunate truth is that the absence of treatments for rare diseases and disorders have prompted those affected by rare conditions and/or their family caregivers to actively find ways to develop a cure or therapy. Some have tackled drug development for rare conditions by raising money via fundraisers, establishing a foundation, crowdfunding (e.g., GoFundMe), applying for sponsorships, grants, partnerships, and more. In addition to knowledge from lived experience, patients focus on research into their disease to the point that academics, scientists, and other stakeholders acknowledge them as experts. Some patient organizations have also established small pharmaceutical companies to manage the intellectual property of the drugs they helped develop.2
The approach taken by patient groups may be a cost-effective model to funding the development of orphan drugs, but it places significant burdens on individuals living with rare diseases as it requires plenty of round-the-clock work and challenging fundraising. Significant work remains in recognizing and appropriately compensating patient organizations and individual advocates for the time and unpaid expertise they provide.
Canada
Health Canada only has a draft approach as to which treatments would qualify as an orphan drug for rare diseases or disorders.3 However, the federal government made a commitment of $1 billion to invest in a rare disease strategy for Canada in its Budget Plan for 2019, distributing funds in 2022 and 2023, with $500 million allocated each year.7 While Canada continues to lay the foundations for a rare disease framework, several other countries made significant progress years ago. In 2012, the US Food and Drugs Administration (FDA) Safety and Innovation Act was enacted, allowing pharmaceutical companies to receive a faster drug review if their product is for a rare pediatric disease.2 However, their work in rare diseases originates as far back as 1983 with the US Orphan Drug Act.
The Canadian Organization for Rare Disorders (CORD), a registered charity representing a national membership of organizations for rare diseases and disorders, has been on a years-long advocacy campaign to establish a national rare disease strategy. The Gastrointestinal Society is a member and works collaboratively with CORD to promote education, awareness, and timely access to treatments for rare GI and liver conditions.
Threats
Drug availability to Canadian patients is seriously at risk as companies evaluate the impact of the proposed PMPRB pricing restrictions, which drastically changes the way they review the prices of new drugs entering Canada.8 The Patented Medicine Prices Review Board (PMPRB) is a federal agency and is only one of the several mechanisms we use to price drugs in Canada. PMPRB’s proposed guidelines will come into effect on January 1, 2021, notwithstanding the COVID-19 pandemic and other major issues. These changes are extremely complex, and many stakeholders have voiced concerns on its intended and unintended consequences to patients receiving the medications they need. To learn more, you can read our Impact Report on the PMPRB changes, which is our review of the proposed guidelines and what it really means for patients.
Conclusion
Individual advocates and the patient group community can change the traditional drug discovery pathway and collaboratively work with decision-makers to achieve cost-savings in the public budget. Historical examples show that we have the tools to become disruptors and agents of transformation. There are real-world examples of successful collaborations between those living with rare diseases, patient organizations, academic researchers, scientists, pharmaceutical companies, and government bodies. However, these possibilities can only go so far as to the extent and willingness of other stakeholders in the field to listen, meaningfully engage, and pursue sincere collaborations with patient organizations and individuals living with a rare disease.