Orphan Diseases

Diseases so Rare You've Never Heard of Them

Orphan diseases are diseases that are so rare that most people have never heard of them and the prevalence of some of the rarest orphan diseases can be counted on one hand.  Most orphan diseases are the result of genetics, and they stick with a person for the entire duration of their life.  It is believed that there are approximately 10,000 rare diseases worldwide, with most of them being related to genetics.  The different legal standards as to what constitutes a rare disease and legalities have historically been the biggest hurdle for pharmaceutical companies, but legal definitions are now starting to become standardized across international lines.

Today, it is far more common for orphan diseases to be classified in more broad terms that include diseases for which it is unlikely that the cost of developing a drug for a disease will be recovered from sales, and policies are being passed into law to create more favorable conditions for pharmaceutical companies to invest in orphan drug development.  However, the broad nature of legal jargon and arbitrary number setting in an attempt to legally define what classifies as an orphan disease still creates challenges for rare disease drug development, and somewhat of an ethical dilemma.

Canada’s Approach to Orphan Drugs

One lesser-known fact about orphan drugs is that the focus on orphan diseases kickstarted 30 years ago when the U.S.  became the first country to introduce orphan drug legislation and orphan drug economic incentives in 1983.  Subsequently, it resulted in other countries also introducing their own legislation starting with Singapore (1991), Japan (1993), Australia (1997), the EU (1999), Taiwan (2000), and South Korea (2003).  One country missing from that list is Canada, and it might lead some to think that Canada has overlooked orphan drugs, but that would be wrong.

Canada’s regulatory approach to drugs for orphan diseases can become confusing because it stretches out and involves quite a number of tools that are made available by Health Canada for pharmaceutical companies.  These tools include Health Canada providing advice on clinical trial applications and clinical trial designs in small populations, an accelerated review pathway that can speed up new drug review from the average 300-day mark to a priority review with a 180-day mark review, special data and patent protection, special authorizations to sell drugs otherwise not sellable or distributable in Canada, fee mitigation, and tax incentives for research and development.  In addition to the current tools in place, Health Canada is also undertaking steps to allow for greater use of reviews and decision of trusted foreign regulators, leveraging health technology assessment organizations that assist in new drug development and to reduce time between approvals and recommendations, and improving access to drugs that are not currently authorized for sale in Canada.

The legal definition that Health Canada uses to define and quantify what legally constitutes as being an orphan disease is any disease that affects fewer than 5 in 10,000 people, if simplified comes out to 1 in 2,000 people.  Elsewhere in the world, Japan considers rare diseases to be diseases that impact about 1 in 2,500 people, while the European Commission sees it as 1 in 2,000 people, and the U.S.  about 1 in 1,500 people.  While Canada is certainly in the right ballpark when it comes to aligning with other countries, there are problems with having hard cutoffs for what may or may not be considered a rare disease.

One report published in 2017, in the Canadian Medical Association Journal (CMAJ), seems to indicate that there is cause for concern, while rare diseases on their own are uncommon, rare diseases combined are estimated to affect 1 in 12 Canadians.  If we scale 1 in 12 Canadians to size, it comes out to be over 3 million Canadians, and these numbers suggest that our pharmacare approach on orphan drugs has real implication on the quality of life for many Canadians.  That CMAJ report also highlights loopholes that have allowed for international pharmaceutical patents to be leveraged to carry out price hikes from $500CAD to $110,000CAD, as seen with Emflaza, and it is not uncommon for other orphan drugs to be in the six-figure range like Spinraza which costs $625,000CAD.

Before even getting to the issue of the cost of orphan drugs, it is important to address the issue of orphan disease prevalence and whether a disease that impacts slightly more than the “1 in 2,000 people” benchmark set out by Health Canada should also be eligible to take advantage of “orphan drug” benefits.  This matters because getting approved for an orphan drug entails quite a bit, but the answer should be, “Yes, but…”.  Such a step likely involves changing the playing field and moving away from arbitrary numbers, legal jargon like “significant benefit”, and creating a more favorable environment for pharmaceutical companies to view Canada as having created the necessary conditions to drive pharmaceutical exceptionalism and pharmacological innovation.

What follows the “Yes, but…” for me is that it should be that pharmaceutical companies are required to put together comprehensive reports that highlight a variety of factors including price points and multi-decade forecasting.  If a pharmaceutical company can come up with a drug for less prevalent diseases, then perhaps they deserve having more than a 20-year-long patent, providing the drugs are priced within Health Canada’s “affordable” range.  So, if pharmaceutical companies can demonstrate that a new drug is unlikely to generate a significant return over the term of a 20-year-long patent, then perhaps it is worth considering the possibility of 30-year-long patents, or longer.  As long as the price points for less prevalent drugs fall within Health Canada’s affordable range, then there should be no reason not to extend benefits reserved for “orphan drugs” and not to consider issuing longer-lasting patents, if every stakeholder’s needs are met.

Whatever it takes, it is important not to forget that government policies have created the conditions necessary for the kind of exceptionalism and innovation that resulted in mankind’s greatest achievements including the internet, research computers, and even satellites.  Although the idea of having 30-year-long patents, or even longer, may seem extreme to some, consider that something as insignificant as a Walt Disney’s Mickey Mouse character has enjoyed nearly a 100-year-long copyright patent.  While Mickey Mouse may have cultural significance for society, Mickey Mouse is incapable of providing people struggling with rare diseases a better of quality of life.  So, the idea of patents that go beyond the 20-year standard should be met with an open mind.

How do Provinces look at orphan drugs?

Considering that Canada’s health care insurance plans are determined at the provincial level, the coverage and reimbursement of drugs, including drugs for rare diseases, also fall into that category.  Out of Canada’s ten provinces and three territories, only five have created procedures and protocols for the reimbursement of drugs for rare diseases: Ontario, British Columbia, Alberta, Saskatchewan, and New Brunswick.  But there are real issues with how the provinces define and quantify what is and is not considered as being eligible under provincial health care plans.

In Alberta, a rare disease is defined as a genetic lysosomal disorder occurring in fewer than one in 50,000 Canadians, far different from the standards set out by Health Canada.  Whether coverage for a drug that treats a rare disease is covered is determined by a Ministry-appointed panel which is comprised of a panel of health care professionals with clinical experience.  Although each person’s rare disease specialist is able to apply for different drugs, there are some strict eligibility criteria, and these conditions need to be met for coverage to be approved.  These criteria state that initial and continued coverage is conditional and dependent upon clinical outcomes, ongoing clinical outcome monitoring is mandatory, and there exists withdrawal of coverage criteria that states patients that have inadequate responses or whose health deteriorates is grounds for coverage discontinuation.

In Ontario, instead of a panel of health care professionals, there is a five-member working group that is comprised of a physician, economist, pharmacist, and geneticist, and they report to the Executive Officer of the Ontario Public Drug Program.  Ontario does not have any restrictions on the types of rare diseases eligible for review and requests for coverage can be submitted by either a pharmaceutical company or a physician.  The decision-making framework regarding whether a drug will be covered has seven steps, which might be described as the entrance of the rabbit hole.

Step one has to do with assessing a submitted diseases to determine if it meets the eligibility criteria, one being that the incidence rate is fewer than 1 in 150,000 live births or new diagnoses per year, and a lack of available or adequate control trial data.  Step two deals with a review of the disease.  Step three focuses on assessing the potential effectiveness of the drug based on the best available evidence, but orphan diseases are far too rare and their genetic-influencing nature almost guarantees that it will be impossible to accurately predict how a person might respond to the drug.  Steps four and five focus on evaluating budget and cost impact and identifying additional data follow-ups.  Steps six and seven focus on reviewing the evaluation with disease experts and stakeholders and reassessing the drug over again.

Perhaps it is possible to solely to measure the success of our publicly funded health care program by how it services people most of the time, but there is a greater responsibility to include every person under this coverage.  Perhaps the most glaring issue is how Health Canada has a far lower threshold for what constitutes as being a rare disease and how provinces have what almost seems as unreasonable criteria as to whether a disease is rare and enough and whether it should be covered under the publicly funded health care coverage plan.

On a lighter note, some historical orphan diseases are explainable.

Some orphan diseases go back as far as the 1800s, and one such disease that has developed its own lore is called the “Jumping Frenchmen of Maine”.  This disease was found in a specific group of lumberjacks and its major symptom was an exaggerated startle reflex to stimuli, like a jump or a body jerk.  Another unusual thing about this disease was that the fact that there were reports that individuals would exhibit symptoms of repetition and would follow orders devoutly.  As the name suggests, this particular disease was observed in Maine, but it was also observed in French Canadians and lumberjacks who lived in the nearby areas.

Perhaps this “disease” would be better viewed as the likely result of a combination of factors including lifestyle and cultural factors instead of an orphan disease.  It would likely be easy to diagnose “Jumping Frenchmen of Maine” disease with today’s understanding, perhaps the result of repetitive actions, fatigue, and complex PTSD, during a time when early settlers were still at war with Native tribes and when wild animals were just as big of a threat.

So, while something along the lines of “Jumping French of Maine” disease might be more appropriately placed in a pseudoscience category, similar to how babies that were born with physical defects were once considered to be cursed, orphan diseases should be taken seriously and not mistaken for lore.  What people should think of when they hear someone reference “orphan diseases” or “orphan drugs” is drugs related to oncology, musculoskeletal and nervous system, metabolism, cardiovascular and respiratory, immunological, anti-infectious and hematology.  Preferably not the “Jumping Frenchmen of Maine”.