The World Health Organization (WHO) defines a rare disease as a condition affecting less than 65 per 100,000 people. Some conditions are even rarer. For example, it’s estimated that there are less than 100 cases of mitochondrial DNA depletion syndrome associated with TK2 mutation worldwide. The prevalence is even lower for mitochondrial DNA depletion syndromes associated with mutations in other genes.
However, cumulatively, rare diseases are not so rare at all. According to The Lancet Global Health, there are approximately 300 million people living with rare diseases to date and 7,000 diagnosable rare conditions worldwide.
Yet, there’s still a significant gap when it comes to medical research for rare diseases. Why?
Funding and investment are the primary reasons behind this gap. Whether we like it or not, medical research is, ultimately, driven by commerce.
Medical research is time-consuming and expensive, so biotechs and pharmaceutical companies must weigh up the costs of drug development compared to the returns for eventual commercialisation. In the case of rare diseases, smaller patient populations mean the market potential for products is limited, inhibiting the ability to gain a significant return on investment. Unfortunately, even with fee reductions and other incentives, such as additional patent protection, it often doesn’t make commercial sense to develop a drug for a rare disease.
As a result, around 95% of rare conditions lack a regulatory-approved treatment (The Lancet Global Health).
This needs to change.
In rare diseases, the average time for an accurate diagnosis is four to eight years (The Lancet Global Health). Yet, we know that early diagnosis is essential to finding the right treatment and improving outcomes — whether that be reducing complications, delaying irreversible deterioration or curing the disease altogether. During the diagnostic odyssey, it’s difficult to mobilise the full weight of medical resources and knowledge (particularly when there’s a lack of natural history data), meaning patients are left in limbo, potentially going through unnecessary tests and procedures. So, early diagnosis has a profound effect — not only on the patient but also on the patient’s family and friends.
Clinical research organisations (CROs), such as TMC, play a vital role in assisting medical research studies and finding suitable treatments for rare disease patients now and in the future. However, there are several obstacles associated with conducting clinical trials for rare diseases, particularly when it comes to recruiting and retaining trial participants.
The issue of recruiting and retaining patients
Compared to more common diseases, rare-disease patient populations are small and dispersed — creating unique barriers to recruiting and retaining patients for trials. In fact, research by GlobalData found over 25% of rare disease trials were terminated between 2016 and 2020 due to low accrual rates.
The nature of rare diseases means there may only be a small handful of experts in a given country (if any at all), often concentrated in one or two specialist sites. As a result, it may not be practical to bring patients to these sites for regular visits per protocol — either due to health reasons, cost or having to take time off work or school.
When conducting these trials, it’s also important to consider how the medication is sent to patients and administered. Certain drugs require specialist handling or administration by trained nurses, which can add to logistical challenges. Geography is a factor here. Some locations are well set up for decentralised trials or a hybrid approach (utilising home nursing, for example), but this isn’t always the case. So, it’s important to find the balance between bringing patients in and conducting other trial elements remotely.
Aside from the practical issues of conducting clinical trials for rare diseases, there are also regulatory and ethical considerations, especially when it comes to designing trial protocols.
Placebo-controlled studies are the gold standard for proving a drug works, particularly in phase three when companies are looking to produce the pivotal data that enables them to achieve regulatory filing. However, they are not attractive — or indeed ethical — for patients with serious rare diseases where there are no other available treatment options. Equally, if a patient is being treated with an off-label drug (as is often the case in rare diseases) and satisfied with this treatment plan, they may not want to stop in order to enter a clinical trial.
Overcoming these challenges
As we begin to see the increased use of decentralised trials — or at least a hybrid approach — effective protocol design will become even more crucial for biotechs and pharmaceutical companies seeking regulatory approval. To accelerate pathways for rare diseases, protocols must ensure flexibility and adaptability to achieve a middle ground that works for the majority of patients whilst collecting the required data.
Collaboration and communication are key here, with CROs playing a significant role in outlining regulatory strategies and ensuring clinical trials are set up for success.
CROs must balance patient support with understanding and meeting clients’ needs, acting as a conduit between both. A specialist CRO is especially valuable when it comes to drug development for rare diseases. Although there may be limited experience in that particular indication, a specialist CRO will have the expertise and knowledge to identify correlations across other rare conditions, which they can leverage to solve problems and make appropriate protocol amendments.
Embracing efficiency — without losing sight of the patient
Looking ahead, we’ll increasingly see the integration of artificial intelligence (AI) into the development pathway, working in tandem with CROs to enhance protocol writing and data analysis.
At present, AI is advancing significantly faster than regulatory frameworks. Regulatory innovation and improvement always tend to lag slightly behind, with advances in products and technology then forcing regulatory change. As such, we’ll likely see greater regulatory flexibility in the medium term as regulators try to assess the validity of AI, evaluating the reliability of outputs and suitability for use in medical research.
Eventually, AI will become embedded, with regulatory authorities giving certain AI technologies the stamp of approval for use in drug development. These developments will have potentially massive benefits for patients and drug developers — accelerating the timelines of drug discovery, development and market authorisation to give patients faster and better access to treatments.
However, it’s important not to forget the human element when talking about rare diseases, particularly in the face of developments like AI. Although AI has permeated many industries, the stakes are much higher in medical research — where every decision has the potential to affect someone’s life dramatically.
Although it’s easy to get swept up in the excitement of new technologies, it’s important to remember we’re developing drugs for patients, not robots. Each patient isn’t just a number in a clinical trial; they’re an actual person with a family behind them and a whole back story. So, whilst AI is set to play an increasingly significant role, human oversight remains essential to interpreting AI outputs and taking a patient-centric approach that ensures the impact on people’s lives and well-being is considered.
In the end, AI will undoubtedly reshape clinical trials by improving efficiencies and time to market, but we must ensure our pursuit of efficiency never overshadows the profound responsibility we have to the individual lives at the heart of every clinical trial. The patient must always come first.
This article originally appeared in RARE Revolution Magazine, Autumn 24, Issue 029, RARE Mitochondria