There are around 7,000 rare or ‘orphan’ diseases for which there currently exists no authorised or satisfactory method of treatment. Many are life-threatening or debilitating, and they particularly affect the very young, who often do not survive beyond adolescence. Without treatment, these patients’ quality of life will be seriously affected and their lives may be shortened. This represents the grim reality that they and their families are facing.

There have been great advances in developing ‘orphan drugs’. However, the potential for these new therapeutic approaches can only be realised if they are approved for clinical application. And treatments for rare diseases are much harder to get through the clinical trial and regulatory approval process.The clinical development of orphan drugs is fraught with many practical challenges, but two are really critical at the moment.

The first challenge is designing and running adequate clinical trials for orphan drugs. The randomised controlled trial, designed to minimise selection bias, has been accepted by regulatory authorities around the world as the gold standard. This design is commonly used in studies of new therapies designed to treat common diseases, and it will typically involve a large number of readily available clinical trial subjects.

However, this may not be a feasible model for the trials of orphan drugs, which treat a small population. Clinical trials in rare diseases necessarily enrol fewer trial subjects, and these people are unlikely to be concentrated in a particular geographical region. Add in the significant clinical differences between trial subjects, observed in many rare diseases, and this diminishes the power of the study.

Given the rarity of orphan diseases, arguably the greatest challenge in developing treatments is the timely and adequate recruitment of eligible trial participants. Many regulatory authorities use criteria intended for a larger patient population, such as demanding that two or more pivotal confirmatory studies be carried out. However, the authorities in both the EU and the US have recognised that such a requirement is more challenging to satisfy for treatments intended for orphan conditions, particularly for small and medium sized pharma companies with limited resources.

Because of the low incidence of the disease in each country, given its rarity, there is often a need to enrol patients from a number of countries to obtain a large enough sample size of trial subjects to establish the clinical efficacy. Since trial subjects are geographically dispersed, multi-centre studies must be initiated in various international centres of excellence. However, it can be very challenging to set up multiple trials to meet different regulations and requirements.

The solution would be a common trial design, but the varying regulatory approaches in different jurisdictions don’t currently make this possible. Some regulatory authorities have established parallel scientific advice. However, the respective agencies do not have to arrive at the same view on the study design and it can therefore be difficult in practice to analyse the data derived from studies with disparate trial designs.

Greater cooperation between the regulatory authorities is therefore needed, to agree on the design of multi-centre clinical trials. This would greatly facilitate the development of orphan drugs. With strong international cooperation, it would often be possible to rely upon only one well-designed clinical study to elucidate the true treatment effects of a transformative method of treatment for all global regulatory authorities.

Once an orphan drug has been successfully trialled the second major challenge occurs: How, in this highly regulated sector, to get this innovative treatment onto the market in time to help patients with orphan conditions who will otherwise die? The regulatory authorities understandably require the dataset submitted for product approval to be sufficiently robust. On the other hand, patients with rare, life-threatening and debilitating conditions - and those involved in their care - expect, not unreasonably, expedited product approval to ensure timely access to such life-saving methods of treatment.

Contrary to popular belief, being designated as an orphan product does not automatically permit a regulatory authority to approve it more quickly or with less evidence than drugs intended for non-orphan populations. The standard of approval for orphan products is generally the same as the standard of approval for all other drugs.

Regulatory authorities do generally have some latitude to determine the level of evidence that is required to inform the benefit/risk assessment that underpins product approval. In the EU, the adopted regulatory standard for approval is that clinical data should be based on randomised clinical trials versus a placebo or, as appropriate, with an established medicinal product of proven therapeutic value. Any other design must be justified.

EU legislation does recognise that, in certain exceptional circumstances, a marketing authorisation may be granted on the basis of less comprehensive data, to address an unmet medical need. In addition, for certain rare, life-threatening and debilitating conditions, there is a regulatory pathway for a conditional marketing authorisation to be granted, giving immediate access to the product, if the manufacturer can prove an unmet medical need.

However, the regulatory authorities could benefit from clearer directions to fully embrace less conventional or common approaches to making a risk/benefit analysis for orphan drugs balance in exceptional circumstances. This would mean that new methods of treatment were not unjustifiably delayed or denied, subject to certain specific post-authorisation safeguards. Such an explicitly flexible and pragmatic approach would improve patient care in a clinical setting where there is a demonstrable unmet medical need.

It has been said when a method of treatment fails, researchers must be clear that there is a true lack of biological effect, rather than failure due to inadequate study design. Therefore, the approval process for orphan drugs ought to take full account of the detailed knowledge of the pathophysiology of the orphan disease and the pharmacology of the new method of treatment to facilitate the design of efficient clinical development processes. This would help to determine the amount of clinical data required to inform an assessment of clinical efficacy and safety.

International cooperation on clinical trials for orphan drugs, while highly desirable, will have a limited impact if patients in some countries can’t access new therapies that come through the trials having demonstrated a favourable benefit/risk profile. Given increasingly cost conscious healthcare delivery systems, it’s also important to ensure that patient access is not restricted because the new therapies are not accepted in some country on grounds of affordability.

Dr Lincoln Tsang is a partner at law firm Arnold & Porter. This article is based on his testimony before the Subcommittee on Children and Families of US Senate Committee on Health Education Labor and Pensions hearing on ‘Rare Diseases: Expediting Treatment for Patients’.