There are as many as 8000 rare diseases, affecting 400 million people worldwide, for which there are no effective drugs available.1 With patient numbers being so low for each rare disease, it is often difficult for a pharmaceutical company to achieve a return on its investment on a drug development programme or treatment without additional incentives.
The need to encourage drug development for diseases that would previously have been uneconomic to address led to the Orphan Drug Act being passed in the US in 1983, and to similar legislation being introduced in the European Union (EU) in 2000. In the US, an orphan disease is defined as one that affects no more than 200,000 of the population; this is currently about six people in every 10,000.
The numbers in the EU are slightly lower, fixed at five in every 10,000, rather than being tied to overall population figures. Either way, to be eligible for orphan designation, a sponsor company needs to demonstrate that the disease its drug is designed to treat is this rare.
Orphan designation can also be granted for a disease that does not quite meet these prevalence requirements as long as a company can show that there would be insufficient return on investment when commercialising the drug. This applies in both the US and the EU.
Broadly speaking, the processes to gain orphan drug designation are very similar from both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). However, there are variations in the precision of evidence that they demand.
In the US, for example, both a scientific rationale and proof of efficacy are required to justify orphan status. If clinical data or an appropriate preclinical model do not exist, sponsors can use data including the pathogenesis of the disease, as an alternative, along with the drug’s mechanism of action (supported by a package of in vitro data). Data from the published literature can also be cited.
Author Information: Judith Jones, Director, Regulatory Affairs, Global Regulatory Affairs, and Matthew Mollan, Regional Head of Operations, Early Phase Development, North America, Catalent.
This strategy is less likely to be successful in the EU, however, as the EMA clearly states that clinical or preclinical data are the best ways of demonstrating medical plausibility and the potential for significant benefit. Certainly, there seems to be a trend towards more drugs being given orphan designation in the US than in the EU. From 2019 to 2020, there was a 41% increase in applications for orphan drug designation in the US to 753.2
However, the figures between the two years in the EU were relatively flat, with 233 requests in 2019 and 235 in 2020. The difference is stark and there are efforts under way to harmonise the way orphan drug designation is assessed by the two authorities. If this can be achieved, then it is not unreasonable to expect that the submission requirements would be made more consistent.
Many orphan drugs are developed by small biotech companies that lack their own manufacturing capabilities and are therefore reliant on a fee-for-service manufacturer or a contract development and manufacturing organisation (CDMO) for clinical and commercial supplies of drug product.
Innovators may benefit from partnering with a CDMO with extensive experience in manufacturing at different scales and the necessary flexibility to respond to changes in volume requirements as the project and approvals progress with time.
Such a contractor will usually have sufficient capacity and the correct infrastructure to accommodate a variety of manufacturing scales. This is important: if the necessary equipment is not available immediately, then delays to the project timeline will be inevitable. Outsourcing to a CDMO is likely to be faster and cheaper to meet short-term targets and longer-term goals than to invest in in-house manufacturing capacity.
By their very nature, the manufacturing volumes for orphan drugs will be low as the patient population is so small. However, it is not uncommon for the required volumes to increase with time, particularly for cancer medicines, as additional indications are frequently applied for after the first approval.
An experienced CDMO will also be well-placed to help the sponsor submit an effective package to the regulators for approval. Usually, such partners will have an in-house team of regulatory experts with local knowledge in multiple countries and regions that is well-versed in dealing with all of the relevant regulatory authorities. And if information is required on specific technologies, for example, the regulatory team at the CDMO will be able to respond with accurate intelligence very quickly.
Any type of drug, whether small molecule, antibody or a more complex product, can be given orphan status. Regardless of the type of molecule, clinical trials for orphan drugs can be challenging, and similar issues can be expected when considering study design.
Appropriate efficacy endpoints can be difficult to establish, not least because the understanding of disease pathophysiology and its natural progression are often incomplete. This makes the identification and validation of surrogate biomarkers and critical clinical outcomes difficult.
The low prevalence of the disease necessarily tends to make it harder to enrol and retain patients than for a more commonly occurring clinical trial for a non-orphan indication. Although diagnosed patients may sometimes be identifiable through patient support groups, for example, the pool of patients who might benefit from a new treatment is inevitably going to be low. Many are fairly heterogeneous in nature, which reduces the number still further, and for many orphan diseases, those patients will probably be children.
In addition to orphan designation, many new potential treatments for rare diseases are likely to qualify for a variant of an expedited development programme. Limited active pharmaceutical ingredient (API) supply, combined with uncertain formulation requirements and shortened timelines, exacerbate the challenges facing developers.
Under these circumstances, it might be impossible to do all the activities that are normally expected to take Phase I formulations right through to late-stage development. Strategic investment in Phase I formulation development and derisking is likely to pay dividends in the long run, assuming the project progresses.
Alongside manufacturing capabilities, CDMOs will typically have a team of formulation experts that will be able to suggest and develop an appropriate delivery form, as well as customise the dosages if required to meet any specific concerns about an individual product.
Although the choice of disease target and early laboratory work is done by the sponsor, an experienced CDMO should be able to provide input and assistance in refining the target product profile — while ensuring that the anticipated final product will meet the needs of the target patient population.
Factors that would be considered include the API’s pharmacokinetic and physicochemical properties, the anticipated age range of patients and their likely comorbidities, as well as how easy it is to manufacture the drug product.
Developing a process and formulation at an early stage that can accommodate a wide range of drug loadings is one area that any CDMO partner should prioritise to greatly derisk the impact of changes to that drug loading later as more product data become available.
Establishing a risk-based chemistry, manufacturing and controls (CMC) plan, and sharing that with the regulatory authorities at an early stage, should assist in preparation for any unforeseen challenges that might arise.
Transitions and progressing orphan drug programmes between early and late phase manufacturing within the same CDMO network — even if the manufacturing sites are different — can be easier and faster than if a technology had to be transferred from one company to another.
The experts and operators at the different facilities will be used to working with each other, with similar project management structure, operational processes and collaboration tools in place at the different sites. Further benefits in terms of time and cost savings are likely to be achieved by harmonising equipment, analytical processes and supply chain procurement between the different facilities to ensure smooth tech transfers.
Of course, once approved, the volumes required for the product mean that full-scale commercial equipment is unlikely to be required and late-stage clinical equipment will typically be sufficient to produce the volumes necessary to meet post-approval requirements. Although the batch sizes are smaller, regulators will still expect all compliance requirements for commercial batches to be met, with stability data supporting expiration dates.
This means that the processes should be designed to be sufficiently flexible to address changing demand in the future as well as meeting the requirements of the different regulators around the world. For cancers in particular, it is very possible that multiple indications will ultimately be approved and volumes will rise as a result.
Partnering with an experienced CDMO and planning ahead will make the growing demand more straightforward to meet, as and when further approvals are granted.
When it comes to complex, niche orphan drugs, a large, integrated CDMO can offer advantages to a sponsor as it is likely to have access to an international network of state-of-the-art facilities, alongside a team of highly skilled, experienced technical experts.
Using a single partner with integrated capabilities can reduce the need for a sponsor to manage multiple suppliers and co-ordinate activities between them, as well as assist greatly in accelerating timelines and reducing programme risks to ensure successful orphan drug product development for patients in need.