Therapeutics
potential biomarkers of disease. In addition to these challenges, for the many rare diseases where there are no available therapies, the clinical devel- opment path has not yet been defined and hence there is increased risk and uncertainty as to the clinical endpoints which would be considered appropriate for regulatory approval. R&D organ- isations therefore need to make a significant com- mitment to effectively engage the relatively few physicians and opinion leaders who work on any rare disease, in addition to engaging with patient associations and families dealing with the conse- quences of these disorders to gain a greater under- standing of the natural history of disease, and those therapeutic effects that would have a mean- ingful impact on the lives of patients. Umbrella patient organisations such as NORD in the US and EURORDIS in the EU, as well as patient organisations representing individual diseases, have important and complementary roles to play in supporting the development of therapeutics for rare diseases. Project leaders and key decision- makers in rare disease companies clearly need to be ‘patient-centric’ in their thinking. In addition, payors also need to be engaged early in a pro- gramme to define what will be considered appro- priate measures for reimbursement, with informa- tion on these measures being built into a clinical development plan.
As there is little or no precedent from earlier clinical development programmes for the majority of rare diseases, companies frequently need to commit to natural history studies, which are man- aged in a similar way to clinical trials, prior to ini- tiating any clinical programmes. These studies aim to provide important insights to suggest potential clinical endpoints for inclusion into the clinical development programme and discussion with reg- ulatory authorities, may identify biomarkers that correlate with clinical endpoints, can assess the tra- jectory of disease progression and may define the variability in clinical progression between subsets of patients. For example, a study of nearly 2,000 individuals from families affected by Huntington Disease who had different demographic, clinical and genetic features at baseline6 revealed differ- ences that emerged before clinical diagnosis, and will inform the design and conduct of future clini- cal trials. In addition, a natural history study of patients with infantile-onset Pompe Disease7 care- fully described the rapid progression and fatal course of this devastating disease, and confirmed that early symptom onset was correlated with an increased risk of early death. It is important that data from studies such as these are readily avail-
Drug Discovery World Spring 2013
able in the public domain as they will underpin future drug discovery and development pro- grammes. The cost and time associated with natu- ral history studies can be an impediment to the ini- tiation of clinical programmes, and moving for- ward such studies, that provide insights into the basic biology of disease, may be an appropriate area for increased future partnership between industry and research funding agencies. In addi- tion, patients with rare diseases are particularly active in online patient communities, some of which collect patient-reported outcomes. In effect, they are conducting natural history studies through social networking. While data integrity needs to be ensured, it will be important to consider how such information may provide helpful insights to shape clinical programmes and provide support for regu- latory submissions.
The most obvious challenge in conducting clinical trials in rare diseases is the small numbers of patients available for clinical studies. Enrolment of patients into clinical studies in sufficient numbers to generate meaningful comparative data is therefore a major challenge, usually requiring the participation of many sites across multiple geographies, frequent- ly with very few patients enrolled at each site. This may cause delays in the recruitment process which can add cost and uncertainty to the programme. Higher per patient clinical costs are also driven by the fact that the fixed costs for setting up each clin- ical site are spread over a smaller number of patients. In addition, the manufacturing process to support biological products in rare diseases can have some specific challenges. For example, changes or improvements in the manufacturing process for complex glycoproteins frequently results in some changes in the characteristics of the protein prod- ucts. Generally, comparability studies between the two different products in man are required to sup- port approval for substitution. However, in rare dis- eases such comparability studies are particularly challenging as there are few patients available for
Figure 1
The R&D paradigm in rare diseases
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