Stephen Lynn - Joining the dots
The process of drug trialling has taken on a relatively new important phase. Post-marketing surveillance strategies are becoming a necessary part of an orphan drug manufacturer’s responsibilities. In summary this is ongoing monitoring of a drug’s impact in real world, even once it’s gone through the traditional clinical trials steps.
These strategies are likely to include patient registries and natural history datasets, which may allow drug treatments to be carefully tracked and the patients monitored for drug safety and efficacy. Biopharmaceutical companies spend many millions of dollars per year implementing and maintaining surveillance registries for their own products.
Over the last 8 years TREAT-NMD has built up a Global Patient Registry with more than 13,500 Duchenne muscular dystrophy (DMD) patients enrolled world-wide (and a similar system for other diseases, such as SMA and other neuromuscular conditions). The registry in its current form is instrumental in supporting translational research, especially feasibility studies on behalf of commercial partners. This has allowed for the definition of data content for each disease/gene, defining the regulatory and ethical framework, identifying and analysing existing national registries, and training curators for quality control of new and existing registries.
The primary aim of this TREAT-NMD activity was to allow feasibility assessment, planning and recruitment for clinical trials. Other secondary objectives included collecting epidemiological data, establishing genotype-phenotype correlations, defining natural history, assessing burden of illness, treatment outcomes and standards of care. In essence we’ve started to build a national picture of neuromuscular diseases.
Replicating this way of working across other disease areas by linking the global registries with individual surveillance databases, which are all managed through a central source, would be both cost effective and time efficient. Establishing a surveillance registry as a centrally managed platform would allow it to be sustained by stakeholders, in any particular industry. Building a registry platform would allow it to be sustained through multiple commercial partners.
Regulatory authorities are acknowledging the difficulties in collecting safety and efficacy data for novel therapeutic agents intended for use in rare or orphan conditions, where the intended patient population is small. In particular, this means that in the majority of these cases the pharmaceutical industry is not in a position to conduct wide-ranging Phase III clinical trials. As a result, regulatory authorities are granting conditional marketing authorisations based on limited safety and efficacy data, allowing companies to commercialise products on the understanding that the companies will collect and submit post-marketing data on safety and efficacy. For rare diseases, this could potentially be for up to ten years.
This collection of data is called post-marketing surveillance (PMS). All marketed drugs are subject to pharmacovigilance reporting, but the requirements to provide PMS for therapeutic agents with a conditional marketing authorisation are much greater and are based on pro-active data collection rather than merely responding to adverse events as and when they occur. More current, high quality data makes this process easier.
The TREAT-NMD approach is ideal for extension to PMS because it already defines a mandatory dataset and means to share core data. This allows the interface with patients to be variable from country to country, and focuses on the information that will be needed for clinical studies.
The registries alone, and the data that they contain, are not sufficient in themselves to provide a mechanism for PMS. To be useful for PMS they need to be combined with a database set up to collect data on the performance of a therapeutic agent. It is possible to build PMS databases (PMSD) for specific therapeutic agents and this has been the route most commonly adopted to date by pharmaceutical companies. These are termed ‘drug-specific databases’. In orphan indications, a much stronger approach is to build a disease-based PMSD; this not only allows companies to monitor the performance of their own drugs, but to compare the performance of therapies against the progression of the untreated disease from natural history data, and, in time, against other treatments. This is a powerful tool for discriminating between drug-specific events and disease-specific events.
The utility of the registries for industry feasibility studies to support clinical trial planning and patient recruitment has been well demonstrated. The ongoing natural history studies in various countries are currently national studies, and are therefore not currently linked. Some companies are only now releasing their placebo arm data to support these national and academic-led studies. Post-marketing for the first drug in DMD (developed by PTC Therapeutics) is underway as essentially a drug registry, which is supported by Quintiles (commercial CRO) and CINRG (academic CRO). This platform has the potential to be further developed to be a disease-specific registry platform that would utilise the CINRG data capture and management tools as well as the TREAT-NMD registries and other linked data collections. We will find effective treatments faster the sooner we start joining the data dots.
Dr Stephen Lynn is Project Manager of the TREAT-NMD Alliance. He joined TREAT-NMD in March 2007 from the British Consulate General in San Francisco, where he was Vice Consul for Science and Innovation.