National scientific advice: why not make use of it
There is a growing interest in developing orphan drugs. However, the pivotal clinical trial stage is hampered by factors intrinsically related to rare diseases, such as limited number of patients and lack of disease knowledge, both fundamental and clinical. Does scientific advice have an added-value ?
Recent studies revealed that in particular choice of primary endpoint and selection of the most appropriate target populations are crucial factors in successful orphan drug approval [Heemstra et al, 2011, Putzeist et al, 2011]. This raises an important question, namely how to choose the best primary endpoint and most appropriate target population ? Although these studies did not provide conclusive evidence, it makes perfect sense that experience in orphan drug development increases the likelihood for successful approval of an orphan drug. Experience can be acquired either by bringing on board management with the necessary experience and/or through partnerships with experienced pharma companies.
Another strategy that I would like to bring forward is to engage with regulatory agencies and to make use of their scientific advice instruments. Most sponsors are aware and appreciate that both FDA and EMA provide free (or at a reduced fee) scientific advice to sponsors of orphan drugs. However, some sponsors, in particular less experienced ones, may be less aware that in the EU scientific advice can also be acquired at the national regulatory agencies. For your convenience I have provided a list of a number of EU member state regulatory agencies that provide scientific advice (with a hyperlink to relevant information, last accessed 2 apr 2012).
- College ter Beoordeling van Geneesmiddelen (the Netherlands)
- Laegemiddelstyrelsen (Denmark)
- Lakemedelsverket (Sweden)
- Medicines and Healthcare products Regulatory Agency (UK)
- Bundesinstitut für Arzneimittel und Medizinprodukte (Germany)
- Agence française de sécurité sanitaire des produits de santé (France)
- Agencia Espanola de Medicamentos y Productos Sanitarios (Spain)
- Bundesamt fur Sicherheit im Gesundheitswesen (Austria)
- L’Agenzia Italiana del Farmaco (Italy)
- Federaal Agentschap voor Geneesmiddelen en Gezondheidsproducten (Belgium)
The importance of regulatory dialogue during the (pivotal) clinical trial stage has been included in a number of studies [Heemstra et al, 2011, Regnstrom et al, 2010]. Regnstrom et al. reviewed all market authorization applications (non-orphan and orphan !) in the EU in the period 2004-2007 with the aim to identify factors associated with successful drug approval [Regnstrom et al, 2010]. They showed that requesting scientific advice at the European Medicines Agency (EMA) was not associated, however, complying with scientific advice was identified as predictive factor for successful drug approval. I like to highlight three relevant clarifications the authors mention in their discussion. First, complying to scientific advice “should not be viewed as a reward for following the regulators’ views”. Scientific advice is clearly intended as a moment during which sponsors can enter into dialogue with regulators to argue their case . If needed, a follow-up scientific advice meeting can be requested. The final scientific advice is often the outcome of this dialogue and/or follow-up. Second, the authors speculate that scientific advice is requested for “more challenging medicinal products and development programs and in situations where regulatory guidance is missing”. Orphan drugs certainly fall within one or perhaps even both categories. Finally, in line with the size and/or experience of a sponsor being a predictive factor for success, it doesn’t come as a surprise that the authors observed that “large companies not only asked for scientific advice more frequently than medium-sized and small pharmaceutical companies but, importantly, they were significantly more compliant with the scientific advice given than their smaller peers”. The importance of compliance with scientific advice as important predictive factor for successful drug approval was also confirmed for orphan drugs using US data [Heemstra et al, 2011].
To successfully navigate its product through the clinical trial stage a sponsor of an orphan drug has to make use of all available resources: in-house expertise, its external network, consultants with relevant expertise, apply for scientific advice at EMA/FDA level, but also make use of scientific advice by the national regulatory agencies in the EU. I wonder how much the latter is currently being exploited by companies, inexperienced as well as experienced.
- Cost-effectiveness analysis of drug regulation: Remedy for rising costs of drug development ?
- FDA & KGI provide quantitative description of the scientific rationale for orphan designation
- Rarediseasematters.org initiates new analysis of orphan drug development in Europe
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