The role of regulatory dialogue in orphan drug development – friend or foe ?

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.

salvarsan-pharmaceutical innovation

A bit of history... In 1909 Paul Ehrlich and his student Sahachiro Hata at the German National Institute for Experimental Therapeutics in Frankfurt developed Salvarsan, a treatment effective against syphilis. The product, manufactured by Hoechst AG, was in the clinic by 1910 (!) and became the most widely prescribed drug in the world at that time. (Source: Wikipedia. Credits image 'Salvarsan-pharmaceutical innovation': Science Museum, London.)

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).

 

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.

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2 Responses to The role of regulatory dialogue in orphan drug development – friend or foe ?

  1. C. R. Camozzi says:

    I do agree with erly interaction with SA of EMA and FDA in order to align theexisting scientific knowledge with regulatory requirements during the review process. The early interaction with regulatory will increase the efficiency of the clinical development program in order to bring a safe and effective therapeutic solution to patients with rare diseases. The conclusion “The importance of compliance with scientific advice as important predictive factor for successful drug approval was also confirmed for orphan drugs using US data ” is not necessarilly correct. Complying with SA is not predictive factor of CHMP approval. There are examples that expose the contradiction.
    The second point that may be explored more extensively is : “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”. In fact the compliance to SA by large and financially powerful companies is linked to the fact that they can afford whatever SA requests/advise. For SME is more complex and innovative options should be implemented. This fact becomes more evedident when the product is an Advenced Therapy like gene or cell therapies.

    • admin says:

      Dear Dr. Camozzi,

      Thank you for your comment, which I really appreciate, because it is based on practical experience. You raise an important limitation of the studies I mention, namely that the results are expressed in likelihood. Your point is well taken: Likelihood should not be interpreted as “if you comply with advice from EMA or FDA your product will be approved”. Your suggestion to explore the difference between large companies and SMEs more extensively is a valid one, but complicated to investigate. Apart from size, they may also favour different types of product and rare disease. As you are aware I am sure SMEs have been the engine behind orphan drug development, including quite a number of advanced therapy product.

      Remco

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