Rare disease matters

For those working in the field of orphan drug development there is quite some interesting scientific literature available. An overview with hyperlinks of relevant scientific publications on orphan drug development has been included in this Month’s blog. However, although the science is interesting, what is important is to learn from the experience of orphan drug developers themselves. Orphan drug development is do-able, but tough and requires persistence.

In my last blog I provided an overview of orphan drugs (OD) approved in the EU in the period 2000-2010. The overview by Joppi et al. covers in depth preclinical and clinical information for each OD. As such it provides very useful background information for those currently working on the (clinical) development of an orphan drug. What I didn’t share with you is that the authors not only provided an overview, but also expressed considerable criticism with regard to the quality of the registration dossiers. The authors in particular questioned the level of clinical development programmes. In their opinion “the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate”.

Several of these aspects have been studied by Heemstra [2008, 2011] and Putzeist [2012]. In particular pivotal clinical trial stage, size/experience of the sponsor and regulatory dialogue were found to be critical factors for successful orphan drug development. There is more literature out there that provides quite interesting reading material (see table below).

Science certainly helps to better understand orphan drug development. However, it is always good to also learn from practice: the orphan drug developers themselves.

I was in luck. At 29-30 November I attended the World Orphan Drug Congress in Geneva to present some of my work. The meeting allowed me to learn about the clinical development programmes of UniQure, Genzyme and Vertex Pharmaceuticals. For those unfamiliar in the OD-field these are not just any companies. Genzyme is generally considered as one of the frontrunners in orphan drug development. UniQure has developed the first gene therapy product Glybera that has been approved in the western world. Vertex pharmaceuticals has been responsible for the development of the new innovative Cystic Fibrosis product Kalydeco. What these companies clearly showed is that clinical development of an orphan drug is certainly not impossible, but tough and not without risk. To name a few: the number of patients is limited, regulators seem to be uneasy with innovative products and rare diseases can be highly heterogeneous in phenotypic expression.

Above all the companies expressed an incredible amount of persistence to reach their goal: Making a therapy available to the patient.

I wish everybody a merry Christmas and for 2013: Be persistent in whatever you do, I certainly will !

Related posts

• What you always wanted to know about Orphan Drug development……
• China has joined the fight against rare disorders
• Estimating rare disease prevalence: a tough nut to crack ?
• The role of regulatory dialogue in orphan drug development – friend or foe ?

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This week a wonderful overview of orphan drugs (OD) by Joppi, Bertele and Garattini was published in the October issue of the European Journal of Clinical Pharmacology. The overview covers in depth preclinical and clinical information for each OD approved in the EU in the period 2000-2010. As such it provides very useful background information for those currently working on the (clinical) development of an orphan drug.

Those thinking of entering or those that have just entered the orphan drug arena, should be aware. Approval of an orphan drug is certainly feasible, but is accompanied by difficulties, in particular during the clinical development stage. The crucial question that every orphan drug developer will (have to) address is: which development strategy is most likely to be successful. SMEs are faced with the decision to license or sell promising products to larger companies or to develop the product under their own steam. Larger pharma, although not new in the OD area, are not always aware of the peculiarities that surround clinical development of an OD. A standard clinical development strategy in OD development is the exception rather than the rule.

The latter is best demonstrated by the recent overview of orphan drugs approved in the EU provided by Joppi, Bertele and Garattini  and published in the October issue of the European Journal of Clinical Pharmacology. For those unaware, the authors provided a similar overview in 2009. The 2012 overview provides in depth preclinical and clinical information for each OD approved between 2000 and 2010. Apart from general details, like product name and indication, the overview includes: whether protocol assistance was used; dose finding study performed; the type of pivotal trial, including details (control, end-point, number of patients and duration of the study).

Last year I received a request for a detailed overview of approved ODs from the CEO of a quite successful OD company. The 2009 overview not only contained the necessary information, but allowed me to fulfill the request within a matter of minutes. As such, I consider the 2012 overview a real added-value for orphan drug developers, be it an SME or larger pharma. Moreover, it emphasizes the added-value of this kind of research as well as the need for research that enhances our understanding of the orphan drug development process. There is much more information out there. Some of it I will present at the World Orphan Drug Congress in Geneva on 30 Nov. Hope to see you there !

Related posts

• China has joined the fight against rare disorders
• Estimating rare disease prevalence: a tough nut to crack ?
• The role of regulatory dialogue in orphan drug development – friend or foe ?
• FDA & KGI provide quantitative description of the scientific rationale for orphan designation

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Telemedicine, social media, mobile medical Apps, stem cells……. just a few examples of innovations that are quickly becoming an integral part of modern (rare disease) health care. At the same time these innovations in medicine seriously challenge our current regulatory framework. 

On 30 April 2012, the European Medicines Agency (EMA) released a reflection paper on the classification of advanced therapy medicinal products (ATMPs) for public consultation. In principle, gene therapy, cell therapy, and tissue-engineered medicines should qualify as ATMPs. However, what became clear to me after having read the reflection paper is that in reality classification of ATMPs is complicated.

In particular classification of stem cell therapies may be the subject of considerable discussion. For those not fully familiar with the concept of stem cells, I can highly recommend a wonderful introductory video by the Irish Stem Cell Foundation, a non-profit organization. In brief, there are three types: embryonic, adult, pluripotent. Each type has a unique set of pros and cons.

In the EMA reflection paper it is stated that ”Products consisting of cells or tissues may scientifically be at the border between Tissues and Cells directive (Directive 2004/23/EC) and the advanced therapy Medicinal Products (ATMP) regulation (Regulation (EC) No 1394/2007). Whether stem cells will classify as an ATMP depends on the level of manipulation during preparation of the product, because this entails a risk of change in the product’s biological characteristics. A second important question is whether the product is “intended to be used for the same essential function in the recipients”.

Where does this leave adult autologous stem cells ?  In the US, 21 CFR 1271 has recently been changed, and consequently many adult autologous stem cell therapies will (have to) be considered as drug products. However, in a recent issue of the Journal of Translational Medicine Freeman & Fuerst argue that this type of therapies should be considered as practice of medicine, rather than a drug product. Of course, protecting the interest of patients should always come first and the authors do not question the important role of the FDA in safe-guarding the health of the US. However, Freeman & Fuerst express a serious concern that implemented regulatory changes hold little societal benefit and are in fact stifling medical innovation in the area of adult autologous stem cell therapy.

What it all seems to boil down to is striking the right balance between ensuring patient safety and allowing timely access to innovations in medicine with a real added-value.

Unfortunately, like beauty, the right balance is in the eye of the beholder.

Related posts

• Estimating rare disease prevalence: a tough nut to crack ?
• The role of regulatory dialogue in orphan drug development – friend or foe ?
• 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

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How can one retrieve reliable and acceptable data on rare disease prevalence and do specific resources exist that can be consulted ? That was an inquiry I recently received. Having received similar questions in the past, I wondered if orphan drug developers find it difficult to estimate rare disease prevalence ?

Products intended for the diagnosis, treatment or prevention of rare diseases that fulfill a set of predefined criteria are eligible for an orphan designation. In the EU, a rare disease is defined as a disease with a prevalence fewer than 5 patients per 10 000 residents. In the US, a rare disease is defined as a disease with a maximum of 200 000 patients.

A bit of history……………John Snow was an English physician living in the 19th Century. He is considered to be one of the fathers of epidemiology, because of his work in tracing the source of a cholera outbreak in England (Source: Wikipedia)

It will take a considerable effort to determine if orphan drug developers find it difficult to estimate rare disease prevalence. A survey could do the trick. Yet I believe there is a more simple way to start with.  There is already information that, if made available, can shed a lot more light on this issue and will allow the rare disease community as a whole to benefit in many different ways. Let me explain.

To assist orphan drug developers, both the EMA and FDA provide guidance for estimating the prevalence of a rare disease. In particular, the EMA points to consider document strikes me as highly informative and as an excellent starting point for orphan drug developers to collect reliable and acceptable prevalence data.

In the EU almost 1000 orphan designations have been granted thus far. One could argue that this enormous group of winners demonstrate that providing convincing prevalence data to the EMA is feasible. However, this is only one side of the story. A recent publication in Nature Reviews Drug Discovery revealed that ”the success rate of these applications is approximately 70%”. This means hundreds of orphan designation applications exist that have been withdrawn before the EMA could issue an opinion, which I assume would have been negative. This group of withdrawn orphan designation dossiers contains a wealth of information. Just to start: review of these dossiers could quickly reveal whether the inability to provide convincing prevalence data has been an important reason for withdrawal.

Unfortunately, as stated in an EMA FAQ-document: “When the application is withdrawn, no information on the application is made public”. Quite understandable as such a policy avoids the release of so-called commercially-confidential information. However, if we turn to withdrawn marketing authorization applications, the EMA has a completely different policy. For each marketing authorization application withdrawn after day 120 of the centralized procedure, the EMA issues a so-called withdrawal assessment report, which can be quite extensive [Example]. I am curious to learn what differentiates withdrawn marketing authorization applications from withdrawn orphan designation applications with regard to release of information ?

With regard to estimating rare disease prevalence, in my view, there is also a lot we can learn from the huge group of orphan designation winners. What kind of search strategies did they use? Which data sources were consulted ? I fully understand that the release of commercially-confidential information has to be avoided under all circumstances. However, recent scientific publications [Regnstrom, Putzeist] clearly show that sharing valuable know-how by the EMA is certainly not a mission impossible. The latter is not only highly appreciated by orphan drug developers, but is also in the interest of the rare disease community as a whole.

The obvious question that remains: Will this be a tough nut to crack?

Related posts

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