China is quickly becoming a medical research powerhouse to reckon with. A recent literature search revealed that articles related to basic medical science and clinical research from China increased each year between 2000 and 2009 [Hu]. On average by 31% and 22%, respectively. In 2011, China was ranked fourth according to number of medicine-related publications in the SCImago Country Ranking (In 2000: rank 18). A truly remarkable achievement, although some concern has been expressed with regard to the quality and trustworthiness of the published research. China’s contribution to rare disease understanding is growing as well. A comparison of scientific output for 88 rare metabolic disorders and a dataset of 84 rare nervous system diseases between 1996-1998 and 2009-2011 revealed that China now belongs to the top-10 countries (see Figures below).

China’s growing role in (rare) medical research will certainly make a difference in our understanding of a number of rare diseases. However, to make a truly meaningful difference for the patient, disease understanding has to be translated into orphan drug development or some form of health care innovation. Therefore, it is important to know that China is not only making a difference in understanding disease, but is also focussing more and more on biopharmaceutical innovation [Rezzai]. A recent publication by Rezzai et al.revealed that China has built close to 20 high-tech parks with a life sciences component in the last fifteen years. R&D expenditures as a portion of its gross domestic product has doubled between 2002 and 2007 (~ US$102 billion in purchasing power parity). Finally, between 1999 and 2007 approximately US$200 Million of public funds was devoted to financing biotechnology companies. Perhaps China’s innovation power is best exemplified by SiBiono’s innovative gene therapy product, marketed as Gendicine for treatment of head and neck cancer since 2009.

The combined progress in research and innovation provides China the means to not only generate disease knowledge, but at the same time capitalize on this newly acquired knowledge in drug development. The first “Made in China” orphan drug approved in the EU or US may become a reality soon.

Relative contribution of Top-15 countries to the total scientific output for 88 rare metabolic disorders (1996-1998) - click to enlarge

Relative contribution of Top-15 countries to the total scientific output for 88 rare metabolic disorders (2009-2011) - click to enlarge

Relative contribution of Top-15 countries to the total scientific output for 84 rare nervous system disorders (1996-1998) - click to enlarge

Relative contribution of Top-15 countries to the total scientific output for 84 rare nervous system disorders (2009-2011) - click to enlarge

Note on Methodology: In brief, PubMed was used to determine for every “SCImago” top-15 country the total scientific output. For every disease (prevalence 0,1-50/100,000) a PubMed search string according to Heemstra et al. [2009] was prepared. Via concatenation search strings were combined into one PubMed search string.

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• Orphan drug development: do-able, but tough and requires persistence
• 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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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 !

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• What you always wanted to know about Orphan Drug development……
• China has joined the fight against rare disorders
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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 !

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One of the major hurdles in the rare disease area is translating specific disease knowledge into an orphan drug development program. When I learnt about the Wellcome Trust Pathfinder Award scheme, my response was one of great enthusiasm. Although funding isn’t the only solution, the aim to kick-start early R&D studies in rare diseases certainly contributes to overcoming the translational hurdle. The focus of the scheme on public-private partnerships will also help. After all, apart from funding, there is general consensus that when it comes to developing an orphan drug; collaboration is considered a key success factor. What’s not clear to me is why one of the eligibility criteria of the Pathfinder Award scheme is “Evidence that the company has previously developed and subsequently taken to market one or more product lines arising from its own research and development is required“. In my opinion what would make the scheme even more appealing is if SMEs with no prior experience in bringing a product to the market would also be eligible.

Author: J. Patrick Fischer

Since the introduction of specific orphan drug legislation SMEs have played a central role in the development of the majority of orphan drugs [Torrent-Farnell, ICORD 2005]. In a way this group can be regarded as the engine behind orphan drug development. Besides kick-starting many orphan drug development programs, SMEs have shown to be able to move orphan products from proof of concept into the early clinical trial stage thereby adding significant value. Some have tried to reach the market on their own, but for the late stage clinical development many SMEs sought some sort of partnership with a larger pharmaceutical company. Of course, not every orphan drug development program has been successful, but that’s part of the business. We should focus on the success stories. At the start of the Orphan Drug Act in the US in 1983, companies like Amgen, Genentech and Genzyme were just starting up. These companies were one of the first that profited from the economic incentives to stimulate product development for rare diseases. It allowed them to bring their first products to the market, but more importantly it made a difference for children and adults suffering from Gaucher disease, severely growth retarded children and patients with kidney failure.

A more recent example is AMT/Uniqure, a Dutch SME. Seed funding from public and private sources enabled the company to establish a proof of concept for its technology platform. Additional venture capital and an initial public offering allowed the company to develop the first gene therapy product that has been approved in the western world !

Therefore, my plea to allow SMEs with no prior experience in bringing a product to the market to benefit from the Wellcome Trust Pathfinder Award scheme. I believe this will provide a real boost to pharmaceutical innovation in the area of rare diseases.

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Source: Fresh Water, Author: Ferdinand Reus, Arnhem

The Myrovlytis Trust, a UK-based charity, is making a difference for patients suffering from Birt-Hogg-Dubé syndrome. It does so in many different ways and is accompanied by many more charities. 

Since its foundation in 2007 the Myrovlytis Trust has been funding research into Birt-Hogg-Dubé syndrome (BHD), an inherited genetic condition linked to benign skin growths, collapsed lung and kidney cancers. Recently, the Orphanet Journal of Rare Diseases published a Letter from Vicki Colledge and John Solly of the Myrovlytis Trust. Using BHD as example, the authors argue that symposia, focused on a specific disease, provides a platform to promote research collaboration. Moreover, for extremely rare disorders symposia may be the ultimate way to promote a productive rare disease community and an important information source for patients and other stakeholders. The Myrovlytis Trust is currently expanding its work into related rare genetic kidney disorders.

The Myrovlytis Trust is certainly not the exception to the rule. Many rare disease charities exist (see 200 other examples) and they complement the great work performed by rare disease patient organizations. Some are (still) small, others are huge. Rare disease charities have been around for over 50 years, but it seems that many have been founded in the last decade (See figure below). Whatever their size or foundation year, their work and ambitions go far beyond pump-priming research. Some examples:

Distribution of 200 rare disease charities based on foundation year

• starting a company
• education
• Registries
• Raising awareness
• Community building
• Fund raising tools.

Be sure to visit the Myrovlytis Trust website and get a flavour of what a rare disease charity is all about. Besides funding research rare disease charities have something else in common.

They have the conviction that they can make a difference in the lives of rare disease patients. I for one am thoroughly convinced that they are succeeding.

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This year my family and I spent our summer holiday in one of the most natural, unspoilt environments in Europe: South West Ireland. We stayed just outside the idyllic town of Kenmare, and every other morning I walked to the town’s bakery for some Irish soda bread and not so Irish croissants. One morning my eyes caught a glimpse of a flyer which mentioned “Bee for Battens”. It turned out to be the announcement for a fundraising event for Battens disease, a rare fatal neuro-degenerative condition that affects babies, young children and juveniles. I continued my walk, and to my surprise encountered another announcement for a rare disease fundraising event. This time glutaric aciduria type 1. Being confronted with fundraising events for two extremely rare metabolic diseases in such a remote area inspired me to learn more about Irish rare disease charities.

The driving force behind the Bee for Battens campaign is the Saoirse Foundation, a parent-initiated charity. One of the foundation’s goals is to promote research into the management of Battens disease. Being a founding member of the new Batten Disease International Alliance, the foundation clearly understands that rare diseases know no boundaries (even if they consist of water in the case of Ireland).

Interestingly, the Saoirse Foundation is a member of the Irish Medical Research Charities Group (MRCG), which supports Irish charities “to increase both the quality and quantity of healthcare research being done in Ireland”. In 2006 the MRCG convinced the Irish Department of Health to award “€1 million per annum to the Health Research Board (HRB) for the co‐funding of research projects with medical research charities”. So far, 71 projects have been funded through the MRCG/HRB joint funding scheme. Next to the Saoirse Foundation there are quite a number of other rare disease charities that have joint the MRCG. Be sure to have a look at the website, because the MRCG does much more.

I have to say the Irish co-funding scheme really beguiles me. In fact, it looks like an incentive that could work in other countries. Especially, since every country hosts quite a number of rare disease charities. A little “government” support could make a real difference. Having said that I am also aware that some of these charities really cherish their independence.

Of course, the question remains whether Ireland is unique in its approach to stimulate rare disease research. Perhaps similar co-funding schemes exist in other EU countries. Living in Europe I am very fortunate.  We have the European Union Committee of Experts on Rare Diseases (EUCERD) that provides a wonderful (but quite extensive) annual report on the State of the Art of Rare Disease Activities in Europe. I consulted part V of the 2012 report, but didn’t come across anything remotely similar in other countries.

Ireland may be green, but its way of funding rare disease research is certainly not

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About a week ago I was having a look at a list of countries ranked according to number of medicine-related publications between 1996 and 2010 (SCImago Journal & Country Rank). What struck me the most was that, compared to 1996, in 2010 the top of the list was no longer the exclusive domain of western world countries and Japan. China entered the Top-10 (rank 4, behind the US, UK and Germany), and going down the list I also noticed that Turkey, South-Korea, India and Brazil had really “upgraded” their medicine-related scientific output and even surpassed several western world countries.

This intriguing development encouraged me to find out if the area of rare disorders is following the same trend. To obtain a first impression I prepared a dataset of 88 rare metabolic disorders with a prevalence of 0,1 – 50 patients per 100,000 inhabitants (Source: Orphanet). Next, I used PubMed, the world’s largest repository of biomedical citations, to determine for every “SCImago” top-15 country (1996 and 2010) the total scientific output of the 88 rare metabolic disorders in the period 1996-2011. To achieve my goal I prepared for every disease a PubMed search string according to Heemstra et al. [2009], and via concatenation I combined these search strings into one “all-inclusive” search string and performed the country-specific searches in PubMed.

Although, as you can imagine, the whole exercise has been quite time-consuming, the overall outcome is certainly worthwhile. The two figures below provide a list of the Top-15 countries and their relative contribution to the total scientific output for the 88 rare metabolic disorders at the start (1996-1998) and the end (2009-2011) of the study period, respectively. Comparing the two figures immediately reveals that between 1996-1998 and 2009-2011 Turkey, South-Korea, India and Brazil have surpassed Israel, Sweden, Switzerland, Belgium and Denmark. China did even better and has entered the Top-10.

Relative contribution of Top-15 countries to the total scientific output for the 88 rare metabolic disorders (1996-1998)

Relative contribution of Top-15 countries to the total scientific output for the 88 rare metabolic disorders (2009-2011)

It may sound strange, but I actually regard this trend as a blessing in disguise. Why ? Because a closer look at the raw data reveals an increased scientific output for almost every country included in the study. It’s just that the scientific output by Turkey, South-Korea, India, Brazil and especially China is increasing at a much steeper rate than the western world countries and Japan.

This trend combined with other recent developments (see list below) clearly demonstrates that China has joined the fight against rare disorders.

• Increased awareness
• Emergence of biopharmaceutical innovators
• Innovative drug R&D
• Call for specific orphan drug legislation
• Development of the first rare-disease registry

With countries like Brazil, Turkey, South-Korea, and India also joining it is really turning into a global fight. This will certainly make a difference in the lives of rare disease patients around the world.

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.

http://www.youtube.com/watch?v=8JTw2RpDo9o

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.

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• FDA & KGI provide quantitative description of the scientific rationale for orphan designation

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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?

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• FDA & KGI provide quantitative description of the scientific rationale for orphan designation
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To further accommodate readers, rarediseasematters.org has initiated an e-newsletter service. The e-newsletter includes the most recent blogs as well as interesting regulatory science and other news.

Moreover, as subscriber, if there is a specific “rare disease” subject for my blog that you’re interested in, send me an e-mail: remco@rarediseasematters.org.

It’s not a problem if it requires a certain amount of research. If it is within my area of expertise, I will do my best to include your request in my regular blog. However, being a personal initiative (= free time), I give no guarantees with regard to when and if I will fulfil your request. I thank you for your understanding.

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Remco