Regulators move patient engagement to the next level: benefit-risk assessment

Regulatory agencies continue to recognize that the drug review and approval process benefits from the input received from patients or their carers. On 26 September the European Medicines Agency (EMA) announced the launch of a pilot project to involve patients in the assessment of the benefits and risks of medicines in its Committee for Medicinal Products for Human Use. It is just another step in EMA’s ongoing drive to continuously engage in dialogue with patients and consumers.

In accordance with Arnstein’s ladder of citizen participation, involving patients in the healthcare sector can take many shapes and forms. When we specifically focus on the pharmaceutical R&D process, three main levels can be identified. Patients or their carers can be invited to share their real life experience (Information); to contribute their view and preferences (“Advice”); to participate as a true partner in decision-making (“Co-production”). The highest level of participation is where patients are completely in the driver’s seat, for example as principal or as funder of a project (“Control).

EMA’s mission is to foster scientific excellence in the evaluation and supervision of medicines, for the benefit of public and animal health. It believes that patients can bring value to the regulatory process in relation to their real life experience of the disease and treatment. This stimulated me to better understand 1) at what levels does EMA involve patients in its review and decision-making process, and 2) has the added-value of patient engagement be made tangible?

A quick scan of the EMA website already makes one thing clear: The agency engages with patients in a professional and thorough manner.

I have always thoroughly enjoyed the wealth of information that EMA shares with the outside world. It has allowed me and fellow-researchers to perform several studies on orphan drug development. Also in this instance the Agency did not let me down. Through its website a staggering total of 24 documents concern engagement with patients and consumers were at my disposal. Especially, the 2007-2013 annual reports on EMA’s interaction with patients, consumers, healthcare professionals and their organizations provide a really comprehensive overview of the Agency’s work with patients and consumers and explains how patient engagement has evolved over time. Not unimportantly, the documents provide the necessary descriptive statistics I was looking for.

Although EMA has engaged with patients since its inception, it was not until 2005 that the Agency generated a formal framework on how to engage with patients and consumers. Shortly after the Patients’ and Consumers’ Working Party, a core group of representatives from patients’ and consumers’ organizations, was put in place and since then provides feedback and expert advice to EMA on all matters of interest to patients in relation to medicines.

In those early days engagement could be considered as minor league and basically was limited to input on a couple of official EMA documents, like European Public Assessment Reports (EPARs) and Patient Leaflets, and formal membership of one Scientific Committee and the Management Board. In the following seven years the scope and number of patient & consumer involvement in EMA activities has experienced a huge transition. Nowadays engagement can be considered as major league. Patients have become formal members of various Scientific Committees, Working Groups, and the Management Board. Between 2008 and 2012 on average they provided input on 75-80% of EPARs and package leaflets. In addition, nowadays they frequently provide the patient perspective during various advisory group and scientific (advice) meetings.

The burning question of course is: which activities can be considered as patients sharing their real life experience (“Information”); which as patients contributing their view and preferences (“Advice”), and which as patients participating as a true partner in decision-making (“Co-production”). Since workshops and conferences organized by EMA are attended by multiple stakeholders, patients are one of many who merely provide “Information” during such meetings. Inviting patients as experts to Advisory group and scientific (advice) meetings or to review formal documents is another matter. For me these activities qualify as patients contributing their view and preferences (“Advice”). Finally, as a formal member of a Scientific Committee or the Management Board patients contribute to the formal decision or advice in a similar fashion as other members. Consequently, for me these activities qualify as “Co-Production”. Using these definitions, I reviewed the annual reports 2007-2013 and grouped all reported patient & consumer involvement as “Information”, “Advice” or “Co-Production”.

Between 2007 and 2013 the overall number of patient & consumer involvement in EMA activities increased from 76 and 551.

The result depicted in the Graph below reveals that the engagement of EMA with patients & consumers has increased considerably in the last seven years at all three levels. Since 2011 the increase appears to be leveling of. In the last three years around 60% of total involvement is related to invite patients & consumers as ad-hoc experts for documentation reviews, especially patient leaflets and EPARs (~40%), and to provide the patient perspective during various EMA advisory group and scientific (advice) meetings (~20%). Although it took me some effort to identify them, all patient and consumer representatives that participate in EMA activities can be found in the European Experts list.
Around 10% of the total annual patient & consumer involvement with EMA can be considered as “Co-production”. The Patients’ and Consumers’ Working Party forms an important part of this involvement. This is complemented with patients being a member of the Agency’s Management Board and all its Scientific Committees, except the Committee for Medicinal Products for Human Use (CHMP). Of course, depending on the success of the pilot project to involve patients in the assessment of the benefits and risks of medicines in the CHMP the latter may change in the future.

Figure: Development between 2007 and 2013 of patient & consumer involvement in EMA activities categorized as contributing “Information”, providing “advice” or contribute to formal decision process/”co-production”

Figure: Development between 2007 and 2013 of patient & consumer involvement in EMA activities categorized as contributing “Information”, providing “advice” or contribute to formal decision process/”co-production”

What I find important to mention is that going through the annual reports and related documents I did not pick up any signs of tokenism. When it comes to review of EPARs and package leaflets, a steady 40%-50% of patient’s comments results in a change to the text under review. Patient representatives also provide input in the scientific advice process, and a survey by EURORDIS revealed that in around 50% of cases they believed to have made an important contribution to the final outcome. In 2013 patients participated in over 80% of all Scientific Advisory Group and ad-hoc expert meetings. The 2013 Annual report highlights several examples of tangible input by patients that were included in the final advice or report. In 2013 Parents/patients provided valuable input that helped the CHMP reach its final recommendation in relation to a proposed medicine to treat Duchene muscular dystrophy.

EMA also continuously learns from existing experience and to define recommendations and proposals for action through regular consultations with patients & consumers. In 2009 EMA published the outcome of a consultation that focused on how to further develop the interaction with patient & consumer organizations in a more structured way. One aspect that was emphasized was the importance of appropriate support and training for patients/carers involved in the various EMA activities to ensure that “they are fully prepared to participate and know what is expected of them as patient representatives”. Recently, the Agency published a complete training strategy for patients and consumers involved in EMA activities. A 2010 questionnaire by the Agency revealed that at that point in time overall patients & consumers involved in EMA activities were satisfied with the overall process and the opportunity to engage. At this point you may wonder whether there is nothing wrong with the way the Agency engages with patients. Is there any room for improvement? I believe there is.

As mentioned by the Agency in various key documents, Committee meetings are conducted in English. Although this is understandable from a practical point of view, it does limit the pool of patient representatives to those that are fluent enough to allow a meaningful contribution. Occasionally consulting organizations not fulfilling all the eligibility criteria to be involved in EMA activities only partially solves the problem. Moreover, as depicted in the table below, review of the Annual reports 2007-2013 reveals a skewed distribution towards “non-eligible” patient/consumer organizations originating from English speaking countries.Presentation2

There is a need to invest in novel and innovative ways of engagement that allow EMA to tap into the huge pool of patient experts in the rest of Europe, and thereby also spread the burden for patient experts, many of whom work as volunteer.

There are a couple of other things with room for improvement, like financial support, but overall I am impressed how EMA consistently and increasingly involves patients in its review and decision-making process. Although it remains difficult to make the added-value of patient engagement tangible, the Agency does provide concrete examples where patients’ input has made a difference. A thorough investigation into the added-value of patient engagement would be very welcome. It would provide additional insight as well as a set of valuable teaching cases that can benefit other regulatory agencies and patients.

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Rare disease advocates moving into biotech

Yesterday evening Bernard Muller & Robbert Jan Stuit, both diagnosed with ALS, appeared on Dutch television. As established entrepreneurs they founded their own biotechnology company Treeway to speed up ALS research and the development of new therapies. Their website mentions “therapy developed by patients for patients“. They are not the only ones…

Especially in the area of rare diseases, patient advocacy has been an important driving force behind research and therapy development for many diseases. This advocacy has taken the shape of community building, fundraising for research, setting up and maintaining patient registries and biobanks, and even venture philanthropy.

Bernard Muller & Robbert Jan Stuit do not stop there. They see themselves as patient entrepreneurs and with their company Treeway have chosen to be in the driver seat when it comes to drug development for ALS. Their slogan “one man can and will find a way, why not be that man?” applies to more patient/parent entrepreneurs.

The most well-known is probably John Crowley. Father of 2 children diagnosed with Pompe’s disease. He joined Novazyme Pharmaceuticals in 2000 as CEO a year after the company was founded to work on a therapy for Pompe. In 2001 Novazyme was acquired by Genzyme, where until end of 2002 Crowley was in charge of the company’s global Pompe program that ultimately led to the approval of Myozyme in 2006. Watch the 4-min YouTube video below and become inspired.

Different disease, similar story. Daniel de Boer, father of a child diagnosed with Cystic Fibrosis, co-founded in 2012 ProQR Therapeutics, which since then underwent an impressive growth and currently counts about 30 people. Like John Crowley he has teamed up with Henri Termeer, former CEO of Genzyme.

Karen Aiach, mother of a child with San Filippo disease, co-founded in 2009 French biotech Lysogene, which currently focuses on an intracerebral gene therapy for San Filippo. This should pave the way for potential therapies for other life-threatening genetic disorders of the central nervous system. The company has recently successfully complete a phase I/II clinical trial. In a 6-min YouTube video Karen Aiach explains San Fillipo, the genetic therapy and what Lysogene is all about.

Interestingly, in its quest for a cure for San Filippo, Lysogene is joined by another “patient-driven” biotech on the other side of the Atlantic ocean. Phoenix Nest was co-founded in 2012 by Jill Wood and Sean Ekins together with several other parents of children diagnosed with a subtype of San Fillipo, Mucopolysaccharidosis IIIC.

What I find interesting about these entrepreneurs is that, except for John Crowley, they do not have a history within pharma. Instead they originate from the internet, maritime & oil, real estate or financial industry. It is their solid business background that has probably helped them to successfully build a team of scientific, clinical and biotech experts. Are they different from rare disease advocates that focus on peer-support, information and research support? In essence they are not. Like other rare disease advocates, they basically want to make use of their specific skills and work towards a solution for the terrible disease they have been confronted with. They just feel the urge to do that as a biotech entrepreneur.

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Importance rare disease patient advocacy recognized in scientific literature

The concept of patient advocacy organizations and its added-value in the rare disease area is certainly not new. However, a new trend may well be that advocacy initiatives are increasingly becoming the topic of a scientific publication. Many publications are (co-)authored by patient advocates themselves.2012-08-11-08.06.01

Last week I attended a meeting in London and shared with the audience an overview of the role of rare disease patient organizations in biomedical research. This role is also known as the fourth role and complements the three classical roles that the majority of patient organizations fulfill: Peer support, Patient advocacy and Information. As EURORDIS revealed in 2009 in one of its surveys the fourth role by patient advocacy groups is rule rather than exception. Their survey revealed that 37% of 309 organizations financially supported research. Moreover, the contribution of patients to advances in biomedical research is much more than simply funding.

While preparing for my presentation I did a background search on rare disease patient advocacy in Pubmed. I was especially interested to find out whether scientific literature is also being used to clarify the fourth role mentioned above. My Pubmed search (or actually multiple searches, but who is counting) eventually resulted in 14 citations with a specific patient advocacy initiative as the main topic (see below). Furthermore, these citations were complemented by several papers that provided a high-level description of the fourth role of patient organization in the field of rare diseases.

What I really liked about having an overview like this is that it allowed me to identify some commonalities. For example, what becomes clear is that the starting point of an advocacy initiative is often if not always to reach out to patients, researchers, clinicians and to build a community. As Colledge and Solly clearly mention the aim is to “generate a sense of a single BHD community, removing barriers”. This makes perfect sense, considering the problem that many rare disease patients/families face and which is eloquently defined by Terry: “No one knew how this disease progressed; no comprehensive plan to study the disease, nor was there a plan emerging; no one knew how many people had the treatment; there was no treatment, the gene had not even been discovered yet”.

This community building can take the shape of a conference or meeting as described for neuroacanthocytosis, but can also be virtual and take the shape of a wiki as is the case for Marshall-Smith syndrome. Those that have been around for some while often have gone on to build patient registries and/or generate and maintain biobanks, for example the Chordoma Foundation.

What came to me as rather a surprise was the actual publication date of the papers. Ten of the fourteen papers were published in the last 2 years. In the table below I have provided an overview of my search together with hyperlinks to abstracts (and full papers where available). These “case studies” may serve as a source of inspiration to patient organizations that are currently considering to play a more active “fourth” role in biomedical research. To overcome potential language obstacles with non-English-speaking patient organizations, perhaps an idea would be to provide translations of papers through the RareConnect service of NORD and EURORDIS.

Patient organization Year of publication Hyperlink to abstract
Advocacy for Neuroacanthocytosis Patients 2013 An Ultra-rare Disease? Where Do We Go from Here?
Jonah’s Just BegunHannah’s Hope FundHereditary Neuropathy Foundation 2013 Multifaceted roles of ultra-rare and rare disease patients/parents in drug discovery.
PXE International 2013 (but also 2007, 1997) Disease advocacy organizations catalyze translational research.
Chordoma Foundation 2012 One in a million: A common goal for an uncommon cause connects patients who share a rare disease.
Lam Foundation 2012 How much would you give to save a dying bird? Patient advocacy and biomedical research.
International Marshall-Smith Support group 2010 Phenotype and natural history in Marshall-Smith syndrome.
Progeria Research Foundation 2012 Progeria: translational insights from cell biology.
Myrovlytis Trust 2012 The rare disease challenge and how to promote a productive rare disease community: case study of Birt-Hogg-Dubé symposia.
Friedreich’s Ataxia Research Alliance 2014 Foundation-industry relationships–a new business model joint-venture philanthropy in therapy development.
US Hereditary Angioedema Association 2013 Rare disease partnership: the role of the US HAEA in angioedema care.
Muscular Dystrophy AssociationALS AssociationALS Society of Canada Motor Neurone Disease Association UK 2013 Funding agencies and disease organizations: resources and recommendations to facilitate ALS clinical research.
Daniella Maria Arturi Foundation 2011 Patient advocacy in Diamond Blackfan anemia: facilitating translational research and progress towards the cure of a rare disease.
Spierziekten Nederland 2010 The role of patient advocacy organisations in neuromuscular disease R&D–The case of the Dutch neuromuscular disease association VSN.
Cystic Fibrosis Foundation 2009 Cystic fibrosis foundation: achieving the mission.

NOTE: Another example was supplied by:

22q 11 Ireland Support Group in 2014: Developing an information leaflet on 22q11.2 deletion syndrome for parents to use with professionals during healthcare encounters.

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New in OJRD: Drug development for exceptionally rare diseases: tough but possible

Level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products. To what extent is this linked to sponsors deciding to apply for an orphan designation ? A recent publication in the Orphanet Journal of Rare Diseases provides more insight into this matter.

Star_of_africa_The study was inspired by the observation that, although not abundantly, approved orphan medicinal products for exceptionally rare diseases (<10 patients per 1 million) certainly exist. The University of Utrecht and Rare Disease Matters wanted to know whether orphan designation applications for exceptionally rare metabolic diseases were associated with the level of available scientific knowledge and prevalence. Other factors included in the study were metabolic disease class, prognosis and time of first description of the disease in the literature.

In total, 166 rare metabolic genetic diseases were included in the analysis. For only 42 (25%) of the diseases an orphan designation application was submitted at either FDA or EMA before January 2012. A multivariate analysis identified preclinical proof of concept of a potential medicinal product as major knowledge related determinant associated with an orphan designation application. Prevalence of the disease was also found to be associated with filing an application for an orphan designation.

To continue to article->OJRD

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New book chapter on Translating rare disease research into potential therapies

Drug innovation cycle: From clinical picture to product becoming available to patient

Drug innovation cycle: From clinical picture to product becoming available to patient

Proust once said “The real voyage of discovery consists not in seeking new landscapes, but in having new eyes”. 

In a new book chapter “Why R&D into rare diseases matter“, I explain that translation of rare disease research into orphan drug development continues to represent one of the most important steps towards alleviating the burden for patients suffering from a rare disease. Developing an orphan drug is certainly feasible, but also tough, not without risk and requires a great deal of persistence. Countries across the globe have joined the fight against rare disorders. Apart from western world countries and Japan, other countries, like China, India and Turkey have stepped into the arena thereby really making it a global fight against rare disorders. Of course, this should be done in close interaction with all stakeholders, including patient organizations and learned societies.


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Rare disease-focused foundations: start small, think big

Rare disease-focused foundations have been founded by patients or their relatives with the aim to generate sufficient disease understanding that can form the basis for a potential treatment. Well-known examples are the Cystic Fibrosis Foundation and the Muscular Dystrophy Association who grant tens of millions of dollars in the area of research. However, such endeavors are certainly not the exclusive domain of large foundations. There are many smaller ones who start small, but already think big. 

Patient organizations have been instrumental in raising awareness for rare diseases. This is only one aspect of the central role that patient organizations continue to play in the field of rare diseases. Another one that allows them to make a difference is funding research. A 2009 survey by the European organization for rare diseases EURORDIS revealed that 37% of the patient organizations that responded to the survey (N=309; overall response rate 40%) had funded research in the last five years. Half of these organizations spend more than 30 000 euros yearly and one quarter spend more than 112 000 euros a year. Such a level of funding may come across as small, but please bear in mind that for some exceptionally rare diseases this may actually represent the first step into unravelling the pathobiology of these diseases.


These small foundations follow in the footsteps of larger ones, like the Cystic Fibrosis Foundation, the Muscular Dystrophy Foundation and the French Muscular Dystrophy Association (AFM). These large foundations have moved beyond the classical role of research funder. They have adopted a venture philanthropy business model to pro-actively accelerate the transition of basic research to product development. Part of the model is to form strategic partnerships with biotech and pharma companies. If you want to read more about this subject, I can highly recommend an article by Gambrill. It contains a concise overview of five (rare) disease-focused foundations who adapted their strategy to allow them to reap the benefits from their funded research.

Obviously, such a role may not be envisaged for smaller rare disease-focused foundations. Their limited resources and revenues have to be spent with even greater care than their large counterparts to ensure maximum impact. A study by Wood et al. in the August issue of Drug Discovery Today provides some anecdotal evidence that small foundations are capable of moving beyond the traditional patient role. The authors provide three inspiring stories of Jonah’s Just Begun, Hannah’s Hope Fund, and the Hereditary Neuropathy Foundation. What is fascinating about these stories is that all three foundations pursue rare disease research on a very small budget with very few resources at their disposal, but combine this with an extraordinary ability to connect with scientists and to raise the necessary funds that can make a difference.

These are just three examples of a large group of rare disease-focused foundations that may be small, but already think big.


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RANKL cytokine: potential cure for rare bone disease

putting science into practice (1)

The RANKL cytokine acts as the primary signal for bone removal, and as such plays a crucial role in bone homeostasis. In 2010, Amgen’s denosumab, a monoclonal antibody against RANKL was approved in the US and EU for the treatment of postmenopausal osteoporosis and cancer-related osteolysis. In a recent review in Clinical and Developmental Immunology, Iacono et al. describe that genetic defects in the RANKL cytokine are linked to a specific form of autosomal recessive osteopetrosis (ARO), a rare bone disease. This link may hold a key to a cure for this form of osteopetrosis.

Normal bone growth is accomplished by a balance between bone synthesis and bone resorption. Two cell types play a central role in bone homeostasis: osteoblasts (synthesis) and osteoclasts (resorption).

A shift in the balance towards bone resorption leads to a decrease in bone mass – better known as osteoporosis. An increased bone synthesis leads to osteopetrosis, an extremely rare inherited disorder. Despite this excess bone formation, people with osteopetrosis tend to have bones that are more brittle than normal. Osteopetrosis is not one disease, but actually comprises a clinically and genetically heterogeneous group of conditions, ranging in severity from asymptomatic to fatal in infancy. Patients with a severe form of the disease experience very severe growth retardation and bone defects including deformities. They can develop anemia and become transfusion dependent, requiring the use of chelating agents. Also blindness, deafness and severe headaches are not uncommon. Currently, Hematopoietic stem cell transplantation (HSCT) is considered the only durable cure for the majority of patients affected by osteopetrosis.

In 2007 the group of Sobacchi identified mutations in the RANKL gene in a number of families affected by autosomal recessive osteopetrosis (ARO). These mutations were found to affect the conformation and binding activity of the cytokine, but can also result in protein instability or misfolding. Since it was already known that the RANKL cytokine plays a central role in bone resorption, the authors hypothesized that the RANKL cytokine could be an interesting therapeutic approach for patients suffering from RANKL-dependent ARO. Since HSCT is not effective in patients suffering from RANKL-dependent ARO, an alternative therapeutic approach is clearly warranted. Several pre-clinical studies have confirmed that the administration of soluble RANKL has a great impact on metabolism and structure. However, it was the group of Sobacchi, using a RANKL gene knock-out mouse model, who provided evidence that administration of soluble RANKL almost completely rescued the bone defect by restoring bone removal.

As Iacono et al. conclude:“the recognition of direct RANKL involvement in a genetic rare disease can constitute one of the few cases in which the result of a genetic study could also be translated into a replacement therapy.” Of course the proof of the pudding is in the eating. Next step is to determine whether soluble RANKL is effective in patients affected by RANKL-dependent ARO, and represents a viable therapy for these patients.

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Need for a YoungEUCERD platform to help securing the future of rare diseases

Within Europe consensus exists that future public expenditure on health care requires greater scrutiny and efficiency, in particular in pharmaceutical spending. Although not completely clear, being an integral part of the healthcare system, the field of rare diseases is under scrutiny as well. Flexibility will be required from all parties involved to effectively adapt to the changing healthcare climate. Being flexible has always been a trade of the rare disease community, but the current challenge is a formidable one. This time we may have to come up with really unconventional solutions through a considerable amount of healthy “out of the box” or creative thinking. When it comes to “out of the box” thinking our young and bright scientists and entrepreneurs may hold a key to successfully cope with the challenge that lies ahead of us.

During one of my many google searches I came across the Forbes annual listing of 30 under 30. The listing contains for a total of 15 fields a description of 30 of the brightest young disruptors, innovators and entrepreneurs. In the field of science & healthcare Joshua Sommer, age 24, was at the top of the list. Joshua Sommer is the executive director of the Chordoma Foundation. At the age of 18, he was diagnosed with chordoma, a rare bone cancer for which there was a 30% cure rate and no approved drugs. When he discovered that a lack of research funding was a major cause for little research being done into chordoma he took the initiative to found the Chordoma Foundation. Since its inception the foundation has raised over $2.5 million, funding research in 11 labs.

“Sommer’s advice to people diagnosed with a potentially fatal disease? You have a lot of power” (Forbes website)

Why am I sharing this with you ? Well for one thing there are many more young people like Joshua Sommer out there that are trying to make a difference. Apart from starting foundations, they also start their own companies like Dutch entrepreneur Daniel de Boer did (ProQR Therapeutics). Moreover, there are many young bright scientists that I consider the engine behind the advancement of our understanding of the 6000-8000 rare diseases.

This brings me to the question I would like to share with you. Do we sufficiently “exploit” the energy and brain power of the Joshua Sommers and Daniel de Boers of this world ? When it comes to “out of the box” thinking this generation may hold a key to successfully cope with the challenge that lies ahead of us. They may think of really unconventional solutions. Please remember that this generation through Mark Zuckerberg also delivered Facebook.

The question is how do we channel all this energy and potential flow of radical ideas ? Perhaps it is an idea to create some sort of social platform of the bright and young that acts as a radical think tank. Maybe in Europe perhaps the EU Committee of Experts on Rare Diseases (EUCERD) could take the lead in supporting such a platform. Some of you will remark that EUCERD was formally established via the European Commission (EC) Decision of 30 November 2009 (2009/872/EC). As such the idea may be too radical as the EUCERD can only act within the mandate given by the EC. Fortunately, EC Decision 2009/872/EC allows some maneuverability in this respect. According to Article 7 of the Decision “The Committee may set up temporary working groups”. Furthermore “Working groups consist of external experts selected according to their specific expertise”. A “Working group” of bright young disruptors, innovators and entrepreneurs in the field of rare diseases could certainly fall into this category.

I would love to hear from such a YoungEUCERD platform how they believe we can secure the future of rare diseases.

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“Made in China” orphan drug may soon be reality

Napoleon Bonaparte once said of China, “Let her sleep, for when she wakes, she will shake the world.” When it comes to rare diseases China has awoken and belongs to the top-10 countries based on scientific output. China doesn’t just stop at research.

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

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).

Study Title
Heemstra,   2008 Predictors of orphan drug approval in the European Union.
Heemstra,   2011 Characteristics of orphan drug applications that   fail to achieve marketing approval in the USA.
Putzeist, 2012 Determinants for successful marketing authorization of orphan medicinal products in the EU.
Regnstrom, 2010 Factors associated with success of market authorization applications for pharmaceutical   drugs submitted to the European Medicines Agency
Joppi, 2006 Orphan drug development is progressing too slowly (EU)
Kesselheim, 2011 To define characteristics of orphan cancer drugs and their pivotal clinical trials and to compare these with nonorphan drugs (US)
Mitsumoto, 2009 Pivotal studies of orphan drugs approved for   neurological diseases (US)
Orfali, 2012 Comparison of clinical trials described in package inserts from noncancer orphan and nonorphan drugs
Joppi, 2012 Assess the methodological quality of Orphan Medicinal Product (OMP) dossiers
Bashaw, 2012 Clinical pharmacology and orphan drugs: an informational inventory 2006-2010.
Lev, 2012 The routes to orphan drug designation–our recent experience at the FDA

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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