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Prof Haluk Topaloğlu

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Published: 04 August 2019

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Emerging genetic therapies for rare disorders at high cost, cannot realistically address the global burden of disease - Stakeholders must develop new pathways to ensure safe, fair and sustainable provision of such therapies

A disease or disorder is defined as rare in Europe when it affects fewer than 1 in 2000 people and based on the Food and drug administration (FDA) definition from the US, when it affects less than 200,000 at any one time. Genetic factors contribute to the etiology in 80% of those with rare diseases, and other contributing factors, including infection, account for the remaining the cases. The recent emergence of gene technologies has led to the development of therapies to treat some of the once incurable diseases. Currently, there are more than 230 gene therapy efforts such as splicing modifiers, exon skipping protocols, monoclonal antibodies, and several ‘molecular plaster’ studies. Increasing numbers of these therapies are being demonstrated to show benefit and are being approved by health care authorities leading to availability in the market [1-4].

However, although these discoveries have provided the real possibility of treatment and cure to previously considered untreatable and often life-limiting diseases, at this point several concerns have arisen including primarily the high cost, access to the intervention and the potential risks [5]. These are mainly based on the following independent factors. First, clinical studies are conducted on a narrowly defined group with a minimal number of cases (usually less than 200), but the therapy is expected to be applied to a more diverse population. For example, a molecule has been approved by the FDA in all types of a given rare genetic disorder, however the original study was only conducted in babies less than 6 months of age [1,6]. Secondly at this time the adverse effects portfolio in relation to these treatments is still accumulating, adequate data may not be available on chronic and late stage forms of disease, and uncertainities exist regarding long term benefits [2-4]. The third issue is related to cost regulation. These drugs are extremely expensive costing up to several million dollars which places governmental bodies and health care providers in a difficult position financially based upon the cumulative cost of several hundred re-imbursements every year causing a true burden on the health economy globally [5, 7]. Last but not least is the issue of the expectations of families which may not match with the study end points. In other words, ‘End point goals’ of patients and families in terms of clinically relevant outcomes and improvements in quality of life may differ significantly from those included in study protocols [8].

Since the 1980s there have been enormous developments in the whole gene therapy field which has led to significant expectations in the community. For the time being, these innovative therapies act as disease modifying procedures at often prohibitive costs. But even if they fall short of mitigating all functional limitations in patients or eliminating morbidities and not fulfilling in total the families’ expectations, those involved in the care of affected children continue to think positively. More effective treatments may be here sooner than expected, although we are still years away from definitive treatments. The cost of these interventions will become an increasing obstacle not only for resource poor settings but also for resource-rich regions if the current trend is maintanied. Going forward there needs to be careful consideration of the cost benefit ratio of these interventions given the limited amount of resources available to provide healthcare to the entire population.

The position statement of the ICNA proposes that counterparts, regulators, decision makers and other party stakeholders should work in unity to address this serious global health matter for vulnerable children and families. Characterizing these perspectives can help support decisions. High cost is a potential barrier to accessing treatment worldwide negating the possibility for impact for the majority of those afflicted.

The Position Statement was compiled by Professor Haluk Topaloğlu and reviewed, adapted and endorsed by the ICNA Advocacy committee (Pauline Samia (chair), Adam Kirton, Russell Dale, Chahnez Charfi Triki, Anaita Hedge, Helen Cross, Edward Kija, Silvia Tenembaum, Richard Idro and ICNA officers Jo Wilmshurst and Ingrid Tein.

References:

1. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. New Engl J Med 2017; 377:1723-1732. doi: 10.1056/NEJMoa1702752.
2. Michelson D, Ciafaloni E, Ashwal S, Lewis E, Narayanaswami P, Oskoui M, Armstrong MJ. Evidence in focus:Nusinersen use in spinal muscular atrophy. Report of the guideline development, dissemination, and implementation subcommittee of the American Academiy of Neurology. Neurology 2018;91: 923-933. doi: 10.1212/WNL.0000000000006502
3. Unger EF, Califf RM. Regarding ‘’ Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 2017; 81: 162-164 doi: 10.1002/ana.24842
4. Groen EJN, Talbot K, Gillingwater TH. Advances in therpay for spinal muscular atrophy:promises and challenges. Nat Rev Neurol 2018;14:214-224. doi: 10.1038/nrneurol.2018.4.
5. Burgart AM, Magnus D, Tabor HK, Paquette ED, Frader J, Glover JJ, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr 2018; 172: 188-192. doi: 10.1001/jamapediatrics.2017.4409.
6. Parente V, Corti S. Advances in spinal muscular atrophy therapeutics. Ther Adv Neurol Disord. 2018 Feb 5;11:1756285618754501. doi: 10.1177/1756285618754501. eCollection 2018.
7. Shawi F, Perras C, Severn M. Emerging drugs for Duchenne muscular dystrophy. CADTH issues in emerging health technologies 2017; 161: 1-19.
8. Pacione, M, Siskind CE, Day JW, Tabor HK. Perspectives on spinraza (nusinersen) treatment study: views of individuals and parents of children diagnosed with spinal muscular atrophy. J Neuromuscular Disord 2019; 6:119-131. doi: 10.3233/JND-180330.

This Open Access article was originally published in the Journal of the International Child Neurology Association (JICNA). 

Citation: Samia, P., Kirton, A., Dale, R., Tenembaum, S., Triki, C., Hegde, A., Idro, R., Kija, E., Wilmshurst, J., Tein, I., & Topaloğlu, H. (2019). Position Statement:Emerging genetic therapies for rare disorders. Journal of the International Child Neurology Association. Retrieved from https://jicna.org/index.php/journal/article/view/172

Related:

The Cost of Drugs for Rare Diseases Is Threatening the U.S. Health Care System (A. Gordon Smith, Harvard Business Review, APRIL 07, 2017)
Hesselgrave BL (2003) Helping to manage the high cost of rare diseases. Manag Care Q 11 (1):1-6. PMID: 12790059.
(2017) Treating rare disorders: time to act on unfair prices. Lancet Neurol 16 (10):761. DOI: 10.1016/S1474-4422(17)30295-8 PMID: 28920873.
High cost of undiagnosed rare diseases (ITV Report: 17 December 2018)

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Shesy Rawther

News

Published: 16 July 2019

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Dear Members,

The   International Pediatric Stroke Organization (IPSO)  has recently been incorporated as a global non-profit organization dedicated to pediatric stroke and cerebrovascular disease. It consists of physicians, surgeons, psychologists, nurses, therapists, and scientists.  

We invite you to consult the  letter attached herewith  (IPSO.pdf) and website for more details  :  https://internationalpediatricstroke.org  

All are welcome to express potential interest by joining the working group:  https://internationalpediatricstroke.us20.list-manage.com/subscribe?u=fbd710760330cb982b781c49b&id=07d9906d9f  

Please share this information with your colleagues and networks interested in pediatric cerebrovascular disease.

This specifically includes  specialties other than pediatric neurology  (NCC, interventional, radiology, neurosurgery, hematology, rehab, etc).   

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Shesy Rawther

News

Published: 24 June 2019

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 The ICNA is very happy to hear that Dr. Greg Powell has been awarded an Order of Australia in the       Queen´s   Birthday Honours list for ´distinguished service to the international community of Zimbabwe in the field of   paediatrics as a  clinician and mentor´.

 Dr. Powell, MD, FRCP, FRACP is an Australian trained paediatrician who has lived in Zimbabwe since 1977. He   was a Senior Lecturer at the University of Zimbabwe Medical School Department of Pediatrics from 1977 until  2001.

 Dr.  Powell’s academic interests have centered on childhood disability and children in institutional care. He   established  the  Children’s Rehabilitation Unit at Harare Central Hospital in 1986 and was the consultant in   charge until 2001. He continues to be actively involved in teaching medical students and consulting at the   Rehabilitation Unit on a part time basis.

 We congratulate Dr. Greg Powell for this well deserved recognition!

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ICNA

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Published: 30 May 2019

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Applications are invited from interested Project Supervisors for Seed Grant Funding under the Global Burden of Disease (GBOD) Research Trainee Fellowship program a new initiative of the International Child Neurology Association (ICNA).

The Award

The award consists of $ 2,000 for room and board for ~ 2-3 months plus up to $ 2,000 for roundtrip airfare.

Timeline

1. The deadline date for receipt of proposals on open competition from project supervisors is August 1.
2. The Scoring and Selection of Grants fulfilling Criteria by Research Task Force Committee (10 point scoring system) will be completed by September 1 and results announced on ICNApedia.
3. The deadline for applications from Prospective Research Trainees will be December 1

Proposal Guidelines

The Letter of Intent (2 pages maximum; 11 point font minimum and one inch page margins, word document) from project supervisor to include the following:

1. 1. PI/mentor role (also to append CV) and contact information. The mentor should be an ICNA member and have an accredited University and hospital appointment.
   2. Title of proposal
   3. Research Site and facilities for trainee
   4. Background and significance
   5. Rationale
   6. Hypothesis
   7. Objectives and specific aims
   8. Research Plan/epidemiologic study design and Methods
   9. Statistical Analysis
   10. Budget (including costs for study and room and board for fellow)
   11. The proposal should be submitted by email to This email address is being protected from spambots. You need JavaScript enabled to view it. 

Practical considerations at local site which should be included in the Letter of Intent (LOI)

1. Assurance that approval by the research ethics board of the hosting institution will be in place prior to beginning of fellowship
2. Adequate population of relevant patient cohort at site (approximate estimate of numbers)
3. Ready access to patients and relevant clinical files with any local administrative costs covered
4. Affordable local room and board in place for research trainee within allotted budget
5. Project start date negotiated between supervisor and trainee to begin within one year of awarded seed grant.

Research trainee criteria

1. Must be a member of ICNA
2. Should have completed two years of an accredited child Neurology training program or be within 5 years of completion of their training program
3. Once the successful proposal(s) is posted on the ICNApedia website, research trainee applicants must provide the following to the project supervisor:
   1. CV
   2. Reference letters – from Program director or Division Head and two other direct supervisors
   3. Statement regarding motivation for project (300 words)
   4. Evidence of completion of certificate for ethical standards in clinical research or equivalent
   5. Potential times of availability for research elective

Applicant selection to be decided by project supervisor and contingent upon approval by the ICNA Research Task Force.

Final Report

1. Publication of the study will be due within 6 months of project completion and will be submitted to JICNA.
2. The study data will also be presented at the next upcoming International Child Neurology Congress.