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Generics and Biosimilars Initiative Journal For personal use only. Not to be reproduced without permission of the publisher (editorial@gabi-journal.net).
Generic and therapeutic orphans There are a few examples of private, e.g.
Gates and Clinton Foundations; and public- not-for-profit Novartis Coartem malaria ini- tiative; that target infectious diseases seen mainly in the developing world [5], that are This commentary discusses the need to develop methods designed to make drugs available even to ensure the availability of non-profitable, off-patent when there is no potential for profits.
There is also an off-patent programme run medicines to children and other populations. The history by the National Institute of Child Health and some of the shortcomings of legislative attempts to provide drug therapy to children are briefly reviewed. described briefly. However, too little is Some examples of the inability of the current generics and testing, improvement or labelling of non-generics pharmaceutical industry as well as the cur- unprofitable, off-patent drugs. In fact, there are growing problems just maintaining the rent development and drug production system to ade- availability of such off-patent drugs. quately respond to the needs of children and other ‘orphan’ populations are then discussed. Finally, some and adults, in the developed as well as sions are simply not being developed.
Keywords: Off-patent drugs, orphan, paediatric
Adecade ago Dr Harry Shirkey Prescription Drug User Fee Act [2]. This ing approval today; that do not represent data, clinical trial infrastructure, paediatric friendly formulations and drugs especially labelling and marketing process [1]. While for paediatric use [3]. The success of these opment, testing, production and marketing children over the last decade, inadequate initiatives is likely to have encouraged the of ‘new’ treatments for rare, ‘orphan’ dis- EU to develop similar, improved, and more eases for which no effective therapies are despite major legislative, infrastructure available [6]. These programmes target a dif- ferent, although related, problem which is Legislative initiatives, initially in the US and later in Europe and other countries, have Despite major legislative, pharmaceutical This commentary calls attention instead to marketed, apparently effective, off-patent ment of products to treat children, there drugs for which little or no generic drug include parts of the FDA Modernization Act by current drug development processes.
Children Act (BPCA, Title V of Public Law of which drug shortages occur, or produc- 110-85) which provided financial incentives stimulate discussion of possible solutions tion even stops and for which neither the for testing of on-patent drugs in children.
to these problems especially as they relate of the Pediatric Research Equity Act (PREA, Title IV of Public Law 108-155) which gave mides, valproic acid, and the drugs tested ability and testing of profitable drug prod- nent, they are subject to legislative renew- al every five years–next in September 2012 current, economically driven, drug devel- Author: Professor Philip D Walson, MD, Visiting Professor, Department of Laboratory Medicine, University Medical Center, DE-37073 Goettingen,
Germany, pwalson1@aol.com
Submitted: 23 August 2011; Revised manuscript received: 23 October 2011; Accepted: 24 October 2011 GaBI Journal | www.gabi-journal.net
2012 Pro Pharma Communications International. Al rights reserved Generics and Biosimilars Initiative Journal Bromide was first described by Sir Charles Locock in 1857 [7], as an effective treatment for seizures [8]. It is still used in veterinary medicine [9, 10] where it is available in solid A listing of recently prioritised drugs [14] toxicity, but not lack of efficacy, was a major problem with its use in humans. It is beyond the scope of this article but much if zole, benzathine penicillin G, ampicillin, not most of its toxicity was the result of improper dosing. Because of its extremely there is enough of a patient/disease pop- long half-life (weeks), it should be dosed ulation to guarantee profits is there any inhibitors, beta-blockers, and sodium nitro- chance that the testing necessary to find prusside), asthma drugs (albuterol and deli - very devices), anaesthetic/sedative agents effective. Until about 20 years ago it was treatments for possible terror attacks (prali- doxime and antibiotics), cancer drugs (13- seizures resistant to other available, tradi- cis-retinoic acid, methotrexate, vincristine, served ‘orphan’ populations; paediatric prednisolone, dexamethasone, me thyl pred - were developed [11] and a number of older AEDs had generic versions developed.
allow the NIH to do such testing and for- drugs (lithium and atypical antipsychotics), There was and continues to be no incentive for either brand or generics manufacturers to test bromide adequately to obtain mar- keting approval. Because of this it became essentially impossible to obtain bromide, even for patients whose seizures were total- ly responsive only to bromides. No ‘spon- have come from the generics industry.
sor’ was willing to test, manufacture or sell bromide; and practitioners were unwilling existing NIH funding (always uncertain).
work required to allow its investigational use in patients. In addition, marketing of (PUMA) legislation to deal with this prob- both the older, generic drugs but especially lem. As part of its legislation designed to ucts for small, mostly paediatric popula- expensive, rigorous scientific testing data tions. It is hoped that once such data are available, at no cost, industry partners will became essentially impossible to test the patients whose seizures are responsive only Inc [17]. While too soon to be certain how to bromide. It is possible but highly unlike- NIH to develop both valproic acid as well well this will work, it is important to note as many of the newer anticonvulsants.
cial sources could be obtained and there is Unfortunately, this is an extremely small absolutely no incentive for any for-profit company to perform such testing for a treat- to the problems it is attempting to solve. ed, evolving system to prioritise drugs for script P); and c) use of the innovator’s This is analogous to the situation that exist- paediatric population, severity of the con- ditions being treated and the potential for and is used in other neuro-psychiatric con- atric population. The list of drugs needing products. A priority listing of off-patent ditions, but it was tested and marketed in drugs for which studies are suggested has the US only because of a unique, National cess of the EMA paediatric on-patent drug GaBI Journal | www.gabi-journal.net
2012 Pro Pharma Communications International. Al rights reserved Generics and Biosimilars Initiative Journal off-patent, generics process is illustrated try action to deal with this problem. The PUMA: European Regulation No. 1901/2006. Trouiller P, Olliaro P, Torreele E, Orbinsky J, h e a l t h / h u m a n - u s e / p a e d i a t r i c - m e d i - increases the access to and decreases the Laing R, Ford N. Drug development for neglec- ted diseases: a deficient market and a public- However, it does little to insure access to health policy failure. Lancet. 2002;359:2188-94.
A different, important but related problem Cote TR, Xu K, Pariser AR. Accelerating orphan drug development. Nat Rev Drug Discov. 2010;9: Steinhoff BJ. Antiepileptic therapy with bro- mides-historical and actual importance. J Hist tinued manufacture of lower cost alterna- there were in 2005 (61) and 2006 (58).
tives to more profitable, no more effective Friedlander WJ. The rise and fall of bromide the- rapy in epilepsy. Arch Neurol. 2000;57:1782-5.
Podell M, Fenner WR. Bromide therapy in refrac- included cancer drugs, anaesthetics, opi- Unless or until reliable sources of funding tory canine idiopathic epilepsy. J Vet Intern Med.
are identified which supports the testing, gency ‘sterile injectables’ which are ‘crash Trepanier LA. Use of bromide as an anticonvul- cart’ drugs. While not all were generics red, perhaps some of the funds ‘saved’ by sant for dogs with epilepsy. JAVMA. 1995;207(2): products and the result of a variety of rea- insurers or ‘generated’ by manufacturers French JA. New generation antiepileptic drugs: what do they offer in terms of improved tolera- For patients
bility and safety? Ther Adv Drug Saf. 2011;2(4): medicines given to children. Some laws in Meunier H, Carraz G, Meunier Y, Eymard P, Aimard M. Propriétés pharmacodynamiques de large profits exist. It is not so clear that l’acide n-dipropylacetique. Therapie. 1963;18: US Government Printing Office, Federal Digital profitable populations. It is also at least However, there is little or no incentive for Pharmaceuticals for Children Act (BPCA) Priority List of Needs in Pediatric Therapeutics. Federal Register. 2011;76(63):18228-18229. Available respond to such shortages might decrease.
from: http://www.gpo.gov/fdsys/pkg/FR-2011- ceutical industry share responsibility to Best Pharmaceuticals for Children Act (BPCA), find a way to develop and adequately test National Institute of Child Health and Human medications to be used in children as well Development (NICHD), National Institutes of the brand name or generics industries.
as other non-profitable patient groups.
Health [homepage on the Internet]. [cited 2011 Dec 11]. Priority List of Needs in Pediatric Conflict of inter est
Therapeutics for 2008–2009 as of September 1, 2009. Available from: http://bpca.nichd.nih.
g o v / a b o u t / p r o c e s s / u p l o a d / 2 0 0 9 - S u m m a r y - monitors paediatric off-patent drug trials Giacoia GP, Taylor-Zapata P, Mattison D. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Pediatric for- mulation initiative: selected reports from working groups. Clin Therap. 2008;30:2097-101.
Refer ences
Milne C, Bruss JB. The economics of pediatric Shirkey H. Therapeutic orphans. Pediatrics. 1999 formulation development for off-patent drugs.
markets are small or when marketing exclu- sivity is unavailable or unprofitable. In such Wechsler J. New user-fee renewal legislation will BioWorld Today [serial on the Internet]. 2011 May situations it is highly unlikely that: a) new include new policies affecting reimbursement, treatments will be developed; b) testing to research, regulatory oversight. Formulary. 2011 European Medicines Agency [homepage on the Internet]. [cited 2011 Dec 11]. Revised priority list done; c) new formulations will be created; U.S. Food and Drug Administration [homepage for studies into off-patent paediatric medicinal or d) less profitable treatments will contin- on the Internet]. [cited 2011 Dec 11]. Pediatrics.
products for the 5th Call 2011 of the 7th ue to be marketed or even made available. Research/SpecialTopics/PediatricTherapeuticsRes Commission. Available from: http://www.ema.
There is a need for a combination of pri- europa.eu/docs/en_GB/document_library/Other The paediatric use marketing authorisation GaBI Journal | www.gabi-journal.net
2012 Pro Pharma Communications International. Al rights reserved

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