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Trends in Development of Orphan Drugs - A Review

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1Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, Karnataka, India
2Indegene Life systems Pvt. Ltd, Bangalore, India
3Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, Karnataka, India
4Department of Pharmaceutics, KIET School of Pharmacy, 13 Km Milestone, Delhi-Meerut Road, Ghaziabad, 201006, U.P., India
5School of Pharmacy, The University of the West Indies, St. Augustine, Trinidad and Tobago
*Corresponding author: Manthan D Janodia
Department of Pharmacy Management
Manipal College of Pharmaceutical Sciences
Manipal University, Manipal 576104, Karnataka, India
E-mail: [email protected]
Received August 27, 2013; Published October 08, 2013
Citation: Kumari S, Koundinya A, Janodia MD, Vats AR, Pandey S, et al. (2013) Trends in Development of Orphan Drugs - A Review. 2:801. doi: 10.4172/ scientificreports.801
Copyright: © 2013 Kumari S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Orphan drugs are pharmaceutical agents that treat rare medical condition known as orphan or rare disease. According to U.S Rare Disease Act of 2002, any disease that affects less than 200,000 patients or 1 in 1500 is termed as a rare disease [1-3]. European Union defines rare disease as a life threatening or chronically debilitating disease which is of such low prevalence that special efforts are needed to address it.” It should affect 1 in 2000 persons [2,3]. European Union definition for rare disease also includes some tropical diseases found in developing countries [3]. There are around 5000-8000 rare diseases reported, out of which only 10% have cures [4]. According to the European Organisation for Rare Disease (EURORDIS) 80% of rare diseases are genetic in nature [5].
Literature Review
Orphan/Rare diseases
Lysosomal Storage Disease (LSD) is a rare disease condition, which is currently gaining a lot of attention, and hence research on it is being pursued. Fabry Disease, Pompe Disease, Mucopolysaccharide (MPS1, MPS2, MPS3, MPS4) is different known LSD diseases [6]. Tay-sachs was the first disorder to be described in 1881, Gaucher disease in 1882 and Fabry in 1898. Pompe Disease has a frequency of 1 in 40,000. Fabry disease, MPS I, MPSII (hunter), MPSIV (Morquio syndrome) have frequency of 1:117000, 1:100000, 1:150000, 1:700000, respectively. In India, there are around 33 million patients with around 6000-8000 rare diseases conditions, mostly genetic in nature [6-9]. Some diseases like Madras Motor Neuron Disease and Kyasanur Forest Disease are limited to India. Most of the rare diseases are missing from the classification of rare diseases in the International Classification of Diseases 10 (ICD10), and those which are present are mostly misclassified [10]. It results in the negligence of morbidity and mortality due to rare diseases by Health Information Systems. Therefore to bring a fair representation of rare diseases, a partnership has been established by Orphanet with WHO (World Health Organization). Orphanet has established a database of phenotypes indexed with ICD10 codes, MIM (Mendalian Inheritance in Man) which recodes and gives information on genetic disorders and genes, the mode of inheritance, the age of onset and the class of prevalence based upon all published expert classifications are collected and represented [10,11].
Trends in development of medicines for treatment of orphan/ rare diseases
In the United States, the Orphan Drug Act (ODA) was passed in 1983.This Act provided clinical trial incentives to pharmaceutical companies and also gave them market exclusivity for 7 years. These incentives resulted in more focussed attention of pharmaceutical towards research in the area of rare diseases [8]. Following the same policy as the United States, Singapore (1991), Japan (1993) and Europe (2000) passed laws with aim to promote research and development in the field of rare diseases [12,13]. European Union provides market exclusivity to sell orphan drug for 10 years. Other countries like South Korea, New Zealand, and India are also planning to pass laws specific to rare diseases [2]. Before ODA was passed, FDA approved only 38 drugs with status of orphan drugs, but after passage of ODA that numbers increased significantly. Until May 2010, FDA had approved 353 orphan drugs. Among all the approvals by the FDA, orphan drug approvals contributed 17% from 1984 to 1988; which almost doubled to 31% between 2004 and 2008.Cancers are the most common category of rare diseases, which account for 36% of orphan drug approvals by the FDA between 2000 and 2006. In 2007 USA and European Union took a decision of common application procedure for orphan drugs, so as to make easier and less time consuming for pharmaceutical companies to apply for Orphan drug approvals in both the regions [3]. Table 1 represents the comparison of US and EU legislations regarding orphan drugs.
Table 1: A comparison of Orphan drug Legislation in USA and EU.
Many national institutes have come up with aim to identify different rare diseases. Institutes like National Organisation for Rare Disorder (NORD) and European Organisation for Rare Disorder (EURORDIS) collect data on various rare diseases reported. Rare disease day is observed every year in which different pharmaceutical companies, various government organisations like LSDSS (Lysosomal Storage Disorder Support Society), patients and doctors come on a common platform to know about latest happenings and research going on in the field of rare diseases [2].
The FDA Office of Orphan Products Development (OOPD) provides incentives for sponsors to develop products for rare diseases. Humanitarian Use Device (HUD) program designates a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects fewer than 4,000 individuals in the United States per year [14]. The Orphan Products Grants Program provides funding for clinical research that tests the safety and efficacy of drugs, biologics, medical devices and medical foods in rare diseases or conditions. On the last day of February Rare Disease Day is coordinated at the international level by EURORDIS and NORD in the US and other countries. The Rare Disease Day 2012 theme focused on solidarity, and the need for collaboration and mutual support in the field of rare diseases. Shire supported the Rare Disease Day 2012, a leading nonprofit rare disease advocacy organization, in their Global Genes Project (Market Watch.htm). In India for the first time on February 28th, 2010 rare disease day was observed with support of LSD support society of India. In 2012, 29th February was observed as rare disease day and in India it was organised in Mumbai [2].
Tables 2 and 3 represent data on research and development being carried out in the field of rare diseases/orphan drugs and drugs which are in development pipeline respectively.
Table 2: Research and Development going on in the field of rare diseases/Orphan drugs.
Table 3: Drugs in development pipeline.
Methodology includes systematic literature review with the aim to find out pharmaceutical companies which are leading at present in the rare disease market. The literature search revealed both MNC and biopharmaceutical companies are investing in developing drugs for rare diseases. Three companies Pfizer, Novartis and Shire, were identified which seems ahead of other companies in developing medicines and allocating resources for rare disease segment. A comparison between the numbers of drugs approved for these 3 companies, and the number of these drugs being awarded as orphan drugs status was made for the time period of 2007-2012. Further, to evaluate the trend of development of orphan drugs, the New Molecular Entities (NME) approved by US FDA as orphan drugs over a period of 6 years (2007- 2012) were reviewed.
Results and Discussion
Figure 1 represents the total number of NME approved as orphan drugs over the period of 6 years (2007-2012) by USFDA. The numbers indicate that there is no clear trend in the number of NME approved as orphan drugs. In 2007, 7 NME were granted orphan drug status by FDA, in 2008 10 NME, while in 2009, 7 NME were granted orphan drug status. In 2010, only 3 NME attained orphan drug status, whereas in 2011, 15 NME were approved as orphan drugs. The number again fell and only 6 NME were approved as orphan drugs by FDA in 2012. The comparative results of the 3 companies under study are represented in Figure 2. During the years 2007-2012, 75% of total approved drugs for Pfizer and Shire were granted orphan drug status. Pfizer’s 6 out of total 8 approved drugs were granted orphan drug status, while Shire’s 3 out of total 4 approved drugs were granted orphan drug status. Novartis received USFDA approval for 21 drugs during this period and 10 drugs of these 21 were granted orphan drug status. As represented in Figure 1, there is no clear trend in the annual development of Orphan drugs but interestingly drugs approved for orphan diseases share a major part of the total number of drugs approved (as indicated in Figure 2, for 3 companies).
Figure 1: Orphan drugs approved by USFDA from 2007-2011.
Figure 2:Comparison of Novartis, Pfizer and Shire; Total number of US FDA approved drugs vs. total number assigned Orphan Drug Status.
The three companies identified for this study have made a steady progress in recent years in the field of rare diseases. Shire was one of the companies, along with Genzyme which started research in the area of rare diseases. But at present MNCs like Pfizer and Novartis have entered the orphan drug market and have acquired huge share in this earlier neglected field. From 2009 onwards, big pharmaceutical companies account for 43% of total orphan drug approvals by FDA and claimed over 70% of market share, up from 56% in 2006, according to Business Communication Company (BCC) research (Market Forecasting). The success of Pfizer and Novartis as depicted in our study clearly indicates the growing interest of big pharmaceutical players in rare disease area. For getting the foothold in orphan disease area, MNC’s have basically acquired small biotech companies involved in orphan drug development or have entered in a partnership with them [40]. Shire and Genzyme have Vipriv and Cerenzyme respectively in market for Gaucher treatment; despite this fact, Pfizer paid 60 million dollars to Protalixto acquire latter’s Gaucher disease enzyme replacement therapy Taligurase Alfa [41]. Pfizer also acquired Fold Rx pharmaceuticals, whose main therapy area is developing drugs to treat diseases caused by protein misfolding [42]. Novartis is targeting orphan indications in cancer research. Its molecule Gleevec, first got approval for Chronic Myelogenous Leukemia (CML) and subsequently Gleevec was granted orphan drug status for gastrointestinal stromal tumors too. Till date, Gleevec has got 5 more approvals for different related indications. Presently Gleevac is giving revenues in $2.5 billion and is expected to increase up-to $4 billion with the growth rate of 10-12%.
Sixty percent of the orphan drugs available in market at present are biotech products (monoclonal antibodies, interferons/interleukins, growth hormones, plasma products) [43]. With the diminishing pipeline of drugs and stiff competition, the big pharmaceutical companies have invested in rare disease field and most of their approved drugs are for rare diseases. Our study indicates the growing success of pharmaceutical companies in orphan disease area, but the study is limited in approach as only the US FDA approved drugs were studied. Moreover the rare diseases affecting the population in developing countries are out of scope of current study (Figures 1 and 2).
Future Prospects
Based on the model of fast track courts, the US Senator Kay Hagen has proposed fast track approach for orphan drugs in U.S Congress. The idea is to make provisions for more accelerated review of drugs meant for rare disease by FDA. His views are supported by Biotechnology Industry Organisation (BIO) and GSK. Though FDA has the provision of exemptions, many biotech companies feel that the criteria for using this flexibility is quite unclear as pointed out by BIO. Senator proposes that FDA should review orphan drug cases in the same way as it uses Accelerated Approval Program for AIDS and cancer treatment. According to Accelerated Approval Program, companies can conduct shorter clinical trials and it is based on measured effect of the drug rather than complete clinical results. According to BCC research, orphan drug market reached $84.9 billion in 2009, out of which cancer sector contributed for $30.6 billion. The market is expected to grow at a Compound Annual Growth Rate (CAGR) of nearly 6% to reach $112.1 billion and $49.7 billion for cancer orphan drugs by 2014. The U.S. accounted for 51% of the market in 2009 and is expected to grow at a CAGR of 8.9% to reach $65.9 billion by 2014 [44].
Our study indicates that major multinational pharmaceutical companies are investing in the field of rare diseases and the same pattern is expected to be followed by other pharmaceutical MNCs. The percentage of molecules granted orphan drug status, by FDA, suggest that pharmaceutical companies are diversifying into new therapy areas, which were ignored earlier. The incentives offered by ODA such as grants, market exclusivity and tax breaks seems to be a few important reasons for the recent surge in development of orphan drugs by various companies. The study is limited in its scope to US FDA approved drugs only. Though, there has been a considerable development in the area of orphan drugs and at face value it’s a great achievement for pharmaceutical industry but, still for many rare diseases medication is unavailable, which shows that there is need of right strategy as well as understanding for their risk and benefits.