1、DECEMBER 2018 Orphan Drugs in the United States Exclusivity, Pricing and Treated Populations Introduction In the thirty-five years since the passage of the Orphan Drug Act (ODA) in 1983, the structure of development incentives laid out in the legislation has successfully spurred investment and innov

2、ation in rare disease therapies. Still, approximately 95% of the 7,000 rare diseases remain without any therapeutic options. Recent legislative discussion has focused on whether the ODA development incentives are working as intended or whether they are being manipulated for commercial gain. In this

3、regard, it is particularly important to understand whether the orphan designations granted have delayed generic competition. There has also been significant attention focused on the pricing of orphan drugs both at launch and over time. A persistent issuewith implications for both the pricing and lev

4、els of commercial support needed for these drugsremains that rare disease patients are difficult to diagnose, and as a result, available treatments have limited use by only a small proportion of patients with confirmed disease. This report is a companion analysis to an examination of the orphan drug

5、 market published by the IQVIA Institute in October 2018, “Orphan Drugs in the United States: Growth Trends in Rare Disease Treatments,” and brings a new perspective on the sequence of orphan and non-orphan indications approved and their associated patent and market exclusivities. It also examines o

6、rphan drug pricing relative to patient numbers and how those prices change over time. In a first-of-its-kind comprehensive analysis, the report compares current disease epidemiology to the number of treated patients to demonstrate the challenges in bringing orphan drugs to patients even after theyre

7、 approved. Overall, these analyses bring critical and updated information to the understanding of orphan drugs in the United States. The research in this report was undertaken independently by the IQVIA Institute, with funding from the National Organization for Rare Disorders (NORD). The contributio

8、ns of Onil Ghotkar, Deanna Nass, Urvashi Purval, Vismaye Raje, Alana Simorellis, Durgesh Soni and others at IQVIA are gratefully acknowledged. Find Out More If you wish to receive future reports from the IQVIA Institute for Human Data Science or join our mailing list visit IQVIAinstitute.org MURRAY

9、AITKEN Executive Director IQVIA Institute for Human Data Science 2018 IQVIA and its affiliates. All reproduction rights, quotations, broadcasting, publications reserved. No part of this publication may be translated, reproduced or transmitted in any form or by any means, electronic or mechanical, in

10、cluding photocopy, recording, or any information storage and retrieval system, without express written consent of IQVIA and the IQVIA Institute. This report was produced with funding from the National Organization for Rare Disorders (NORD) Table of contents Executive summary 2 Definitions4 Orphan an

11、d patent exclusivity for orphan drugs 5 Pricing for orphan drugs 11 Patientpopulationsandtreatmentestimatesfororphandrugs14 Notes on sources 17 Methodology 18 References 20 About the authors 21 About the IQVIA Institute 22 1 2 Executive summary One of the key aspects of the Orphan Drug Act of 1983 i

12、s a seven-year market exclusivity granted to drugs that treat rare diseases. In the thirty-five years since the passage of the Orphan Drug Act, a total of 503 drugs have received orphan status from the FDA. Of these, 217 drugs are now no longer protected by either orphan designations or patents, and

13、 yet only 116 of these unprotected medicines currently face generic or biosimilar competitors. Notably, just over half of the unprotected products have faced competition, even decades after the lapsing of exclusivity. In practice, the explicit orphan exclusivity has only rarely been the factor which

14、 has delayed generic or biosimilar competitors. Orphan exclusivity was in effect longer than patent protection for only 60 of the 503 drugs that have received orphan status (see Methodology). Thus, it is most often the lapse of patent exclusivity that enables competition and not the orphan drug excl

15、usivity (ODE). Of note, it appears that the practical aspects of developing and manufacturing drugs for these populations has largely discouraged competitors. For instance, the median annual spending on those expired orphan drugs not facing competition was $8.6 million in 2017 reflecting very limite

16、d commercial opportunities for potential generic challengers. Of these 101 drugs, 30 have additionally been discontinued, suggesting that these medicines were either made less relevant by subsequent innovations or were simply not profitable enough to continue. Considering orphan designations mandate

17、 exclusive market opportunities, the pricing decisions of developers are of particular interest, especially with the recent string of high-profile approvals of orphan drugs with costs in the hundreds of thousands of dollars. In our earlier report,1 an inverse relationship between high price and the

18、number of patients treated was noted. Confirming this point, most orphan drugs were seen to have relatively low prices, and those that do have exceptionally high prices, also treat very few patients. In addition to launch prices, the ongoing pricing actions by manufacturers are of interest, and anal

19、ysis shows that companies have consistently raised prices for orphan drugs more slowly than other branded drugs in the market. This has been demonstrated both historically as well as in a time-aligned comparison relative to the addition of orphan status for a drug. Compared to the orphan drug market

20、 as a whole, spending on those unprotected orphan drugs not experiencing generic competition can be considered modest, with drugs on average reaching just over $100 million in 2017 after approximately 10 years without a competitor. While there are some orphan drugs in this category which have more t

21、han $200 million in spending, they each have some unique circumstances relevant to delayed or absent competition. The highest spending drug in this group was Epogen, where biosimilar applications had been pending for some time and the first was launched in November 2018. Excluding the eight drugs wi

22、th the greatest spending, the average spending on orphan brands not experiencing generic competition drops to just over $22 million in 2017 and an average 10.5 years without competition since the end of prior patent or orphan exclusivities. These aspects of competition and pricing are an important r

23、eminder that the number of patients receiving a treatment is critical to both generating competition and supporting the sustainability of a market. A comprehensive epidemiological examination of 539 diseases that have approved orphan drugs further indicates that treated patients represent approximat

24、ely 10% of disease prevalence for these rare diseases, with notable variability around this mean. In almost every circumstance, orphan drugs target fewer than 200,000 patients, though the actual target populations vary significantly, and the understanding of the number of patients with a disorder ca

25、n evolve 3 over time. Poorly diagnosed diseases can become easier to identify if a new diagnostic is developed, and the wide adoption of genetic testing has helped improve identification for a range of inherited diseases. Additionally, awareness of a disease can be linked to the availability of a tr

26、eatment option, and that awareness can encourage patients to seek treatment. Still, even in the presence of effective treatments, some rare diseases see fewer than 1% of their prevalent patients receiving orphan medicines given that diagnosis and treatment of rare diseases with very small population

27、s remains complicated. This demonstrates the need for a concerted effort, once a drug is approved, to disseminate treatment guidance to the wider medical community and to patients. These efforts may take years even in optimal circumstances, and if patients do not receive a diagnosis, there is little

28、 that can be done. Lastly, these data suggest a stubborn analytical issue, which is that both the treated-patient estimates and epidemiology estimates are highly subject to the vagaries of multiple researchers working separately on specific studies without coordination. There are no comprehensive an

29、d definitive patient registries for many rare diseases, and it remains challenging to identify the size of a very rare patient population with confidence. 4 Definitions It is helpful to use a set of common definitions to fully understand the role that orphan drugs play in the U.S. health system, bot

30、h from a volume and cost perspective. For the purposes of this report, the following terms are used: All medicines include those prescription drugs approved by the FDA and distributed through retail and non-retail channels, including brands and generics, specialty and traditional drugs, and small mo

31、lecules as well as biologics Orphan drugs are generally defined as those medicines with one or more indications approved under the Orphan Drug Act. In some cases, these medicines may also have additional non-orphan indications approved by the FDA but that do not meet the criteria for an orphan drug

32、designation Drug spending in this report measures the total value of spending on medicines in the United States by pharmacies, clinics, hospitals and other healthcare providers and includes generics, branded products, biologics and small-molecules in retail and non-retail channels. It is based on IQ

33、VIA reported values from wholesaler transactions measured at trade/invoice prices and exclude off-invoice discounts and rebates that reduce net revenue received by manufacturers Orphan Drug Exclusivity (ODE) refers to a seven- year market exclusivity from competitors for that medicine specifically f

34、or the designated orphan use. The exclusivity does not preclude generic competition for non-orphan approved uses of that drug. For additional information on other types market exclusivity and patent protection, see Methodology Patent (and other exclusivities) are those exclusivities granted to produ

35、cts by patents or 505(b)(2) approvals which delay, or are expected to delay, market entry of competitors. For additional information, see Methodology Treated patients are an estimate of the number of patients treated in a year with the orphan drug based on spending, approved dosing, cost per dose an

36、d proportion of usage for the relevant indication Prevalence refers to the proportion of the population who have a specific disease within a given time period Incidence refers to the occurrence of new cases of a disease within the population within a given time period 5 One of the more often cited b

37、ut least understood aspects of the Orphan Drug Act is the market exclusivity it grants. With orphan designation, the FDA grants a seven-year market exclusivity for that medicine that applies specifically to that designated orphan use, but this exclusivity does not preclude generic competition for ot

38、her non-orphan approved uses of that drug, nor for orphan uses for which the exclusivity has expired. To best understand the effective market exclusivity of orphan drugs, it is necessary to examine both the timing of orphan designations and the timing of patents and other market exclusivities (e.g.,

39、 pediatric or other exclusivities) for those drugs. Of the 503 distinct drugs to have ever received orphan designations for one or more indications since 1983, 286 remain protected by some form of exclusivity, either ODE or patent exclusivity (see Exhibit 1). Of those 217 that are no longer protecte

40、d, generics are available in the market for 116 of them, while no competitors exist for 101 of them. The medicines currently facing generic competition can provide a view of the total duration of protection provided by both patent and ODE protections. Those not yet facing competition are indicative

41、of challenges that delay the number of generic challengers, such as small-revenue markets. The median spending for an orphan drug without market protection and not facing generic competition was $8.6 million in 2017 (see Exhibit 2). Orphan and patent exclusivity for orphan drugs Of all 503 drugs whi

42、ch have received orphan designations, 217 are now no longer protected by either orphan exclusivity or patent designations, but only 116 of these currently face generic competitors. As of June 2018, there were 101 medicines with lapsed exclusivity or patent protection not experiencing generic competi

43、tion, in some cases, for many years. The median annual spending of these medicines was $8.6 million in 2017 reflecting very limited commercial opportunities for potential generic challengers. The remaining 286 drugs with orphan designations are still protected from generic competition by either orph

44、an or patent exclusivities or both. The exclusivity granted to orphan drugs provides seven years without generic competition for the approved orphan designation but does not prevent generic competition for other approved uses of the medicine. Orphan exclusivity continues longer than patent protectio

45、n in only 60 of the 503 orphan-designated medicines. When an orphan-designated drug receives approval, the duration of protected status is often longer than seven years, as patent protection often extends beyond orphan market exclusivity. 6 ORPHAN AND PATENT EXCLUSIVITY FOR ORPHAN DRUGS Exhibit 1: C

46、urrent Status of Patent Protection and Orphan Drug Exclusivity for Orphan Designated Drugs Source: FDA Orphan Drugs Database, FDA Orange Book, Accessed Sep 2018; IQVIA ARK Patent Intelligence, IQVIA National Sales Perspectives, Oct 2018; IQVIA Institute; Nov 2018 Notes: ODE = Orphan drug exclusivity

47、; patent protection includes other forms of market exclusivity (e.g., pediatric extension, 505(b)(2). The 101 therapies no longer protected by either ODE or patent exclusivity did not have generic competitors as of June 2018. The 116 therapies no longer protected by either ODE or patent exclusivity

48、currently have one or more generic or biosimilar competitors in the market. Drugs with any Approved Orphan Designation = 503 Still Protected by both ODE and Patent Exclusivity Still Protected by ODE Patent Protection Lapsed Still Protected by Patent Exclusivity ODE Lapsed No Longer Protected by eith

49、er ODE or Patent Exclusivity Lacking Competition No Longer Protected by either ODE or Patent Exclusivity Facing Generic/Biosimilar Competition 116 205 10 71 101 Exhibit 2: Spending on Orphan Drugs No Longer Protected by Either Orphan Drug Exclusivity or Patent Protection Source: FDA Orphan Drugs Database, FDA Orange Book, Accessed Sep 2018, IQVIA ARK Patent Intelligence,