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. Author manuscript; available in PMC: 2020 Sep 1.
Published in final edited form as: J Am Acad Dermatol. 2019 May 16;81(3):867–877. doi: 10.1016/j.jaad.2019.05.025

The Impact of the Orphan Drug Act on FDA-Approved Therapies for Rare Skin Diseases and Skin-Related Cancers

Laura Karas 1,2, Christine Y Lu 1, Pankaj B Agrawal 3, Maryam M Asgari 1,2
PMCID: PMC6857728  NIHMSID: NIHMS1529481  PMID: 31103566

Abstract

The Orphan Drug Act of 1983 (ODA) put in place a set of financial and marketing incentives to stimulate the development of drugs to treat rare diseases, and since its passage more than 600 orphan drug and biologic products have been brought to market in the United States. Rapid growth in orphan drug approvals in conjunction with high orphan drug prices have triggered concern that drug makers are exploiting certain aspects of the ODA for financial gain and that some pharmaceutical drugs are receiving orphan status where it is not warranted. The landscape of approved therapies for rare skin diseases has not been well described. In this article, we provide a descriptive analysis of the Food and Drug Administration-approved orphan drugs for the treatment of rare dermatologic conditions and skin-related cancers since the enactment of the ODA. We discuss policy issues that emerge from the analysis and suggest areas for future research. Next, we elucidate ODA loopholes using dermatologic drugs as examples and propose potential reforms. Finally, we consider future directions for orphan drug development in the field of dermatology.

Keywords: Food and Drug Administration, orphan drugs, Orphan Drug Act, drug approvals, rare skin diseases, pharmaceutical drugs

Capsule Summary

• As a result of the incentives for rare disease drug development contained within the Orphan Drug Act, 72 indications have been approved for rare skin diseases, skin-related cancers, and hereditary disorders with prominent dermatologic manifestations.

• We provide an analysis of dermatologic orphan drug approvals and forecast future drug development trends.

Background

Drugs to treat rare diseases were once unattractive investment opportunities due to limited sales volume and expected profit relative to the steep costs involved in drug development, manufacture, and sale. Enactment of the Orphan Drug Act of 1983 (ODA) in the United States (US) tipped the scales by establishing a set of financial and marketing incentives to promote the development of drugs to treat rare diseases, statutorily defined as those diseases or conditions that affect fewer than 200,000 individuals in the US, or those diseases that affect more than 200,000 persons but for which the cost of making and marketing a drug cannot be reasonably recaptured from sale of the drug.1

ODA provisions include a seven-year period of exclusive rights to market an orphan drug following Food and Drug Administration (FDA) approval, a 25% tax credit for clinical trial costs (recently lowered from a 50% tax credit2), and exemption from user fees required for FDA review under the Prescription Drug User Fee Act (roughly $2.5 million per new drug application in 20193). With these incentives in place, over 600 drugs and biologics to treat rare diseases have been brought to market since passage of the ODA more than 35 years ago.4

A concomitant blossoming of genomic research has brought to light previously unknown disease mechanisms and potential therapeutic targets. The 1990s and 2000s saw progress in identification of genes underlying several rare skin disorders, including epidermolysis bullosa simplex, the ectodermal dysplasias, and ichthyoses.5 Rapid, low-cost genome sequencing and the advent of gene therapy have enabled the identification and subsequent replacement, correction, or inactivation of mutated genes.6,7 The era of precision medicine promises to usher in therapies that target personalized genome-level variants.

An upsurge in the number of orphan drugs approved in recent years and extremely high prices for these drugs have triggered concern among patients, payors, and policymakers that drug makers may be “gaming the system” of ODA incentives.8,9,10,11,12 The average annual per patient cost of an orphan drug in 2018 was more than four times the cost of a non-orphan drug (roughly $150,900 versus $33,700, respectively).13 Although orphan drug expenditures comprise roughly one-tenth of total pharmaceutical expenditures,14 the high price of some orphan drugs imposes a burden on patients in the form of out-of-pocket costs while yielding profits for drug companies even in the face of relatively small numbers of patient-users.13,15,16

Three principal ODA “loopholes” have been recognized. First, drug companies can seek orphan designation and approval for narrow subsets of more common diseases, termed “salami-slicing.”11,17,18 Second, a drug that has been on the market for a non-orphan condition may later receive approval for an orphan indication, a practice that falls under the umbrella of “drug repurposing.”8,19 Repurposed orphans receive the same statutory incentives as orphan drugs that first came to market for treatment of a rare disease. Third, a single drug receives a new seven-year exclusivity period for each approved orphan indication, which could prolong market exclusivity beyond a drug’s patent term.20 Exclusivity that outlasts the patent term for even a small number of drugs can cost taxpayers significant sums by delaying generic entry beyond what legislators intended as a quid pro quo “reward” for pharmaceutical innovation.

The landscape of approved therapies for rare skin diseases has not been described in the academic literature. The aim of this article was to provide a descriptive and policy analysis of orphan drug approvals for rare dermatologic conditions and skin-related cancers since the passage of the ODA. We illustrate the most notable ODA loopholes using dermatologic drugs as examples and propose several reforms to better align the current system with the original intent of the ODA. Finally, we forecast the direction of future orphan drug development in dermatology.

Methods

Table I provides definitions of common terms relating to the US drug approval process. Of note, providers may prescribe drugs “off-label” for unapproved uses where those uses are medically warranted.21 We do not consider off-label uses in this article.

Table I.

Definitions of common terms relating to the U.S. drug approval process.

Term Definition
Drug or therapy In this article, we use the terms “drug” and “therapy” interchangeably to describe a pharmaceutical drug or biologic product within the purview of the US Food and Drug Administration.
Orphan designation (orphan status) A status granted by FDA’s Office of Orphan Products Development to a drug meeting statutory criteria for orphan status that enables the drug’s sponsor (i.e. the drug maker) to receive the incentives promulgated within the ODA. The drug’s sponsor typically seeks orphan status for a drug by request to the FDA prior to submitting a new drug application, biologics license application, or supplemental application for US marketing approval.
Orphan drug approval A drug with orphan status that has been granted marketing approval after an adequate demonstration of safety and efficacy.
Indication(s) FDA-approved use(s) of a drug that appear on the drug’s label.
Distinct drug product(s) A single drug may receive marketing approval for more than one orphan indication. For this reason, we occasionally refer to tallies of “distinct drug products,” a term we employ to clarify that every drug is counted only once even if it has been approved for more than one indication.
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The primary data source for this analysis was the publicly available FDA Orphan Drug Product database.22 A master list of all orphan drugs approved from 01/01/1983 to 12/31/2018 was searched to identify drugs approved for primary dermatologic conditions and cancers of cutaneous origin. Multisystem hereditary conditions with prominent dermatologic manifestations were included and confirmed for relevance by an expert reviewer (MA). Orphan drugs designated but not approved were excluded from the analysis.

For each drug, the generic and trade names, designation date, designation, approved indication, marketing approval date, exclusivity end date, and drug company sponsor were extracted. Each drug was classified into one of six disease categories (infectious, immunologic, inflammatory, hereditary, oncologic, and other). Each drug was also classified by type (small molecule, monoclonal antibody, or other protein-based therapy) using the DrugBank database.23 The percentage of indications for cancer and non-cancer related skin conditions that had a pharmaceutical company sponsor among the top 10 drug companies by global revenue (Pfizer, Novartis, Roche, Johnson & Johnson, Sanofi, Merck, GlaxoSmithKline, AbbVie, Bayer, and AstraZeneca) was determined.24 Several dermatologic drugs that exemplify ODA loopholes were identified and used to explain how these loopholes potentially undermine the intent of the ODA.

Results

Seventy-two FDA-approved indications met inclusion criteria for treatment of dermatologic conditions, which constituted roughly 10% of all approved orphan indications since passage of the ODA in 1983 (Figure 1). To put this in perspective, at least 7,000 rare diseases have been identified, of which upwards of 1000 are estimated to be dermatologic diseases.25,26,27

Figure 1.

Figure 1.

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Orphan Indications Approved by the US Food & Drug Administration for Dermatologic Conditions from 1983 to 2018 – Compared to All Approved Orphan Indications.

Note: Roughly 10% of all approved orphan indications treat dermatologic conditions.

During the first 14 years following passage of the ODA (1983–1997), 10 indications were approved for skin conditions and skin-related cancers. Twenty-four indications were approved during the next 14-year period (1998 to 2011), and 38 indications were approved over the last 7 years (2012 to 2018). Mean time from orphan designation to marketing approval was 4.7 years (median: 3.25 years; range: 3 months to 24.7 years). Thirty-seven of the 72 orphan indications were approved for skin-related cancers (51.4%); 21 for hereditary disorders (29.2%); 7 for infectious diseases (9.7%), 3 for inflammatory disorders (4.2%); 2 for immunologic diseases (2.8%), and 2 for other diseases and conditions (2.8%) (Table II). Figure 2 provides a graphical illustration of these approvals over time according to disease category. Twelve of the 72 dermatologic orphan indications (16.7%) were specified for use in pediatric or adolescent patients. Fourteen of the 72 indications (19.4%) targeted a biomarker-derived subset; of these, 10 indications were specified for treatment of melanoma containing BRAF V600E, V600K, or V600 wild-type mutations.

Table II.

Orphan drugs approved to treat dermatologic conditions, by disease category.1

INFECTIOUS
1. Clofazimine Treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum.
2. Thalidomide Acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) and as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrences.
3. Miltefosine Treatment of visceral leishmaniasis due to Leishmania donovani; cutaneous leishmaniasis due to Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis; and mucosal leishmaniasis due to Leishmania braziliensis.
4. Liposomal amphotericin B Treatment of visceral leishmaniasis.
5. Varicella Zoster Immune Globulin Post-exposure prophylaxis of varicella in high risk individuals to reduce the severity of varicella.
6. Vaccinia Immune Globulin (indication 1)
Treatment and modification of aberrant infections induced by vaccinia virus that include its accidental implantation in eyes (except in cases of isolated keratitis), mouth, or other areas where vaccinia infection would constitute a special hazard; eczema vaccinatum; progressive vaccinia; severe generalized vaccinia, and vaccinia infections in individuals who have skin conditions such as burns, impetigo, varicella-zoster, or poison ivy; or in individuals who have eczematous skin lesions because of either the activity or extensiveness of such lesions.
7. Vaccinia Immune Globulin (indication 2)
Treatment and/or modification of the following conditions, which are complications resulting from smallpox vaccination: eczema vaccinatum; progressive vaccinia; severe generalized vaccinia; vaccinia infections in individuals who have skin conditions such as burns, impetigo, varicella-zoster, or poison ivy, or in individuals who have eczematous skin lesions because of either the activity or extensiveness of such lesions; aberrant infections induced by vaccinia virus that include its accidental implantation in eyes (except in cases of isolated keratitis), mouth, or other areas where vaccinia infection would constitute a special hazard.
IMMUNOLOGIC
1. Rituximab Treatment of adult patients with moderate to severe pemphigus vulgaris.
2. Ibrutinib Treatment of adult patients with chronic graft versus host disease (cGVHD).
INFLAMMATORY
1. Topical metronidazole Treatment of acne rosacea.
2. Adalimumab (indication 1)
Treatment of moderate to severe hidradenitis suppurativa (Hurley stage 2 and Hurley stage 3 disease).
3. Adalimumab (indication 2)
Treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older.
HEREDITARY
1. Hemin Amelioration of recurrent attacks of acute intermittent porphyria (AIP) temporarily related to the menstrual cycle in susceptible women and similar symptoms which occur in other patients with AIP, porphyria variegata and hereditary coproporphyria.
2. Midostaurin Treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).
3. Cromolyn sodium Treatment of mastocytosis.
4. Imatinib mesylate (indication 1; indication 2 is oncologic)
Treatment of adult patients with aggressive mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown.
5. Interferon gamma 1-b Treatment of chronic granulomatous disease.
6. Ceramide trihexosidase/alpha-galactosidase A For use in patients with Fabry disease to reduce globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types.
7. Migalastat hydrochloride Treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data.
8. Laronidase Treatment for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms.
9. N-acetylgalactosamine-4-sulfatase-recombinant human For patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Galsulfase has been shown to improve walking and stair-climbing capacity.
10. Idursulfase Indicated for patients with Hunter syndrome (mucopolysaccharidosis II, MPS II). Idursulfase has been shown to improve walking capacity in these patients.
11. Vestronidase alfa-vjbk Treatment of mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) in pediatric and adult patients.
12. Elosulfase alfa Patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A Syndrome).
13. C1-esterase inhibitor (human, pasteurized) For routine prophylaxis to prevent hereditary angioedema attacks in adolescent and adult patients.
14. C1-esterase inhibitor (recombinant) Treatment of acute attacks of hereditary angioedema in adult and adolescent patients.
15. C1-esterase inhibitor (human) (indication 1)
Routine prophylaxis against angioedema attacks in patients with hereditary angioedema.
16. C1-esterase inhibitor (human) (indication 2)
Routine prophylaxis against angioedema attacks in adults, adolescents and pediatric patients (6 years old and above) with hereditary angioedema.
17. Ecallantide (indication 1)
Treatment of acute attacks of hereditary angioedema in patients 16 years of age and older.
18. Ecallantide (indication 2)
Treatment of acute attacks of hereditary angioedema in patients 12 years of age and older.
19. Icatibant Treatment of acute attacks of hereditary angioedema in adults 18 years of age and older.
20. Lanadelumab-flyo Prophylaxis to prevent attacks of hereditary angioedema in patients 12 years and older.
21. Everolimus Treatment of adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), including TSC-associated subependymal giant cell astrocytoma (SEGA), TSC-associated angiomyolipoma and TSC-associated lymphangioleiomyomatosis (LAM), not requiring immediate surgery.
ONCOLOGIC
1. Interferon alfa-2a (recombinant) Treatment of AIDS-related Kaposi’s sarcoma.
2. Interferon alfa-2b (recombinant) Treatment of selected patients with AIDS-related Kaposi’s sarcoma.
3. Daunorubicin citrate liposome injection First line cytotoxic therapy for advanced, HIV-related Kaposi’s sarcoma.
4. Paclitaxel For the second-line treatment of AIDS-related Kaposi’s sarcoma.
5. Alitretinoin Topical treatment of cutaneous lesions in patients with AIDS-related Kaposi’s sarcoma.
6. Ipilimumab (indication 1)
For the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm, who have undergone complete resection including total lymphadenectomy.
7. Ipilimumab (indication 2)
Treatment of unresectable or metastatic melanoma.
8. Ipilimumab (indication 3)
An expansion of the indication for the treatment of unresectable or metastatic melanoma in pediatric patients (12 years and older).
9. Denileukin diftitox Treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor.
10. Bexarotene Treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.
11. Brentuximab vedotin (indication 1)
For adult patients with primary cutaneous anaplastic large cell lymphoma who have received prior systemic therapy.
12. Brentuximab vedotin (indication 2)
Treatment for adult patients with CD30-expressing mycosis fungoides who have received prior systemic therapy.
13. Mogamulizumab Treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sezary syndrome (SS) after at least one prior systemic therapy.
14. Mechlorethamine Topical treatment of Stage 1A and 1B mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy.
15. Belinostat Treatment of patients with relapsed or refractory peripheral T-cell lymphoma.
16. Pralatrexate Treatment of patients with relapsed or refractory peripheral T-cell lymphoma.
17. Romidepsin (indication 1)
Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.
18. Romidepsin (indication 2)
Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.
19. Imatinib mesylate (indication 2)
Treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).
20. Vorinostat Treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies.
21. Aldesleukin Treatment of adults with metastatic melanoma.
22. Peginterferon alfa-2b Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.
23. Vemurafenib Treatment of unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test.
24. Trametinib Treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA approved test.
25. Dabrafenib Treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA approved test.
26. Trametinib + dabrafenib (indication 1)
Treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for trametinib in combination with dabrafenib.
27. Trametinib + dabrafenib (indication 2)
Adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.
28. Pembrolizumab (indication 1)
Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
29. Pembrolizumab (indication 2)
Treatment of patients with unresectable or metastatic melanoma.
30. Pembrolizumab (indication 3)
Treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.
31. Nivolumab (indication 1)
Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
32. Nivolumab (indication 2)
Adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.
33. Nivolumab + ipilimumab Treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma.
34. Talimogene laherparepvec Indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.
35. Cobimetinib For the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, in combination with vemurafenib. Cobimetinib is not indicated for treatment of patients with wild-type BRAF melanoma.
36. Avelumab Treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma.
37. Encorafenib + binimetinib Treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.
OTHER
1. Mafenide acetate solution For use as an adjunctive topical antimicrobial agent to control bacterial infection when used under moist dressings over meshed autografts on excised burn wounds.
2. Propranolol Treatment of proliferating infantile hemangioma requiring systemic therapy.
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1.

Some drugs received approval for more than one dermatologic orphan indication. In such cases, the drug name appears again in this list, along with a numbered indication.

Figure 2.

Figure 2.

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Orphan Indications Approved to Treat Skin Conditions and Skin-Related Cancers, By Disease Category.

Eleven therapies were approved for more than one dermatologic orphan indication (9 drugs or drug combinations were approved for two dermatologic indications each, and 2 drugs—ipilimumab and pembrolizumab--were each approved for three dermatologic indications). Tallying every drug once, there were 59 distinct drug products approved for dermatologic conditions. Twenty-nine of these were small molecule drugs (49.2%), 10 were monoclonal antibodies (16.9%), and 20 were protein-based therapies (34%), including interferons, blood factors, and immunoglobulins. Thirty-nine drugs (39/59 or 66.1%) were approved for a single rare disease or condition, while 20 drugs (33.9%) had approvals for multiple rare diseases.

The pharmaceutical company sponsors with the largest number of dermatologic orphan indications were Novartis (9), Bristol-Myers Squibb (7), Shire and its subsidiary Dyax (5), Merck (4), Celgene (3), BioMarin (3), and Eisai (3). Among indications for skin-related cancers (n=37), 19 (51.4%) had a pharmaceutical company sponsor in the top 10 drug companies by global revenue. In contrast, among indications for non-cancer related skin conditions (n=35), only 6 (17.1%) had a sponsor among the top 10 drug companies.

Discussion

The upward trend in orphan drug approvals for skin diseases and skin-related cancers mirrors the overall trend in orphan drug approvals (Figure 1).28 The climbing rate of approvals reflects several forces at work: an increased awareness of and attention to rare diseases, a market that tolerates extremely high prices for orphan drugs, and the new-found ability to extend exclusivity for potentially lucrative orphan drugs. In recent years, infectious diseases have been infrequent targets of new therapies, with only two infectious disease therapeutics (for varicella zoster and leishmaniasis) approved in the past decade. Similarly, few drugs have been approved to treat autoimmune and inflammatory disorders. The only orphan drug approved for a blistering disorder was rituximab for treatment of pemphigus vulgaris in 2018. However, several therapies are in the pipeline, including a gene therapy for recessive dystrophic epidermolysis bullosa involving intradermal injections of genetically modified fibroblasts,29 an investigational monoclonal antibody in early phase clinical development for pemphigus vulgaris and pemphigus foliaceus,30 and a C5 and leukotriene B4 inhibitor under development for bullous pemphigoid.31

Over the past decade, a number of drugs were approved to treat hereditary disorders with prominent skin involvement due to enzyme deficiencies, including the mucopolysaccharidoses and Fabry disease. Many genodermatoses remain without effective treatment options, such as the non-acute porphyrias, syndromic and non-syndromic ichthyoses, the ectodermal dysplasias, and precancerous conditions such as xeroderma pigmentosum.

Orphan drug approvals for cancers of cutaneous origin dominated among dermatologic orphan drug approvals, with melanoma constituting the leading disease target. Anti-cancer drug-predominance in our cohort is consistent with findings of a predominance of anti-cancer therapies in orphan drug development overall.32 Targeting R&D investment in oncology drugs may be a strategic business decision; due to the versatility of their use for multiple cancer types, orphan oncology drugs can offer a higher profit-potential than can non-cancer orphan therapies.33

An estimated 50% of rare diseases occur in children.34 This contrasts with our finding that only 17% of approved indications for rare dermatologic conditions were specified for use in pediatric or adolescent patients. The discrepancy can be attributed at least in part to the challenges of conducting pediatric clinical trials.35,36 Research suggests that legislation such as the U.S. FDA Modernization Act of 1997 and the Pediatric Research Equity Act of 2003 have effectively stimulated the growth of pediatric drug labels.37,38,39,40 The impact of these pieces of legislation on drug development for pediatric dermatologic diseases, specifically, is an area for future research.

ODA Loopholes

Salami-slicing

Salami-slicing of common diseases to attain orphan status is one perceived form of gamesmanship of the ODA.8 For example, pembrolizumab is an anti-PD1 immunotherapy approved to treat 11 different types of cancer, including melanoma.41 A multitude of clinical trials involving pembrolizumab are underway for other cancer types and for use in combination therapies.42 The prevalence of melanoma in the US was over 1,200,000 persons in 201543; however, orphan drugs to treat melanoma apply to a narrow subset of the cancer, often metastatic disease, thus allowing the indication to fall within the 200,000-person prevalence threshold of the ODA. An indication is often winnowed even further based on specific genetic variants, such as the V600E or V600K mutations. As of December 31, 2018, pembrolizumab had three approved dermatologic orphan indications and four additional orphan indications for non-dermatologic cancers.44 Of note, pembrolizumab is widely regarded as a “blockbuster” drug, with sales exceeding $2 billion in the fourth-quarter of 2018 alone.45

Mass-market drug repurposing

Repurposed orphan drugs are mass-market drugs that later gain approval for orphan indications; such drugs are sometimes referred to as “partial orphans” to recognize that they have both orphan and non-orphan uses.8,46 For example, adalimumab, which currently holds the position of top-selling pharmaceutical drug worldwide,47 was first approved for the treatment of rheumatoid arthritis in 2002 and later gained approval as an orphan drug for hidradenitis suppurativa (HS) in 2015. FDA-approved biosimilars to adalimumab do not have indications on-label for treatment of HS because orphan market exclusivity shields adalimumab from competition for this particular indication through 2022 in adults and 2025 in a pediatric population. In 2017 Kaiser Health News reported that more than 70 orphan drugs were first approved for the mass market.8 Repurposing has implications for a drug’s profitability because a repurposed drug can derive revenue from both orphan and non-orphan sales. For example, adalimumab derived approximately 4% of its $13.6 billion in total sales revenue from orphan indications in 2016.46

Market exclusivity prolongation

The ability of orphan exclusivity to extend beyond the patent term when exclusivity additively accrues from multiple orphan indications is another cause for concern.20 The relationship between the total duration of orphan exclusivity versus patent life for pharmaceutical drugs is an area ripe for further research.

Proposed Reforms

Elimination of the prevalence-based definition of orphan status and replacement with a definition based on commercial non-viability could reduce the ability of drug companies to profit excessively from orphan drug approvals by making orphan status contingent on adequate evidence that a drug is not expected to be commercially profitable.48 Measures to curb excessive profits are justifiable in light of the fact that a sizeable proportion of orphan drugs and scientifically “novel” drugs are discovered in a university setting, funded by taxpayer dollars.49

In order to limit the benefits of salami-slicing, FDA could require, for any given drug, that all subsequent orphan indications assume the exclusivity end date of the first approved orphan indication (i.e. one orphan drug, one exclusivity end date). Similarly, the FDA could bar repurposed drugs from receiving orphan market exclusivity, on the grounds that these drugs are not true additions to the therapeutic arsenal and have revenue streams from non-orphan indications. A potential downside to the above-mentioned reforms is that they disincentive drug companies from seeking FDA approval for secondary orphan indications. While providers can prescribe off-label for non-approved uses, FDA approval generally benefits patients vis-à-vis insurance coverage and access to dermatologic therapies.50

The Future of Dermatologic Drug Development

In keeping with scientific advancements and market trends, we forecast a growth in nucleotide-based therapies including gene therapy, antisense oligonucleotides, and small interfering RNA (siRNA); an increase in orphan approvals for biomarker-derived subsets; and a steady movement of large pharmaceutical companies into the rare disease space. Nucleotide-based therapies may disrupt the drug development bent toward orphan anti-cancer drugs as large companies seek to develop or acquire rights to new curative gene therapies for exceedingly rare non-oncologic disorders.51 Academic institutions play an increasingly critical role in drug development, delineating biological changes that can become new drug therapies, repurposing existing drugs for new indications, and developing therapies for ultra-rare conditions often ignored by industry. Continued growth of academic-industry partnerships can accelerate translation of novel drug targets into FDA-approved therapies.52 Finally, the role of the skin microbiome in skin disease has attracted interest within the dermatologic community, and metagenomic profiling of skin microbial communities may provide a basis for novel diagnostic tests and therapies.53,54,55,56 This is an exciting new frontier that holds promise in treating various dermatologic conditions in the future.

Conclusion

In sum, the past 35 years has yielded 72 approved orphan indications for dermatologic conditions. Anti-cancer treatments represent a large proportion of all approvals and likely will continue to do so in the near term. A reformed system of orphan incentives can curb misuse of the ODA, and help achieve more affordable drug prices, while retaining its force as a stimulus of innovation.

Funding sources:

This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24 AR069760 to MA).

Conflicts of Interest: Dr. Asgari receives grant funding to her institution from Pfizer Inc. The other authors (LK, CYL, PBA) have no conflicts of interest to disclose.

This work has not been presented or published previously.

Abbreviations and Acronyms

FDA

Food and Drug Administration

HS

Hidradenitis suppurativa

ODA

Orphan Drug Act of 1983

R&D

Research and development

US

United States

Footnotes

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References

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