Drugs and biologics receiving FDA orphan drug designation: an analysis of the most frequently designated products and their repositioning strategies

Abstract

Background:

The Orphan Drug Act was created to stimulate the development of drugs and biologics for rare diseases. Investigating products that have received orphan drug designation provide a greater understanding of rare disease drug development, as well as the repositioning business models of developers.

Research design and methods:

We used a dataset containing all orphan drug designations between 1983 and 2019. To analyze the orphan products, we constructed a variable, ‘unique product,’ that allowed for the standardization of generic names of drugs and biologics. Additional analysis was performed on the most frequently designated unique products and their repositioning strategies.

Results:

We found 5,099 orphan drug designations representing 3,269 unique products, of which 508 had an orphan-designated approval from FDA. Unique products with only a single designation represented 2,448 (75%) of the total products and 26 (1%) products had 10 or more designations. Over 60% of these unique products with 10 or more designations were antineoplastics or immunomodulators.

Conclusions:

The most designated unique products revealed a continuum of repositioning strategies, from the repurposing of approved drugs to parallel indication development programs for recently developed drugs. The fact that over 3,000 unique products have been studied for rare diseases indicates that future repositioning opportunities may become increasingly available.

1. Introduction

The Orphan Drug Act (ODA) was enacted in 1983 to stimulate development of drugs and biologics for rare diseases or conditions. The ODA primarily defined a rare disease or condition as one that affects fewer than 200,000 people in the United States [1]. (The ODA also allowed for designation based on the cost recovery provisions of the act, rather than the 200,000 prevalence definition.) To stimulate this development, the ODA created multiple financial incentives for developers that currently include [1]: research and development tax credits [2]; waived US Food and Drug Administration (FDA) user fees; and [3] the potential for a seven-year period of marketing exclusivity if the drug is approved for use in the rare disease or condition [2,3].

To be eligible for these incentives, developers must first request and be granted orphan drug designation (‘designation’). This designation program is administered by the Office of Orphan Products Development within the FDA. Developers requesting designation must demonstrate that [1]: the disease being treated, prevented, or diagnosed is rare; and [2] the scientific rationale is adequate to support a medically plausible basis for expecting the proposed drug or biologic will be effective in that rare disease [2,4]. Notably, multiple drugs can receive designation for one rare disease or condition and one drug can be designated for multiple rare diseases or conditions, if the above criteria are sufficiently demonstrated for each individual designation.

Recent studies have demonstrated the increasing importance of rare diseases in the drug development landscape [5–7]. The number of orphan designations nearly tripled between the decades of the 2000s and 2010s and orphan drugs in 2020 represented close to half of all new FDA drug approvals [6,8,9]. Multiple studies have also investigated other facets of the effect of the ODA on rare disease drug development, such as the increase in new orphan indication approvals as well as the value of the orphan drug marketing exclusivity to companies [10–15]. However, no research has systematically analyzed the specific small-molecule drugs and biologics that have been orphan designated.

Studying these orphan products illuminates two important dimensions of orphan drug policy. First, the analysis will provide a greater understanding of the trends in rare disease drug and biologic development. In this research, we examine those drugs and biologics that have most frequently been designated and describe their characteristics, target diseases, and mechanisms of action.

Second, our analysis provides a greater understanding of the business strategies within rare disease drug development [16,17]. Orphan drugs with only one designation may indicate a development program that is focused on only one rare disease. Drugs with multiple designations may be examples of repositioning strategies, whether that is via parallel indication development by the same sponsor, or the repurposing of an off-patent drug decades after its initial approval [18,19]. To elucidate this dimension, we analyze examples of repositioning seen in the most highly designated unique products.

Repurposing is appealing in the rare disease space, especially for nonprofit developers such as patient groups, due to its relative affordability as a development strategy [17]. These products usually have a known safety profile, may be being used off-label for the targeted new disease, have the potential for greater patient access in the form of generic versions, and may have reduced development timelines. While repurposing may not necessarily advance the newest or most innovative treatment options, the strategy may offer an economical, de-risked product to patients [20]. Recent research indicates that repurposing appears to be an increasingly important trend in rare disease drug development [17].

2. Methods

We began with a list of all orphan drug designations from 1983 to 2019 from an internal FDA database. These designations are also publicly available on FDA’s website through a searchable list (while the data in this list is identical to the dataset used for this analysis, the organization of the two datasets differs; contact the corresponding author for further details) [21].

The variables used for this analysis included: designation date, associated approvals, the sponsor (i.e. company or entity) that originally requested the designation, disease, or condition the product was designated for, and the product’s generic name. In addition to these variables, we categorized designations by: the therapeutic area targeted by the development program and the product type, e.g. small-molecule drug or biologic. (In this manuscript, the term ‘drug’ is used to refer to both small molecules and biologics, unless otherwise noted.)

To aggregate and analyze orphan drug products, we constructed a new variable, ‘unique product,’ that allowed for the standardization of generic product names. Unique products are those with different chemical structures, biological structures, or biologic targets. For example, pharmaceutical salts, isomers, enantiomers, recombinant versions of products, and formulations (tablet, capsules, oral solution) are not considered unique products for the purpose of our analysis. An exception to this was interferon alpha and beta products, where they were not broken down into their subcategories (i.e. interferon alpha 1a, interferon alpha 1b, etc). Note that our definition of unique product was constructed for research purposes and differs from the multiple regulatory definitions of ‘same drug’; they should not be considered equivalent.

We also performed an in-depth analysis of the unique products with 10 or more associated designations, which we refer to as ‘highly designated products.’ We chose a threshold of 10 designations to allow for a manageable yet comprehensive analysis of these products. For these drugs, we determined their primary effect using the Anatomical Therapeutic Chemical (ATC) pharmacologic or therapeutic subgroup, a drug classification system maintained by the World Health Organization [22]. The ATC subgroup was used to analyze whether there existed any trends in primary drug effects within the highly designated products.

To better understand the business models underpinning rare disease drug development, we also analyzed the repositioning strategies in these highly designated products. The term “repositioning” was chosen for this analysis because it represented a wide variety of business models, outside of novel drug development. We defined repositioning using the broad definition described in Allarakhia (2013):

Drug [repositioning] involves finding new indications for existing drugs or potential drug candidates. Drugs or candidates include those in clinical development whose mechanism of action is relevant to multiple diseases; drugs that have failed to demonstrate efficacy for a particular indication during phase II or III trials but have no major safety concerns; drugs that have been discontinued for commercial reasons; marketed drugs for which patents are close to expiry; and drug candidates from academic institutions and public sector laboratories not yet fully pursued.

[19]

For this analysis, we focused specifically on two components of this repositioning definition [19,23]. First, we looked closely at the most designated unique approved drugs that were being developed for a new indication(s) by a new sponsor. These were typically products that had been in use for an extended period of time. Additionally, their safety profiles were better defined, and exclusivity and patents had expired. We refer to this component as ‘traditional repurposing.’

Second, we focused on examples within the most frequently designated unique products where a single sponsor investigated multiple indications for the same drug. These products had mechanisms of action that worked across a variety of diseases and were typically developed by larger companies with significant regulatory and marketing experience. The intention for the overall development strategy likely included expansion plans occurring in parallel or sequentially over a period of time. We refer to this strategy as ‘parallel indication development.’

To assess the repositioning strategies, we studied three variables related to these highly designated products. First, we looked at the number of sponsors represented within the designations for the unique product. Second, we assessed the number of targeted therapeutic areas within the designations for the unique product. Finally, we calculated the time between the first designation and the most recent designation for each highly designated product.

These three measures provide multiple dimensions to assess repositioning strategies: unique products that utilize a traditional repurposing strategy may see higher numbers of sponsors, higher numbers of therapeutic areas targeted, and greater time between first and most recent designations; while unique products that utilize a parallel indication development strategy may see only one sponsor, lower numbers of therapeutic areas targeted, and shorter time between first and most recent designations.

3. Results

From 1983 to 2019, 5,099 orphan drugs were designated and, as of 31 December 2019 724 (14%) of these designations had at least one associated approval [8].

There were 3,269 unique products designated during this period, with an average of 1.6 designations and a range of between 1 and 30 designations per unique product. Of these products, 508 (16%) had at least one associated orphan-designated approval.

Unique products with only a single designation represented 2,448 (75%) of the total products. There were 740 (23%) unique products that had between two and five designations, 55 (2%) products that had between six and nine designations, and 26 (1%) products that had 10 or more designations.

Overall, biologics represented 41% [2,089] of designations and small-molecule drugs represented 59% [3,010]. The proportion of drugs and biologics designated has remained remarkably stable over time. In the 1980s, the proportion of biologics was 41% (126), while drugs were 59% (181); in the 1990s, it was 43% (281) versus 57% (379); in the 2000s, it was 40% (459) versus 60% (694); and in the 2010s it was 41% [1,223] versus 59% [1,756].

3.1. Targeted therapeutic area

Designations were categorized into one of 21 different therapeutic areas (Table 1). The three targeted therapeutic areas with the highest number of unique products were: oncology (1,258, representing 38% of all designated unique products), neurology (515, 16%), and infectious disease (306, 9%).

Table 1.

Orphandesignated unique products by targeted therapeutic area, 1983–2019.

Targeted Therapeutic Area	Number of Unique Products Designated	Total Number of Designations	Percent of Unique Products Within Targeted Therapeutic Area
Oncology	1,258	1,910	66%
Neurology	515	674	76%
Infectious Disease	306	436	70%
Metabolism	238	280	85%
Hematology	194	254	76%
Transplant	161	207	78%
Pulmonary	158	206	77%
Gastroenterology	152	195	78%
Ophthalmology	136	153	89%
Vascular	110	135	81%
Endocrinology	102	140	73%
Rheumatology	96	119	81%
Dermatology	83	94	88%
Pharmacology/Toxicology/Poisoning/Chelators	69	87	79%
Nephrology & Urology	52	54	96%
Immunology	46	54	85%
Cardiology	35	41	85%
Orthopedics	29	31	94%
Obstetrics & Gynecology	17	17	100%
Otolaryngology	6	6	100%
Nutrition	5	6	83%

The last column in Table 1 presents the proportion of unique products within each targeted therapeutic area. This was calculated by taking the number of unique products in a therapeutic area and dividing by the total designations in that therapeutic area. (Note, this calculation does not distinguish unique products with designations in multiple therapeutic areas.) The targeted therapeutic areas that have the smallest proportion of unique products are oncology (66% unique), infectious disease (70%), and endocrinology (73%).

3.2. Unique products with 10 or more orphan drug designations

We identified 26 unique products that had 10 or more associated orphan drug designations, for a total of 379 associated designations (Table 2). As of 31 December 2019, 92 of these designations had at least one associated approval. Small-molecule drugs represented 14 of these highly designated unique products, while 12 were biologics.

Table 2.

Summary statistics of the unique products with 10 or more orphan drug designations, 1983–2019.

Unique Product	Number of Designations	Number of Orphan Designated Approvals	Product Type	Primary Product Effectaa	Designated Targeted Therapeutic Area(s)b
Interferon Alfa	30	4	Biologic	Immunostimulant	Onc [22]; ID [5]; Rheum [2]; Heme [1]
Alpha-1 Proteinase Inhibitor	21	1	Biologic	Antihemorrhagic	Pulm [13]; TP [5]; Endo [2]; ID [1]
Immune Globulin	21	5	Biologic	Immune System Product	Neuro [10]; Rheum [5]; ID [2]; Card, GI, Heme, Imm [1]
Somatropin	21	16	Biologic	Hormone	Endo [14]; ID [4]; Derm, GI, Ob/Gyn [1]
Cannabidiol	19	2	Small Molecule	Nervous System Product	Neuro [12]; TP [3]; Onc [2]; Derm, GI [1]
Paclitaxel	19	2	Small Molecule	Antineoplastic	Onc [19]
Cyclosporine	17	0	Small Molecule	Immunosuppressant	TP [8]; Ophtho [4]; Neuro, Pulm [2]; ID [1]
Sirolimus	16	1	Small Molecule	Immunosuppressant	Derm [6]; Pulm [3]; Heme, Vasc [2]; GI, Onc, Ophtho [1]
Thalidomide	15	2	Small Molecule	Immunosuppressant	ID, Onc [4]; GI, TP [3]; Vasc [1]
Ibrutinib	14	8	Small Molecule	Antineoplastic	Onc [13]; TP [1]
Nitric Oxide	14	2	Small Molecule	Respiratory System Product	Pulm [6]; Vasc [4]; ID [2]; Heme, Imm [1]
Amphotericin B	13	3	Small Molecule	Anti-infective	ID [13]
Doxorubicin	13	2	Small Molecule	Antineoplastic	Onc [13]
Interferon Beta	13	2	Biologic	Immunostimulant	Onc [5]; ID, Neuro [3]; Pulm, Rheum [1]
Melatonin	13	0	Small Molecule	Nervous System Product	Neuro [5]; GI, Onc, Pharm [2]; Metab, Vasc [1]
Coagulation Factor VIIa	12	7	Biologic	Antihemorrhagic	Heme [10]; Pulm, Vasc [1]
Pembrolizumab	12	8	Biologic	Antineoplastic	Onc [12]
Phenylbutyrate	12	2	Small Molecule	Metabolism Product	Metab [5]; Neuro [4]; Onc [2]; Heme [1]
Angiotensin [1–7]	11	0	Small Molecule	Vasodilatorcc	Neuro, TP [3]; Onc [2]; Derm, Pharm, Vasc [1]
Bevacizumab	11	5	Biologic	Antineoplastic	Onc [9]; Ophtho, Vasc [1]
Brentuximab	11	4	Biologic	Antineoplastic	Onc [11]
Sargramostim	11	3	Biologic	Immunostimulant	Onc [5]; Pulm, TP [2]; Derm, Pharm [1]
Arsenic	10	1	Small Molecule	Antineoplastic	Onc [9]; TP [1]
Filgrastim	10	6	Biologic	Immunostimulant	Onc [3]; Pharm, TP [2]; Imm, ID, Neuro [1]
Melphalan	10	2	Small Molecule	Antineoplastic	Onc [9]; TP [1]
Nivolumab	10	4	Biologic	Antineoplastic	Onc [10]

^aBased on Anatomical Therapeutic Chemical (ATC) classification system, Level 1 or 2, where applicable, for approved indications.

^bTherapeutic Area abbreviations: Card = Cardiology; Derm = Dermatology; Endo = Endocrinology; GI = Gastroenterology; Heme = Hematology; Imm = Immunology; ID = Infectious Diseases; Metab = Metabolism; Neph/Ur = Nephrology/Urology; Neurology = Neuro; Ob/Gyn = Obstetrics and Gynecology; Onc = Oncology; Ophtho = Ophthalmology; Ortho = Orthopedics; Pharm = Pharmacology/Toxicology/Poisoning/Chelators; Pulm = Pulmonary; Rheum = Rheumatology; TP = Transplant; Vasc = Vascular

^cBased on proposed mechanism of action.

More than half of these unique products with 10 or more designations could be classified according to two primary effects: antineoplastics, which represented nine (35%) of the most designated unique products, and immune system products (including immunostimulants and immunosuppressants), which represented eight (31%) of the most designated unique products.

3.3. Analysis of repositioning in the unique products with 10 or more orphan drug designations

The current repositioning strategies of the most designated unique products were analyzed by three metrics (Table 3). The number of sponsors for each highly designated unique product ranged from 1 to 14, with an average of six sponsors per unique product (Figure 1). The number of therapeutic areas targeted by the designations of each highly designated unique product ranged from 1 to 7, with an average of 3.7 therapeutic areas per unique product (Figure 2). The time between the first and most recent designation for each highly designated unique product ranged from 5.8 to 35.8 years, with an average of 19.7 years per unique product (Figure 3).

Table 3.

Three repositioning strategy metrics associated with the unique products with 10 or more orphan drug designations, 1983–2019.

Unique Product	Number of Designations	Number of Sponsors	Number of Targeted Therapeutic Areas	Years Between First and Most Recent Designation1
Interferon Alfa	30	9	4	27.6
Alpha-1 Proteinase Inhibitor	21	9	4	35.8
Immune Globulin	21	11	7	29.7
Somatropin	21	6	5	20.2
Cannabidiol	19	7	5	5.8
Paclitaxel	19	14	1	18.5
Cyclosporine	17	11	5	22.0
Sirolimus	16	14	7	12.4
Thalidomide	15	4	5	28.8
Ibrutinib	14	1	2	5.8
Nitric Oxide	14	7	5	26.2
Amphotericin B	13	6	1	27.8
Doxorubicin	13	12	1	19.4
Interferon Beta	13	4	5	10.1
Melatonin	13	4	6	25.9
Coagulation Factor VIIa	12	4	3	25.0
Pembrolizumab	12	1	1	6.9
Phenylbutyrate	12	10	4	16.5
Angiotensin [1–7]	11	3	6	16.5
Bevacizumab	11	3	3	12.3
Brentuximab	11	1	1	11.8
Sargramostim	11	4	5	30.2
Arsenic	10	3	2	20.4
Filgrastim	10	3	6	26.9
Melphalan	10	5	2	23.4
Nivolumab	10	1	1	6.0

¹Most recent designation as of 31 December 2019.

Figure 1.

Repositioning strategy continuum of unique products with 10 or more orphan drug designations, as measured by number of sponsors, 1983–2019.

Figure 2.

Repositioning strategy continuum of unique products with 10 or more orphan drug designations, as measured by number of targeted therapeutic areas, 1983–2019.

Figure 3.

Repositioning strategy continuum of unique products with 10 or more orphan drug designations, as measured by the time between first and most recent designation (in years), 1983–2019.

4. Discussion

Our analysis found that between 1983 and 2019, 3,269 unique products were designated by the FDA for the treatment, prevention, or diagnosis of rare diseases or conditions. A quarter of these products have been designated multiple times, indicating a substantial level of repositioning (i.e. development that is not for a novel product) occurring over the last four decades. However, only 508 (16%) of the unique products have been approved for an orphan-designated indication.

As 75% of the unique products in our study had only a single associated designation, there may still be significant opportunities for additional repositioning of orphan-designated drugs. There may be multiple reasons why we are seeing this high proportion of products with one designation. First, there could be a large lag in repositioning timing, as many of these unique products were designated in the last 10 years and therefore may not have had enough time to develop other repositioning avenues [8]. Second, because many products receive designation in the pre-clinical phase, it may be that development was discontinued due to safety concerns, which would limit repurposing [24]. Finally, an increasing trend toward precision medicine (e.g. gene therapy products) may imply limited repositioning opportunities for these types of products.

We also found that the potential for repositioning opportunities did not appear to be uniform across targeted therapeutic areas. The range in proportion of unique products within targeted therapeutic areas was substantial. For example, all (100%) of the designated products in otolaryngology were unique products, compared with only 66% in oncology. These proportions can be interpreted as the level of within-therapeutic area repositioning. Oncologic unique products are therefore the most likely to be also developed for other rare cancers, while no otolaryngology unique products were developed for other rare otolaryngology conditions. The differences in repositioning opportunities between targeted therapeutic areas can likely be attributed to similarities in pathophysiology and genetic mutations for diseases within therapeutic areas, such as cancers.

Unique products with 10 or more designations represented only 1% of the total products, indicating that this high level of repositioning is very infrequent within orphan drug designations. These 26 products were evenly split between drugs and biologics. Unsurprisingly, over 65% of these unique products were antineoplastics or immune system products, drug types designed for diseases with common affected pathways. These pathways enable the mechanisms of action of these types of drugs to be effective in multiple phenotypically distinct diseases or conditions.

These most frequently designated unique products represent the full continuum of repositioning: from traditional repurposing to parallel indication development. This range of repositioning strategies indicates a dynamic development landscape for these unique products treating rare diseases. We discuss some novel cases in-depth below.

Four products – three monoclonal antibodies (brentuximab, nivolumab, and pembrolizumab) and one small molecule, ibrutinib, had more than 10 designations but only a single sponsor, consistent with the repositioning strategy we term ‘parallel indication development.’ Additionally, three of these unique products represented only one targeted therapeutic area (oncology), while one spanned just two targeted therapeutic areas (oncology and transplant). The products have also been very successful: each has between four and eight orphan-designated approvals (eight being the second highest number of approvals for a unique product seen in the data).

Sirolimus, a potent immunosuppressant with a well-known mechanism of action, is a classic example of traditional repurposing: it tied for the highest number of initial designation sponsors (n = 14) and the highest number of targeted therapeutic areas (n = 7) [16]. Alpha-1 proteinase inhibitor, also known as alpha-1 antitrypsin, is another example of traditional repurposing, with the longest amount of time between the first and most recent designation. The earliest designations for this product were for replacement therapy for alpha-1 antitrypsin deficiency, yet following research demonstrating the ability of alpha-1 antitrypsin to reduce the production of proinflammatory cytokines, the more recent designations were for the treatment of graft-versus-host disease [25,26]. Both of these examples of traditional repurposing illustrate how the evolution of science informs development and how, subsequently, repositioning may occur.

An unusual example of repositioning within the most frequently designated unique products is cannabidiol. This product has numerous sponsors and targeted therapeutic areas, but a relatively short window between first and most recent designations. Cannabidiol appears to be neither an example of traditional repurposing, nor parallel indication development, but rather another repositioning strategy altogether. While cannabidiol is a drug that has been well-known to science for decades, the first approval of the active moiety by FDA was in 2018 for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older [27,28].

In addition to the 19 cannabidiol product designations described in the results, four other cannabis-derived drugs (including delta-9-tetrahydrocannabinol and cannabidivarin) have received 10 designations, resulting in a total of 29 cannabinoid designations since 2013. It appears that the increased industry interest in this drug class is due to multiple factors: the relatively recent increase in US cultural acceptance of medical cannabis product use, new scientific discoveries in the ability to isolate and synthesize the active moieties of cannabis, and advances in the understanding of pathology that involves the endocannabinoid system [29].

Future research may wish to compare these results to other regulatory markets (such as Europe) or the repositioning in the non-rare disease space [30]. Additionally, future research could study the types of companies participating in repositioning (e.g. large vs small, public vs private, academic vs industry) and the relationship between company type and approval.

4.1. Limitations

There are several limitations to this analysis. First, the results are only generalizable to the rare disease space. We limited our analysis to orphan-designated drug development programs, and therefore do not consider any repositioning that occurred in the non-rare space [20]. Second, by definition, there may be a substantial lag to repositioning. Therefore, we are not able to identify possible future repositioning that will likely occur with some of these unique products, especially the ones that are early in their development. Finally, the creation of a unique product variable may be prone to subjectivity. However, we have attempted to fully describe our methodology to increase accurate reproducibility.

5. Conclusion

This study found that, among the 5,099 orphan drug designations that occurred between 1983 and 2019, there were 3,269 unique products were represented and 508 of these products had at least one orphan-designated approval. One percent of these unique products had 10 or more designations, which reveal a range of repositioning strategies of sponsors, from the repurposing of previously approved drugs to parallel indication development for recently developed drugs. Seventy-five percent of the unique products had only a single associated designation, indicating that many opportunities may exist for new repositioning strategies for these drugs and biologics. Future repositioning opportunities may become available as more of these unique products lose patent protections and marketing exclusivities.