The U.S. Orphan Drug Act of 1983 and associated incentives have fostered delivery of novel treatments for rare cancers. Quantitative cross-sectional analysis on the U.S. Food and Drug Administration Orphan Drug Product database found that more than one-third of all orphan drug approvals address needs of patients suffering from rare cancers.
Keywords: Orphan Drug Act, Orphan drug development, Rare diseases, Rare cancer
Abstract
Background.
Rare cancers are a heterogeneous group of conditions with highly unmet medical needs. Although infrequent in individuals, rare cancers affect millions of people who deserve effective treatments. Therefore, we systematically analyzed the impact of the U.S. Orphan Drug Act of 1983 on delivery of novel treatments for rare cancers.
Methods.
Quantitative cross-sectional analysis was conducted on the U.S. Food and Drug Administration Orphan Drug Product database according to Strengthening the Reporting of Observational Studies in Epidemiology Statement criteria between 1983 and 2015.
Results.
Since 1983, a total of 177 approvals have originated from 1,391 orphan drug designations to treat rare cancers, which represents 36% of all approvals within the U.S. orphan drug act (n = 492). Two compounds (1%) to treat rare cancer were withdrawn after approval. Median time from designation to approval was 2.49 years (interquartile range 1.13–4.64) and decreased significantly over time (p < .001, linear regression). Over the last decade, rare cancer treatments have been transformed from nonspecific cytotoxic agents toward targeted therapies, such as protein kinase inhibitors and monoclonal antibodies, representing the largest groups of innovative rare cancer treatments today. Most compounds were approved to treat solid tumors and hematological malignancies.
Conclusion.
The U.S. Orphan Drug Act and associated incentives, such as 7 years of marketing exclusivity, have fostered delivery of novel treatments for rare cancers. More than one-third of all orphan drug approvals address needs of patients suffering from rare cancers. Over the last decade, the understanding of tumorigenesis and genetic driver mutations in different tumor entities has produced innovative treatments, of which many were first approved within the U.S. Orphan Drug Act.
Implications for Practice:
Over the last 30 years, the U.S. Orphan Drug Act successfully delivered numerous novel treatments for rare cancers, of which some were subsequently used in other, nonorphan indications. The understanding of molecular mechanisms of diseases is directly connected to the search for novel therapies. The constant pursuit to translate basic research findings into clinical practice is a crucial prerequisite to address unmet medical needs in rare cancers, as in other rare diseases. Oncological drug development proves to be a major player in overall orphan drug research, displayed by more than one-third of all U.S. Food and Drug Administration-approved orphan drugs with oncological indications.
Introduction
Cancer is the leading cause of death in the U.S. and Europe today and even surpasses death by cardiovascular disease [1]. Although all patients suffering from cancer deserve effective and well-tolerated therapies, most funding is given to research and drug development in more common oncological diseases, such as breast, lung, prostate, and squamous cell skin cancer, compared with rare cancers [2]. Generally, a rare disease is defined as a condition affecting fewer than 7.5 people in 10,000 or fewer than 200,000 in the U.S., or fewer than 5 in 10,000 in the European Union [3–6]. Considering that all childhood and many adult malignancies—such as gastrointestinal stromal tumors (GIST), acute myeloblastic leukemia, or glioblastoma multiforme—fulfill the definition of a rare disease, as an overall group, millions of people are afflicted by rare cancers [6]. In oncology, novel treatments are urgently needed because unspecific therapies such as cytotoxic drugs or radiotherapy are limited by adverse events and variable treatment success. In recent years, identification of signaling pathways involved in tumorigenesis created new targets for specific cancer therapy [7–10]. Since 1983, the U.S. Orphan Drug Act has aimed to stimulate investment in the development of therapies for rare diseases. Various incentives are granted, such as 7 years of marketing exclusivity, tax credit for 50% of clinical trial costs, protocol assistance, U.S. Food and Drug Administration (FDA) fee waiver, and orphan grants programs [11].
Because the molecular understanding of tumorigenesis has accelerated over the last 10 years and new therapeutic principles have entered the market, we hypothesized that the U.S. Orphan Drug Act might have influenced the field of designation and approval of orphan drugs. Numerous scholars, policymakers, and politicians consider the U.S. Orphan Drug Act a tremendous success [12]. However, many questions remain unresolved. What is the output of the U.S. Orphan Drug Act for patients with rare cancers? Are antineoplastic agents receiving U.S. Orphan Drug Act benefits truly innovative? Has the FDA lowered the bar for approving orphan-designated drugs, and, if so, has such lowering harmed patients? Can time from designation to approval for potential new treatments that receive an orphan drug designation today be estimated based on previous performance? In order to answer these questions, we analyzed the impact of the U.S. Orphan Drug Act on new treatments for patients with rare cancer diseases.
Methods
This study was designed, executed, and analyzed, taking into account the principles outlined in the Strengthening the Reporting of Observational Studies in Epidemiology Statement (STROBE).
We downloaded all orphan drug-designation data entries from the FDA database Search Orphan Drug Designations and Approvals (available at http://www.accessdata.fda.gov/scripts/opdlisting/oopd/) between January 1, 1983 and May 6, 2015. The list was then manually cleared from nononcological indications by a board certified pediatric oncologist (C.S.).
The following variables were extracted from the database and analyzed: generic name, orphan designation status, orphan designation date, FDA orphan approval status, approved labeled indication, and marketing approval date. Time to approval was defined and calculated as the time period from orphan drug designation until approval by the FDA. To evaluate the impact of the U.S. Orphan Drug Act on approval of novel cancer treatments, we analyzed whether antineoplastic agents were first approved within the U.S. Orphan Drug Act or whether they were already available for nonorphan indications. Treatment indications were categorized into brain tumor, lymphoma, malignant hematology, solid tumors, stem cell transplantation, and concomitant therapy. Approved compounds were grouped according to their drug class and pharmacological category, which was derived from their Anatomical Therapeutic Chemical (ATC) code and mechanism of action outlined in the FDA label. Drug classes were defined as small molecules, radioconjugates, and biologics, which were further differentiated into monoclonal antibody and other. We considered small molecules as chemically synthesized low-molecular mass molecules (typically <1,000 Da), which can be fully characterized by analytical techniques [13, 14]. In contrast, biologics are structurally complex large-molecular mass proteins derived from living cells through biotechnological processes, such as recombinant DNA, controlled gene expression, or antibody methods [13, 14]. Radioconjugates were defined as radiolabeled chemically synthesized compounds.
Methods of descriptive statistics were applied to summarize characteristics from each of the identified pharmacological compounds. Categorical variables were summarized with frequencies and percentages, and continuous variables were summarized with mean, standard deviation, and median, minimum, and maximum values. Changes in time to approval during the observation period were assessed with a linear regression model. All calculations were performed with SAS Enterprise Guide (Version 9.1; SAS, Cary, NC, http://www.sas.com).
Results
In total, 36% (177 of 492) of all orphan drug approvals were related to rare cancers. The database analysis identified 1,391 orphan drug designations for rare cancers, representing 41% of total orphan drug designations (n = 3,425). For oncologic diseases, 13% (177 of 1,391) of orphan drug designations resulted in approval, compared with 14% (492 of 3,425) of total designations. In oncology, diaziquone was the first orphan drug designated to treat primary brain malignancies (grade III and IV astrocytomas), on October 11, 1983. The designation was withdrawn before approval. The first approved compound related to rare cancer was pentamidine isethionate to treat Pneumocystis carinii pneumonia, on October 16, 1984. Over three decades, orphan drug designations and subsequent approvals increased (Fig. 1). Two approvals were withdrawn (i.e., gallium nitrate for treatment of hypercalcemia of malignancy and iobenguane sulfate I 131 for use as a diagnostic adjunct in patients with pheochromocytoma). Most orphan drug approvals were for solid tumors, followed by malignant hematology (Table 1). In addition, 28 concomitant therapies for conditions related to rare cancers were approved (e.g., leucovorin for rescue use after high-dose methotrexate in the treatment of osteosarcoma or amphotericin B for treatment of invasive fungal infections) (Table 1). Most approvals for rare cancers comprised antineoplastic agents, of which most were protein kinase inhibitors and monoclonal antibodies (Table 2). Of all approved antineoplastic agents, 74% (72 of 97 compounds) were first approved within the U.S. Orphan Drug Act (supplemental online Table 1). The remaining 25 compounds had already been approved for nonorphan indications before they were designated and approved to treat rare cancers. Compounds classified as miscellaneous agents were predominantly approved as concomitant therapy in rare cancer. Over three decades, development and subsequent approval of antineoplastic agents to treat rare cancers has shifted from nonspecific cytotoxic antiproliferative agents—such as immunomodulators, cytotoxic antibiotics, alkylating agents, and antimetabolites—toward a more targeted therapy, i.e., use of monoclonal antibodies and protein kinase inhibitors (Fig. 2). Regarding their drug class, 127 approvals comprised small molecules, and 42 biologics, of which 24 comprised monoclonal antibodies, and 8 approvals comprised radioconjugates. The median time period between designation and respective approval was 2.49 years (interquartile range 1.13–4.64; n = 176). Time from designation to approval decreased significantly over three decades (p < .001, r 2 = 0.01, linear regression) (Fig. 3).
Figure 1.
(A): Number of FDA orphan drug designations by year: overall (open bars) and orphan oncological indications (filled bars). (B): Number of FDA orphan drug approvals by year: overall (open bars) and orphan oncological indications (filled bars). The close of database for our analysis was May 2015; therefore, the numbers for the year 2015 are not fully representative.
Abbreviation: FDA, U.S. Food and Drug Administration.
Table 1.
Disease groups of approved orphan drugs for oncological indication
Table 2.
Pharmacological category and subcategory of approvals and number of approved compounds for rare cancer
Figure 2.
Number of orphan drug approvals over time of antineoplastic agents by selected pharmacological subcategories, i.e., immunomodulators, cytotoxic antibiotics, alkylating agents, antimetabolites, monoclonal antibodies, and protein kinase inhibitors.
Abbreviation: FDA, U.S. Food and Drug Administration.
Figure 3.
Time to approval of compounds intended to treat rare cancer by year. The time from orphan drug designation to approval in years could be predicted with the following regression model: Time [years] = 255.4 + (−0.1260 × year of orphan drug designation), n = 176 (available data for 176 approvals); 95% confidence interval (CI) for slope: −0.1814 to −0.07067; r2 = 0.01; p < .0001. The 95% CI is indicated by the dashed lines. Three compounds had approval dates that preceded their respective orphan designation dates, which, according to the U.S. Food and Drug Administration, was due to special circumstances.
Discussion
Productivity Output
More than one-third (177 of 492) of all orphan drug approvals were related to cancer treatment. In contrast, over the last three decades, the U.S. Orphan Drug Act delivered 14 orphan drug approvals for lysosomal storage diseases [15], 14 approvals for rare rheumatological disorders [16], and 9 approvals for rare seizure disorders [16]. It appears possible that there are more innovative orphan drugs in disease areas where the mechanism of disease is well understood, such as tumorigenesis in cancer, enzyme deficiencies in lysosomal storage disorders, and inflammatory pathways in rheumatological disorders, whereas the precise causality of epilepsy still remains to be elucidated. Of note, before the U.S. Orphan Drug Act, 34 drugs were approved from 1967 to 1983 that would have met the orphan drug definition [17]. The steady increase of designations and approvals illustrates the impact of the U.S. Orphan Drug Act and associated incentives for drug development for rare diseases [18]. Indeed, there has been a growing interest by pharmaceutical and biotech companies in developing products to treat rare diseases [19]. Therefore, patents and regulatory exclusivity properties are likely the core approaches to foster orphan drug development [18, 20]. Today, it is suggested that orphan drugs have similar revenue-generating potential to nonorphan drugs [21]. Particularly, smaller and shorter clinical trials and various cost-benefit incentives granted by the U.S. Orphan Drug Act may outweigh challenges in clinical development of orphan drugs, such as lack of validated endpoints or recruiting and logistical problems [21].
Development success was comparable between rare cancer treatments and overall orphan drugs, as reflected by similar approval rates. In addition, the proportion between designations and approvals for rare cancers and overall designations and approvals remained constant. In general, the clinical trial design—particularly choice of the endpoint and target population, inexperienced sponsors, and a low level of interaction with the FDA—contribute to nonapproval as an orphan drug [22]. Therefore, obtaining FDA advice in designing and conducting the pivotal clinical trials may be particularly important for sponsors of innovative biotechnological molecules, new molecular entities, or innovative formulations that are applying for orphan drug designation [22].
Time from designation to approval decreased over time, which could be accounted for by an accelerated development process or request of the orphan drug designation toward the end of the development process. Indeed, an analysis of the clinical trial development process of orphan drugs approved between 2007 and 2009 showed that orphan drug designations occurred at the final steps of the development process [17]. Nevertheless, time to approval calculated in this cross-sectional analysis allows an approximate estimation of potential future approval of currently filed orphan drug designations. In addition, it is estimated that the earlier a patient has access to an orphan drug, the earlier premature death from rare diseases is reduced [23].
Innovation and Efficacy
In recent years, the molecular understanding of tumorigenesis has transformed cancer therapy from broad cytotoxic agents to targeted therapies. FDA approval of rituximab, a monoclonal antibody against CD20 expressed on B-lymphocytes, in 1997 was an important milestone in targeted cancer therapy [7, 8]. The approval of protein kinase inhibitors, such as imatinib under the U.S. Orphan Drug Act for chronic myeloid leukemia and GIST in 2001, considerably extended the spectrum of targeted cancer therapies [9, 10]. Both drugs were first approved within the U.S. Orphan Drug Act. Almost three-quarters of antineoplastic agents (72 of 98 compounds) were first approved within the U.S. Orphan Drug Act. However, in general, approximately 25% of orphan drugs have also received marketing approval for at least one nonorphan indication [23]. Today, protein kinase inhibitors represent the largest group of orphan anticancer treatments. Given that, for example, imatinib, a protein kinase inhibitor, has even reached blockbuster status—i.e., a drug that generates annual sales of at least $1 billion for the company [24]—one may consider the definition of an orphan disease too broad because it mainly focuses on disease prevalence rather than including financial aspects. The perspective of carving out some revenue may have stimulated development of competing compounds for the same indication [25]. For example, imatinib, dasatinib, and nilotinib share the market for treatment of chronic myeloid leukemia. Although marketing exclusivity within the U.S. Orphan Drug Act prohibits FDA approval of the same drug for the same orphan indication for 7 years, similar compounds can enter the market for the same orphan indication [18, 25]. Particularly, orphan drugs in chronic rare conditions such as multiple myeloma, chronic lymphatic leukemia, or chronic myeloid leukemia can secure revenue for pharmaceutical companies, stimulating “me-too” developments for such indications. As demonstrated in lysosomal storage disorders, the U.S. Orphan Drug Act may bias drug development toward compounds that are (a) likely to be approved while moving along an already established pathway toward registration, and (b) likely to generate revenue, e.g., me-too compounds [15]. The number of innovative antineoplastic agents that were truly developed with an orphan disease in mind may be small (e.g., imatinib or crizotinib). Although orphan drugs may be byproducts in pharmaceutical research and development programs, and would have been developed irrespective of the U.S. Orphan Drug Act, the increase of targeted therapies in recent years demonstrates the synergistic effects between mechanistic basic research and drug development for the approval of novel effective therapies for rare cancers.
Safety Aspects
Orphan drugs are developed faster and with substantially fewer patients exposed in smaller and fewer clinical trials compared with classical drug-development programs. Therefore, safety signals may not become immediately evident. Thus, orphan drug approvals often require follow-up through registries. Withdrawals of rare cancer drugs have been infrequent; only two compounds were withdrawn since 1983, i.e., gallium nitrate and iobenguane sulfate I 131. Gallium nitrate was not withdrawn for safety reasons [26], and iobenguane sulfate I 131 was discontinued [27]. This suggests that there have not been numerous safety concerns in orphan drug development for rare cancers.
Limitations
The analysis of orphan drug development is limited to the data provided by the FDA. Other regions, such as the European Union, were not included in this study because the FDA database is the largest and oldest. Although drug approval status can vary between different regions of the world, we consider the results of this analysis to be generalizable. Time from designation to approval is influenced by time of designation. The date of orphan drug designation can be somewhat arbitrary. Specifically, a company may choose for intellectual property consideration an orphan drug designation late in the drug-development process. Time to approval decreased significantly over time, but r2 was rather small, with 0.01, which is a limitation of the goodness of the fit for the model. However, the knowledge of the historical time from designation to approval record is useful because it allows for the approximate estimation of future potential drug approval time frames for recently designated compounds. The close of database for our analysis was May 2015; therefore, the numbers for the year 2015 are not fully representative. It is not possible to estimate the number of orphan drugs that would have been approved without the U.S. Orphan Drug Act, and a formal comparison between the drug-development output before and after the U.S. Orphan Drug Act is difficult [18] for the following reasons. (a) Increased investment in pharmaceutical research and development could have facilitated the discovery and development of orphan drugs as a byproduct of research for nonorphan conditions [18]. (b) Biopharmaceutical technology has changed over the years, which may have stimulated drug development independent from the U.S. Orphan Drug Act. (c) Public initiatives and orphan disease patient groups have increasingly encouraged orphan drug development over time [18]. (d) Other U.S. regulations (e.g., the Hatch-Waxman Act or the Small Business Innovation Development Act) increased patient and marketing exclusivity periods or dedicated research grants to small businesses that target orphan drug development more often [18]. Conversely, one could postulate that the U.S. Orphan Drug Act has supported innovative technologies because of financial incentives and scientific and regulatory support, which somewhat mitigates the risk of failure.
Conclusion
The U.S. Orphan Drug Act successfully fostered delivery of novel treatments in rare cancers. In particular, many innovative antineoplastic agents were first approved within the U.S. Orphan Drug Act, illustrating the impact of attractive incentives on translation of basic research into clinical practice. Although pharmaceutical companies primarily seek orphan drug status to get longer marketing exclusivity and return on investment, patients with rare cancers benefit from the U.S. Orphan Drug Act because novel therapies have been developed for patients who would otherwise be out of the scope of the traditional industry approach.
See http://www.TheOncologist.com for supplemental material available online.
Supplementary Material
Acknowledgments
C.S. was supported by the University of Heidelberg Frontier Program. A.L. received a personal scholarship from the Dr. August and Dr. Anni Lesmüller Foundation. The funding sources had no influence on study design, collection, analysis, and interpretation of data, writing of the manuscript, and the decision to submit the manuscript for publication. M.R. gratefully acknowledges inspirational conversations with Louis Bohuon.
Footnotes
For Further Reading: Robert E. Martell, David Sermer, Kenneth Getz et al. Oncology Drug Development and Approval of Systemic Anticancer Therapy by the U.S. Food and Drug Administration. The Oncologist 2013;18:104–111.
Implications for Practice: Regulatory approval of oncology drugs is the cornerstone of the development process and approval characteristics shape eventual utilization. Approval trends and characteristics provide valuable information for drug developers and regulators, and ultimately impact clinicians and patients. This review found that approval of oncology agents is occurring in increasingly more challenging settings, suggesting gaps between eventual practice and development in potentially sub-optimal indications. Molecular specifications promise to enhance development, yet widespread use in label indications has not yet been achieved.
Author Contributions
Conception/Design: Clemens Stockklausner, Anette Lampert, Markus Ries
Collection and/or assembly of data: Clemens Stockklausner, Anette Lampert, Georg F. Hoffmann, Markus Ries
Data analysis and interpretation: Clemens Stockklausner, Anette Lampert, Georg F. Hoffmann, Markus Ries
Manuscript writing: Clemens Stockklausner, Anette Lampert, Georg F. Hoffmann, Markus Ries
Final approval of manuscript: Clemens Stockklausner, Anette Lampert, Georg F. Hoffmann, Markus Ries
Disclosures
Anette Lampert: Dr. August and Dr. Anni Lesmüller Foundation (RF); Georg F. Hoffmann: Danone (H); Markus Ries: Shire (C/A, RF), GlaxoSmithKline, Oxyrane, Alexion (C/A). The other author indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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