Evaluation of clinical trials done for orphan drugs versus nonorphan drugs in infectious diseasesan eleven year analysis [2010-2020] : Perspectives in Clinical Research

Secondary Logo

Journal Logo

Original Article

Evaluation of clinical trials done for orphan drugs versus nonorphan drugs in infectious diseasesan eleven year analysis [2010-2020]

Kudyar, Palvi; Konwar, Mahanjit; Khatri, Zoya; Gogtay, Nithya Jaideep; Thatte, Urmila Mukund

Author Information
Perspectives in Clinical Research 14(2):p 56-60, Apr–Jun 2023. | DOI: 10.4103/picr.picr_137_21
  • Open



The US Orphan Drug Act (1983) defines orphan drugs as promising therapies intended to treat diseases that affect fewer than 2,00,000 people.[1] The World Health Organization defines a rare disease as one that has a prevalence of 1/10000 population or less. The European Union’s definition is slightly different and includes a prevalence of not more than 5/10,000 population in its definition. In India, on January 13, 2020, an expert committee constituted by the Ministry of Health and Family Welfare put out a draft National Policy for Rare Diseases in India and this policy was finalized in 2021. This policy uses location of the disease, its level of rarity, and whether [or not] it is amenable to a clinical trial rather than prevalance for classification.[2]

The US Orphan Drug Act was an early act that provided significant impetus to orphan drug development as it provided financial incentives and an exclusivity period of 7 years for orphan drug approvals to the pharmaceutical companies with a goal to provide new treatments for patients.[3] Prior to 1983, only 38 orphan drugs had been approved by the US Food and Drug Administration (FDA), whereas consequent to the act, 667 orphan drugs got approval by the US-FDA.[4]

There have been several studies in the area of orphan diseases and their drug development that have analyzed the overall outcomes of the US legislation with most focusing on the number of orphan designations over time.[5] Orphan drugs in oncology appear to get approval based on alternative trial designs [relative to traditional study designs] in comparison to the non-orphan drugs.[6] Similar data in other areas such as infectious diseases are lacking. This area is one that demands continuous development of novel treatments where the last orphan drug approval was that of nifurtimox (for Chagas disease) in August 2020. Against this backdrop, this study was carried out with the primary objective of evaluating overall characteristics of orphan versus nonorphan drug approvals as a whole and a secondary objective was to evaluate orphan drug approvals in the area of infectious diseases.



The study (EC-OA-02/2020) was done after obtaining exemption from review by the institutional ethics committee.

Overall search strategy and eligibility criteria

The data for the study were accessed from accessdata.fda.gov and rarediseases.info.nih.[7] Inclusions were all clinical trials supporting new drug approvals for infectious diseases by the US-FDA from January 1, 2010, to December 31, 2020. If a drug was approved for more than one indication, the trial characteristics were selected for the therapeutic area for which it was first approved. Studies that supported the approval of vaccines, vitamins, or plant products for infectious diseases during the study period were excluded.

Evaluation of data and information collected

Monthly approvals were divided as orphan and nonorphan approvals. Orphan drugs as defined by the US-FDA are the therapies intended to treat diseases that affect fewer than 200,000 people.[1] All other approvals were designated as nonorphan approvals. Trial characteristics were taken from the US-FDA labels, summary reports, and regulatory reviews. In addition, information was also gleaned from the clinicaltrials.gov database. The information collected for each approval included the date and indication at the time of approval, the type of approval (priority or standard approval), and the basic features of the trial design of pivotal trials (randomization, blinding, sample size, interventions, and type of primary endpoints).

Outcome measures

These included (a) the proportion of pivotal clinical trials that were randomized or not, (b) whether blinding is present or otherwise, (c) sample size of the trials, (d) if interventions used was an active comparator or a placebo, (e) whether a single primary endpoint was used or otherwise, (f) the phase of clinical trial (whether I/II/III), and (g) the type of review of the drug (whether priority/standard). A comparison of all these pivotal clinical trials characteristics of orphan versus non-orphan drugs was done.

Statistical analysis

Both descriptive and inferential statistics were applied to the data. Quantitative data such as total approvals were expressed as median [range], and binary categorical data such as study characteristics (randomization, blinding, use of an active comparator, and single primary endpoint) were expressed as proportions. Normality of quantitative data was assessed using the Kolmogorov–Smirnov test. Association of the type of drug approval (whether orphan or nonorphan) with respect to the characteristics of trial design, randomization, blinding, endpoints, and comparator group was evaluated at a significance level of P < 0.05 using Chi-square test and Fisher’s exact test, and a crude odds ratio (with 95% confidence intervals) was generated. The Mann–Whitney U test was applied to compare the sample sizes of the clinical trials. All statistical tests were done using SPSS (Version 25) (IBM Corp., Armonk, New York, USA) at 5% significance.



A total of 1122 drugs were approved in the 11-year period and 395 (35.2%) of these were orphan approvals. A total of n = 84 drugs were granted approval for infectious diseases over the study period (January 1, 2010, to December 31, 2020], of these n = 18/84 (21.4%) were designated as orphan drug approvals and n = 66/84 (78.5%) were designated as nonorphan drug approvals [Table 1].

Table 1:
Demographic characteristics of drug approvals by USFDA from 2010–2020

The highest number of approvals of drugs for infectious diseases was in 2018 (n = 18) [Figure 1]. In the same year, the highest number of orphan drugs was also approved, n = 4/18 (22%), and the highest number of approvals for nonorphan drugs was seen similarly in 2014 and 2018, n = 13/66 (19%).

Figure 1:
New drug approvals for infectious diseases by the US Food and Drug Administration from 2010 to 2020

Clinical trials characteristics

For the orphan drugs, n = 35 pivotal trials were done for 18 drugs to obtain approval, and for the non-orphan drugs, n = 115 pivotal trials were done for 66 drugs.

Randomization and blinding in clinical trials

Randomization for treatment allocation (n = 100/115, 87%) was seen to be significantly higher in trials with nonorphan drugs as compared to orphan drugs (n = 15/35, 42%)(Crude Odd’s Ratio (cOR): 8.8 [3.7, 21.04]), P < 0.0001. Similarly, double blinding was also significantly higher in the non-orphan drug trials (n = 69/115, 60%) relative to orphan drug trials (n = 13/35, 37%) (cOR: 2.5 [1.1, 5.5]), P = 0.013 [Table 2].

Table 2:
Characteristics of pivotal clinical trials of orphan versus nonorphan drug approvals

Sample size in the trials

The median number of participants in the clinical trials for the orphan drugs (n = 89 [45–766]) was significantly lower than that for the nonorphan approvals (n = 452 [20–1721]) (P < 0.0001).

Use of a comparator and choice of endpoint in the trials

An active comparator was used in 68/115 (59%) of the pivotal trials for nonorphan drugs, while it was used in only 19/35 (54%) of the pivotal trials for orphan drugs (cOR: 1.2 [0.5, 2.6]) P = 0.616. A total of n = 12/35 (34.2%) trials for orphan drugs used a placebo to establish the efficacy of the drug, while it was used in 30/115 (26%) of non-orphan drug approvals. A single primary endpoint was used in 65/115 (56.5%) trials with non-orphan drugs, while it was used in 19/35 (54%) of the trials evaluating orphan drugs (cOR: 1 [0.5,2.30] P = 0.251. There was no association seen between the use of multiple or composite primary endpoints in the trials with regard to the type of drug approvals (whether orphan or nonorphan, P > 0.05).

Phase of trials

The approvals for both orphan and nonorphan drugs were based on pivotal clinical trials done in various phases. A total of n = 20/35 (57.1%) and n = 15/35 (42.8%) of orphan drugs were approved based on phase II trials and phase III trials, respectively. Whereas, for the nonorphan drugs, n = 99/115 (86%) were approved based on phase III trials and a few n = 8/115 (7%) got approval based on phase II trials. The pivotal phase II trials were significantly higher for orphan drugs as compared to nonorphan drugs (P < 0.0001).

Type of review

All 18 orphan drugs received priority review from US-FDA, whereas only n = 41/66 (62%) nonorphan drugs received a priority review (cOR: 22.7 [1.3, 393.8]) P < 0.001.


Our analysis of US FDA database showed that a total of 1122 drugs were granted approval over a period of 11 years, of which 395 were accorded approval as orphan drugs and only 18 of these approvals were for infectious diseases [Table 3]. Nonrandomized (58%), open-labeled (63%) studies with a small sample size were the predominant feature of the pivotal trials for orphan approvals. More than half (57%) of these trials were phase II trials as compared to only (7%) of the trials for nonorphan drugs (P < 0.00001). One hundred percent of orphan drugs underwent priority review as against only 62% for nonorphan drugs.

Table 3:
Orphan drugs approved for infectious diseases from January 2010 to December 2020

Our study found that in the last 11 years, a total of n = 18/1122 (1.6%) new orphan drugs got approval for infectious diseases which is a rather low number given the unmet need in this field. The reasons are manifold. Drug development in this area is risky, expensive, and time-consuming as resistance develops over a period and the return on investment is unpredictable. This is even more so for orphan drugs. In 1993, a grant program was instituted and the National Institution of Health Office of Rare diseases was set up to encourage pharmaceutical manufacturers to develop new drugs for rare conditions by providing considerable resources.[8] In India, similarly, the National Rare Drugs Policy, 2021, aims to support the local development and manufacture of drugs for rare diseases at affordable prices, by encouraging public sector units [PSUs] and establishing legislative measures for creating a conducive environment for indigenous manufacturing of drugs for orphan diseases.

Pivotal trials for orphan drugs tend to be nonrandomized and open-label as compared to the nonorphan drugs due to the very nature of these diseases. Testing of orphan drugs such as miltefosine (leishmaniasis) and triclabendazole (liver fluke) makes blinding virtually impossible in these studies. Winstone et al. in their review of clinical evidence packages for treatments approved by the European Medicines Agency (EMA) established that randomization and blinding that are key methodological aspects of randomized controlled trials for nonorphan drugs are not well entrenched in orphan approvals, but their lack in and of itself does not preclude regulatory approval.[9] Similarly, a smaller sample size for orphan drugs is possibly the result of low disease prevalence. Kesselheim et al. also had similar results stating that the rarity of the diseases makes enrolling a sufficient number of participants inherently difficult as compared to the nonorphan drugs.[6] However, there is also a contrasting view here that even when the prevalence is relatively high compared with other orphan conditions (as is the case for many of the products included in this review), trials may still be conducted in an inadequate number of patients. A study by Joppi et al., for example, found that pivotal trials in treatments for Fabry disease included only 41 and 56 patients out of a potential patient population of 10,000 in Europe.[10]

With respect to the duration of approvals, it was seen that the US-FDA granted approval to more than 50% of orphan drugs based on phase II trials with bedaquiline being an important example. This finding was mirrored in the study by Bell et al. who also found that orphan drug trials are terminated early and the drugs were accorded permission by the FDA.[11] The US-FDA regulation requires a “design that permits a valid comparison with a control” for both orphan and nonorphan drugs.[12] The control may be a placebo, dose comparison, or an active treatment. We found that a total of n = 12/35 (34.2%) pivotal clinical trials for eight orphan drugs had a placebo control. These drugs were indicated for diseases like Castleman disease (lack of standard of care), for which large multicentric trials were done. Placebo may have been used in these trials to establish the efficacy of the novel interventions. We did not find any significant difference between the use of a comparator and choice of an endpoint between orphan and nonorphan drugs trials. This is keeping in line the fact that regulators do not lower the bar of methodological rigor when it comes to trials with orphan drugs.

Our study has several limitations. We have analysed only the US FDA approvals of orphan drugs. Other regulatory agencies’ database like the European Medicines Agency (EMA), Pharmaceutical Medical Devices Agency (PMDA), Therapeutic Goods Administration (TGA) can also be included in the analysis to get more holistic data. Furthermore, only the arena of infectious diseases was focused on in this study, and in the last decade, many orphan drugs have been developed for other therapeutic areas.


There are considerable differences in the pivotal trials for approval of orphan relative to nonorphan drugs. Our analysis suggests that early phase, nonrandomized, unblinded trials with lesser number of participants seem adequate to obtain regulatory approval from the US-FDA for orphan drugs.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1. Available from: http://rarediseases.info.nih.gov/about-ordr/pages/31/frequently-asked-questions. [Last accessed on 2021 Apr 18]
2. Available from: https://main.mohfw.gov.in/sites/default/files/Final%20NPRD%2C%202021.pdf. [Last accessed on 2021 May 11]
3. Miller KL, Lanthier M. Investigating the landscape of US orphan product approvals. Orphanet J Rare Dis 2018;13:183
4. Coté T, Kelkar A, Xu K, Braun MM, Phillips MI. Orphan products:An emerging trend in drug approvals. Nat Rev Drug Discov 2010;9:84
5. Melnikova I. Rare diseases and orphan drugs. Nat Rev Drug Discov 2012;11:267-8
6. Kesselheim AS, Myers JA, Avorn J. Characteristics of clinical trials to support approval of orphan vs. nonorphan drugs for cancer. JAMA 2011;305:2320-6
7. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/&https://rarediseases.info.nih.gov/diseases/fda-orphan-drugs. [Last accessed on 2021 Apr 10]
8. Sharma A, Jacob A, Tandon M, Kumar D. Orphan drug:Development trends and strategies. J Pharm Bioallied Sci 2010;2:290-9
9. Winstone J, Chadda S, Ralston S, Sajosi P. Review and comparison of clinical evidence submitted to support European Medicines Agency market authorization of orphan-designated oncological treatments. Orphanet J Rare Dis 2015;10:139
10. Joppi R, Bertele V, Garattini S. Orphan drug development is progressing too slowly. Br J Clin Pharmacol 2006;61:355-60
11. Bell SA, Tudur Smith C. A comparison of interventional clinical trials in rare versus non-rare diseases:An analysis of ClinicalTrials.gov. Orphanet J Rare Dis 2014;9:170
12. Available from: http://www.fda.gov/orphan/progovw.htm. [Last accessed on 2021 Apr 18]

Drug approvals; infectious diseases; orphan drugs; rare diseases; US Food and Drug Administration

Copyright: © 2022 Perspectives in Clinical Research