The work, goals, challenges, achievements, and recommendations of orphan medicinal product organizations in India: an interview-based study

Rare diseases (RDs) are debilitating medical conditions that affect a small percentage of the population. Research and development (R&D) to treat such diseases was long neglected by the pharma industry because of the likelihood of poor commercial outcomes. However, many countries have implemented policies that incentivize industry to develop ‘orphan drugs’ (ODs) to treat RDs [1]. The United States (US) was the pioneer, and enacted the Orphan Drug Act (ODA) in 1983 [2]. Several countries followed suit [3]. European Union legislation in 2000 covered a wider range of orphan medicinal products (OMPs), which included any product intended to diagnose, prevent, manage or treat RDs [4].

Orphan policies have been highly successful in driving RD R&D, and this has benefited both patients and the industry [5, 6]. Since 1983 the US Food and Drug Administration (USFDA) has awarded an orphan designation to 4905 products in-development, 771 of which have received marketing approval [7]. This has also impacted the overall landscape of innovative drug development [8, 9]. Over one-quarter of all new molecular entities (NMEs) that were approved from 1983 to 2017, inclusive, in the US had an orphan designation and in 2018, 34 of 59 approved drugs did [5, 10]. ODs also bring significant financial returns to the pharmaceutical industry. Worldwide OD sales are predicted to grow at a compound annual growth rate (CAGR) of 11.3% from 2018 to 2024, which is double the rate predicted for non-orphans [11]. Furthermore, ODs are expected to capture 20% of worldwide prescription sales by 2024 and to reach revenues of $262bn [11]. In most countries, OD policies are complemented by RD policies that have empowered patients with awareness, access to treatment and healthcare coverage [12]. A review of the policies of 35 countries showed that 33 countries provide reimbursement for ODs [13]. This has contributed to the sustainability of the industry by ensuring that patients can access these drugs despite their high prices.

In India, approximately 70 million patients suffer from an RD [14]. The prohibitive cost of any available OD, the absence of insurance coverage for most patients, delayed diagnosis and the lack of awareness of RDs and their management among doctors are some of the important challenges faced by these patients [15]. After much pressure from advocacy groups, in February 2017, the Government of India (GoI) announced The National Policy for Treatment of Rare Diseases (NPTRD). However, this was put in abeyance in November 2018 [16]. NPTRD primarily focused on making existing treatments available to patients through government funding. This approach has three major shortcomings: (a) providing treatment at the global price makes it impossible, financially, to cater to such a large patient pool; (b) many of the ODs, based on precision medicine, have been developed for a different population, and might not be effective for Indian patients [17]; and (c) some RDs may be more prevalent in India and need more urgent attention [18]. Further, in India, till recently, there was no official definition of RDs or ODs. However, the Central Drugs Standard Control Organization, which is the national regulatory body for Indian pharmaceuticals and medical devices, recently announced the New Drugs and Clinical Trials Rules, 2019 (NDCTR), which came into effect on 25 March 2019 [19]. These rules, for the first time, defined an OD as “a drug intended to treat a condition which affects not more than five lakh [5,00,000] persons in India”. It also provided three key incentives for the approval of ODs: (i) ODs which have been approved and marketed in certain other countries, may not require local clinical trial data to be submitted along with the application to import the drug into India. (ii) candidate ODs can avail of an accelerated approval process. (iii) the application fee for the conduct of clinical trials for ODs may be waived.

In the absence of policies for RDs, ODs or OMPs until recently, very limited RD R&D has taken place in India. Although, there have been studies of patient advocacy groups in India [14, 15], the Indian RD industry has not been studied so far. In many countries, such studies have provided valuable insights for policy-makers [3, 20, 21].

Therefore, for this study, we identified organizations that are involved in the development of products or services that aid in the diagnosis, prevention, management, or treatment of RDs. Collectively, we have classified these organizations as Orphan Medicinal Product Organizations (OMPOs). The study’s aims were to understand (i) the OMPOs’ areas of work and the nature of their work, (ii) their goals, (iii) the challenges they faced and how they were overcoming these, (iv) their achievements, and (v) their recommendations to the government to help their R&D, their success as commercial entities (where applicable), and patients’ access to their products or services.

These OMPOs are diverse both in terms of the RDs they cater to, and the products or services which they offer, or plan to offer. However, their experiences are a reflection of the Indian RD industry overall.

We have used a qualitative case study research methodology that has been used by others to study the healthcare industry [22, 23]. The reporting of the study was assessed using the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist, which helped to assesses the completeness of the reporting of the study [24].

Basic information about the 14 OMPOs, and the interviewees representing them, is provided in Table 1. The two organizations established in 2019, CDD and Genetico, are primarily covered in the section ‘Organizational details’. Elsewhere, the analysis relates to the 12 other OMPOs, unless otherwise specified.

To summarize our findings, most of the OMPOs were formed from 2012 onwards. As such, their R&D is still largely in the early stages, although six have brought products or services to market. Even those at a later stage are struggling to stabilize or scale-up. They cover a wide range of products across the three major segments of RD care, that is diagnostics, treatment, and management, for different groups of RD patients. The OMPOs also belong to different industries such as biotech, medical devices, food and pharma. Although self-funding has been an important driver, institutional funding by angels, venture capitalists (VCs) and the government has played an important role. Several of the OMPOs have spent over 100 million rupees to date. Most of the organizations started work with a focus on RDs, although a few came to this area later. With the exception of the diagnostic companies, most of the OMPOs do not have any competing products in the Indian market. Most of the products and services offered by these organizations are more affordable than the global alternatives. The cost could drop significantly if the high-quality products required for production, currently imported, were locally available. Only five OMPOs have received regulatory approvals, of which four are from India, and in seven cases, no regulatory approval is required. Most of the founders have developed their organizations’ technologies on their own, sometimes with formal or informal scientific advice from other organizations, thereby accelerating their R&D. Of those who received support from the government, most benefited by funding, and the rest through tax exemptions. Most sought greater support from the government through an OD policy, and through health coverage for patients. Eight OMPOs have protected their products with patents, with most of the filings being in India. Despite the heterogeneity of the OMPOs, they had many common challenges including inadequate funding, the lack of tailored government policies, the need for a supportive ecosystem, the lack of facilities for animal studies, and the absence of various kinds of data related to RDs. The OMPOs believe that a common OMP policy would address many of these issues. As listed above, the provisions made by the NDCTR relating to accelerated approval and waiver of application fees for clinical trials will benefit the five OMPOs which are in trials, or which hope to conduct trials.

We need to place the rise of these OMPOs in context. The pharma industry in India has evolved over the last 50 years or so. From 1972, for a few decades, product patents of pharmaceuticals were not recognized. This led to the rapid growth of the generics’ sector and today India is a global leader in this area [26]. In the 1990s, it made forays into discovery research, and since the early 2000s, there has been a rise in the number of biomedical and biotechnology firms [26, 27]. Although there was a surge in the development of ODs in the US after the passage of the ODA in 1983, India did not witness much interest in this field until fairly recently. In 2012, NATCO became the first Indian company to receive an FDA OD designation for one of its products [27]. So far, only two other Indian companies, Lupin and Regrow Biosciences, have received an OD designation in the US or in Europe for their products. One of them has also received marketing approval, from the European Commission [28, 29]. To the best of our knowledge, no other product from India has received an OD designation or reached the market in the West.

The slow growth of this sector is similar to that seen for drug-discovery in India in general. In the early 1990s it was thought that India would become the drug discovery powerhouse of the world [30]. However this did not happen, and of about 200 drugs that were in various stages of preclinical and clinical development in the country, only one innovative drug, Lipaglyn, reached the market [27, 31]. Subsequently, many Indian companies severely cut back, or abandoned, their R&D activities [27, 32]. Potentially, orphan product R&D could be a niche area for the industry to invest in, should the government provide suitable incentives. Globally, there is a call for the repurposing of drugs for RDs [33, 34], and these 200 compounds, of which 82 progressed to Phase 1 and 34 to Phase 2, could be revisited to test their efficacy for an RD [27]. Furthermore, over these 20 years, India has developed drug discovery expertise, that could be utilized by the OMP industry.

Globally, academia, smaller companies, and biotech firms have led the discovery and development of ODs [35, 36]. A similar trend is seen in our cohort, where most of the organizations are start-ups and 10 of them are biotechs. We also need to view the rise of these start-ups in the context of the general rise in entrepreneurship in India [37]. In recent years the GoI has initiated many programs to nurture innovation across sectors [38]. In the bio-medical sector, the efforts of the Biotechnology Industry Research Assistance Council (BIRAC), established by GoI, are the most notable. It has supported over 1000 entrepreneurs in the last 7 years, some of whom have brought products to market [39]. Thus, the emergence of the OMPOs coincides with a significant rise in biotech entrepreneurship in the country. All the OMPOs studied here have local roots, and started from scratch. Even as recently as the early 2000s, most innovative startups in India were spin-offs from multinational companies [23], and thus the OMPOs discussed here are part of a new breed of indigenous healthcare start-ups in India.

In India there is a general lack of awareness about RDs among various stakeholders [15]. This is evident from the fact that only 450 of the 7000 RDs recognized globally have been identified so far in India [40]. However, the last decade has seen an increase in activism, and of awareness, related to RDs in India, with the emergence of many disease-specific groups and umbrella organizations [15]. It is no coincidence that the development of OMPs picked up in India at about the same time. Notably, it was a high profile story when, following the market shortage in 2016 of D-Pencillamine, used for Wilson’s Disease, patient support groups successfully lobbied a local pharma company to manufacture a better alternative, Tirentine [41]. OMPOs in the study such as CDD, DART, and TBXT are directly related to patient activism since they were started by parents of affected children. Others such as Eyestem, GROW, GUaRDIAN, MedGenome, Pristine, and SMOI also support, or are involved in, patient advocacy. Formalization of patient participation in decision making would help to receive their insights in the early stages of policy formulation.

It is remarkable that despite the absence of an OD policy in India until recently, several organizations have been pursuing such research. Nine OMPOs are focused on making their products and services tailored to, and accessible to, Indian patients. Most of them would like to carry out their entire R&D in India, to ensure that their products are affordable and immediately available to Indian patients. However, due to inadequate funding to carry out clinical trials, four of the OMPOs plan to out-license their products after pre-clinical or phase 1 studies. This is unfortunate, since globally, when such products are acquired by multinational companies, their subsequent pricing makes them inaccessible to most Indian patients [42]. The lack of suitable incentives for the development of OMPs in the country has also led six of the OMPOs to eye international markets, and they are planning to apply to foreign regulatory agencies such as the EMA and the USFDA. Should they succeed in gaining such approvals, they will have access to lucrative markets, which will help fund further R&D. However, gaining such approval is an expensive process [43, 44] and such products may also become inaccessible to Indian patients. The government could help these companies gain international markets by funding such applications on the condition that they subsequently repay the support, or provide their products at affordable prices to Indian patients.

Furthermore, in the absence of prevalence data and government policies that aid access to OMPs, it is difficult to imagine a large market in India. Many Western nations have much better prevalence data and have enabled much higher pricing of OMPs, or policies that enable access, making them attractive markets for any OMP developed in India. However, as mentioned above, such a product may become unaffordable in India. Also many of the OMPOs have benefitted by protecting their IP. One of the authors (GS) published the findings of an interview-based study of 50 Indian biomedical start-ups in 2016. When asked, from a list of possibilities, the primary reasons for patenting, the most common responses were: (i) improve the valuation or image of the company, and attract VC or other funds; (ii) protect technology from imitation; and (iii) improve inter-firm deals. Possibly, similar reasons hold true for the OMPOs of this study.

One of the unintended consequences of the ODA has been the exorbitant pricing of these drugs in the US, and in other countries that implemented a similar Act [45]. While enacting an OMP policy, Indian policymakers should work to ensure patient access to the OMPs. Some of the ways this can be achieved are:

(i) India already has price control mechanisms for generic drugs and certain medical devices, and these could be tweaked to control the prices of novel OMPs [46]. However, in a recent notification, effective from 3 January 2019, GoI has exempted ODs from any price control [47]. This was done to incentivize local pharma to undertake innovation, and to make the Indian market more attractive for companies wishing to import ODs approved elsewhere. This move may enhance the availability of ODs, but it may negatively impact their accessibility.

(ii) In the past, the government has also tackled high drug prices by (a) restricting patent evergreening, by which an organization tries to extend the monopoly rights over a process or product whose patent is on the verge of expiry, by obtaining fresh patents based on minor changes to the protected process or product, and (b) through compulsory licensing, a provision by which the government permits an organization to use a patented process, or produce a patented product, without the patent-holder’s permission, while paying the latter an adequate amount [48, 49]. Such measures could be applied to OMPs as well.

(iii) Globally, the development of ODs by socially motivated, not–for–profit organizations has helped to facilitate access to more affordable ODs, as exemplified by the gene therapies of Genethon in France [50]. Four OMPOs in our study are similar organizations. The government should incentivize more such organizations to take up the development of OMPs, which would help to keep costs down.

(iv) The involvement of academia in early stage drug-discovery could significantly reduce the cost and risk for industry [51]. About 12 years ago it was noted that there was not much academia-industry collaboration in biotech in India [37]. However, in recent years there has been a rise in such collaborations, with BIRAC alone funding 115 projects run as industry-academia collaborations, and involving 88 academic institutes [52]. Also, the majority of incubators for biotech start-ups are either part of academic institutions or are hosted by them, and this helps to spur such collaborations [53]. GROW and GUaRDIAN are academic groups which have partnered with industry, and eight of the OMPOs which are companies have had partnerships with Indian academia. As seen in the biotech sector in general, the OMPOs’ collaborations with foreign academia and industry largely overcame the shortage of local subject matter experts or those with translational expertise [23, 54]. To enhance skill development in the country, the emphasis should be on enabling the creation and sustainability of support systems, as outlined above in recommendations by the OMPOs in the Results section.

(v) If patients are provided healthcare coverage, and they and the medical fraternity are empowered with more information, it will lead to an increase in the demand for such products, which would boost the OMPO sector. Moreover, since many RDs are life-debilitating, patients need life-long management with assistive drugs, foods, and devices [55, 56]. Many of these products are not manufactured locally, making them very expensive. Health coverage schemes should include such products as well.

The biggest achievement of the RD movement in India has been the inclusion of incentives for the OD sector in NDCTR. However, a comprehensive policy that covers all aspects of RD diagnosis, management, prevention and treatment is much needed. Such a policy should support and incentivize the OMP industry. Before NDCTR, the policies concerned with (i) disabilities, (ii) plasma, (iii) stem cells, (iv) medical devices and so on had a positive impact on RD patients and the OMP industry. However, all the OMPOs have faced challenges due to the poor implementation of these policies. Thus, emphasis should be laid on the effective implementation of policies related to OMPs. In earlier studies, four critical factors have been identified for the poor implementation of policies in any country [57]. The OMPOs in this study agreed that these are crucial factors, and cited locally-relevant angles of each. These are (i) communication: The lack of transparent regulatory guidelines; (ii) resources: The lack of funds; (iii) dispositions: The implementing officials may be unfamiliar with the requirements of specific areas; and (iv) the bureaucracy: In India, health is a state subject, and thus state authorities implement any national health policy, which can lead to complications.

Finally, India can take inspiration from the highly successful French model of a multidisciplinary approach, combined with high standards of safety and quality, tailored for the orphan industry [58]. Along with an OD policy, the French government also created the Fondation Maladies Rares (Rare Disease Foundation) and centers of excellence for RD research such as the Agence Nationale de la Recherche and the Hospitalier de Recherche Clinique.

In summary, we have mapped in detail, the work, goals, challenges, achievements, and recommendations to the government of most of the OMPOs in India. This will help the government to identify areas that need further work, and mechanisms to facilitate the OMPOs’ work in general. Future work could detail the precise supportive measures that the government might take, especially keeping in mind what other countries have done.

Separately, we note that this study has several limitations.

Our study aims to draw the attention of policymakers, in particular, to the the work, goals, challenges, achievements, and recommendations of the OMPOs in India. It also emphasizes the urgent need for supportive government policies in this area.