Gaps in translating basic science research from bench to bedside

In today’s world, there is considerable emphasis on self dependence, especially for products (vaccines, drugs and diagnostics) related to healthcare. Historically, most of the research & development (R & D) in India is carried out at its National Laboratories, Institutes of Science & Technology and Central University systems, and a few are involved in new drug development. The size of the pharma industry is small as to venture into new drug development. The total size of the Indian pharma is less than the R & D budget of an international pharma giant. During COVID-19 vaccine development, where the government met the risk budget for R & D and clinical trials, pharma companies did a magnificent job. There was also a rolling regulatory review of trial data and emergency use authorization due to the virulence of the virus and human lives at stake. However, such push can work in specific situations. There is a need to change the overall ecosystem. We discuss here issues involved in product development, specifically translating research in academic institutions into medicines for societal needs, and suggest a way forward.

Academic drug development

Scenario in the USA & the UK: It is noteworthy that in developed countries like the USA, there is a much greater contribution of academia to product development. The National Institutes of Health in the USA spends 80 per cent of its approximately 40 billion dollar budget in awarding 300,000 researchers of 2500 universities and medical schools and research institutions through competitive grant applications1. Of the 252 new drugs approved during 1998-2007 by the United States Food and Drug Administration, the majority were produced by biotech companies, and most were acquired from university projects2. An analysis of 2017 annual reports of the two major US pharma companies shows that research leading to the discovery and development of 20 per cent of drugs originated in universities and academic centres3-5. Further, in the later years, blockbusters such as remdesivir, venetoclax and atezolizumab were from academia6.

In the UK, the UK Research and Innovation provides an annual budget of £25 billion for research and innovations to benefit communities across the UK. The funding covers several centres, which include Medical Research Council, biotechnology and biological sciences, Innovate UK and Science and Technology Facilities Council7. Recognizing that new economic and scientific challenge requires collaboration across sectors, the Academy of Medical Sciences of the UK promotes interaction between academic, industry and National Health Services (NHS)4. Some of the recommendations it made for such interactions included flexible collaboration, appropriate funding, incentives to facilitate translation, recognition that all are credible, equal and scientific partners, proportionate risk based regulatory framework to facilitate research, ensuring patient and public safety, accountability, a suitable framework for collaborative agreements facilitating innovation and Intellectual Property Rights. Such collaboration will result in benefits to academia with access to research resources and guidance from industry. Industry gets access to druggable targets, and through NHS, it can improve safety and patient recruitment. NHS will inform needs and will, in turn, have access to suitable products. The UK Oxford Martin School at the University of Oxford is a good example of an academic centre supporting medicine development. In a recent article, the open science model has been reviewed as having the potential to increase the productivity of pharmaceutical R & D5.

Indian Scenario

Indian industry & academic products: Indian pharmaceutical industry is considered as the pharmacy of the world, catering to 20 per cent of the global needs with an annual sale of over 50 billion US$ export of 17.6 billion US$ worth drugs, biosimilars and vaccines to over 120 countries in the world8. Indian industry has developed as traders and formulation experts, only recently into new drug development initiative. The products identified by some of the pharma houses met with failures either in toxicology or in international clinical trials9.

There are a few examples of new products developed by academia, being taken up by Indian industry and reaching the market, e.g., a number of simple and easy-to-use medical devices have been developed by Stanford-India Biodesign collaboration, and are being marketed by industry both in India and abroad10. Rotavirus vaccine has been developed by All India Institute of Medical Sciences, New Delhi, with funding from Department of Biotechnology (DBT), Ministry of Science & Technology, Government of India (GoI), for product development at the Bharat Biotech International Ltd., Hyderabad (BBIL), and is being used in the National Programme with products provided by industry11.

With the support of department of biotechnology funding, liposomal amphotericin was developed by the department of Biochemistry, Delhi University, further developed, tested in animals and clinically by the department of Clinical Pharmacology, Seth G. S. Medical College and KEM Hospital, Mumbai, India12. The technology was transferred to industry, and became available in the Indian market since 2003. This has been used in the management of leishmaniasis and systemic fungal infections of considerable importance, such as mucormycosis in COVID-19 patients13.

There have been other products developed by the Council of Scientific and Industrial Research (CSIR), Indian Council of Medical Research (ICMR) and DBT in joint collaboration with industry; however, these have been a few, e.g., Japanese encephalitis (JE) vaccine of the ICMR in partnership with Bharat Biotech14. Recently, the development of vaccines for COVID-19 has highlighted the capacity of Indian scientists and industry. Covaxin has been developed jointly by the National Institute of Virology of the ICMR and BBIL15. The DBT has supported the R & D of all the COVID-19 vaccines and diagnostics developed in India.

However, the industry has been cautious in taking products from government-funded projects unless government support comes forth during translational efforts. It looks for products with proof of concept and safety studies showing promise and support for government agencies to minimize risk.

Government initiatives

India spends about 0.7 per cent of its gross domestic product (GDP) on federal R & D compared to the global figure of 2.3 per cent as of 2018 [the United Nations Educational, Scientific and Cultural Organization (UNESCO)]16. Recently, the National Research Fund (NRF) has been approved to provide funding to academic researchers17. The NRF has been established to seed and grow research especially at State and other universities and colleges where research funding is limited. The NRF will receive ₹ 100 billion annually for five years to fund interdisciplinary research in science and technology, social sciences, arts and humanities18. The GoI budget for 2021-22 provided for a massive increase in healthcare spending prioritizing biotechnology and health research.

DBT, CSIR & Department of Pharmaceuticals (DoP) initiatives

The DBT has supported vaccines and new drug development through its programmes like Biotechnology Industry Research Assistance Council/Biotechnology Industry Partnership Programme (BIRAC/BIPP), for COVID-19 vaccine development, facilities for animal challenges, clinical immunology studies and clinical trial sites19. The CSIR has programmes such as New Millennium Indian Technology Leadership Initiative (NMTLI)20 and Open Source Drug Discovery (OSDD)20. The CSIR and Central Drug Research Institutes (CDRI) have developed drugs, e.g. for malaria (Arteether) Bacopa extract, centchroman, Dalzbone herbal for bone health, some candidate drugs such as anti-osteoporotic, platelet inhibitors, anti TB drugs, herbal formulations, recombinant streptokinase21, over 50 patents, several technologies, and diagnostics. The DoP has released common guidelines on pharmaceutical innovation and entrepreneurship to encourage National Institute of Pharmaceutical Education and Research (NIPER) innovation mechanism for technology development and transfer for unmet therapeutic, socially impactful technologies22.

A draft policy to catalyze research and development and innovation in the pharma-meditech sector in India has been formulated. It does mention enabling ecosystem, industry academia linkage, strengthening academic talent and infrastructure, collaboration across institutions and sectors, implementation framework, monitoring and evaluation23.

ICMR Initiative

In India, the ICMR, through its basic medical sciences (BMS) division has been providing around ₹ 300 million funds annually for around 720 research projects, through fellowships, ad hoc projects, task force projects and Centre for Advanced Research (CARe). The basic research is also conducted intramurally in all the ICMR institutes. In 2019, the ICMR established the National Virtual Centre of Clinical Pharmacology with a network of Centres for Rational Use of Medicines and Advanced Research Centres for Product Development (PDC). One of the objectives of the PDCs is to evaluate completed research projects funded by the BMS division and also leads obtained from the ICMR institutes with the potential for translating into products for human use24. In a detailed analysis by the PDCs of completed projects from the BMS, 52 out of a total 171 completed during 2016-18 and 12 out 47 completed in 2021, were identified as having potential for product (drugs and diagnostics) development in initial screening25.

Gaps

Bano et al26 while recently reviewing translational research in biomedical sciences in India, specified gaps between basic science investigations to clinical research and suggested road map and policy consideration to accelerate translational research in India. They also noted that the project reports from the BMS division were exploratory, observational and experimental in nature. Although research projects were good, translational component was missing and a large majority required following proper study design. A more in-depth planning could have helped to achieve these goals. Shahzad et al27 while reviewing global translational medicine initiatives and programmes, commented that India did not have a formal translational education agenda.

Analysis by the PDCs of the shortlisted projects showed that most of them did not satisfy the criteria of novelty and fulfilling unmet needs though they were mostly on diseases of high prevalence/incidence in the country and the sources of drugs for most projects were natural sources, drug delivery system, repurposed drugs, which had human safety dose data25.

Further, it was noted that suitable preclinical regulatory work to translate into clinical development was missing. Five out of the shortlisted 52 projects having sufficient potential for further developing into products required additional regulatory preclinical development studies with suitable experimental design25. The available knowledge and information on safe dose (specially for repurposed drugs), use of positive control (with drugs approved for such disease indication) using standard animal models, validating model if a new model is developed, study design relevant to clinical use and positioning of the drug suitably in the current therapeutic strategies (e.g. National TB programme, treatment guidelines) therefore need to be generated.

CSIR, GoI is also actively involved in developing drugs from basic research and till a couple of years ago only one of its institutes was involved in new drug development and the rest were in drug technology development20. Technology provided by CSIR institutes and IITs (Indian Institutes of Technology) have helped industry to produce generic drugs at highly competitive rates and capture world markets. However, in new drug development, the impact, as yet, has been low. Two drugs of CSIR-CDRI, an antimalarial is sold in several countries of the world and the family welfare drug is included in the National Family Welfare programme and also marketed for the management of dysfunctional uterine bleeding and mastalgia in our country20. Presently, about 4-5 CSIR institutes are involved in new drug development20. However, collaboration between basic science pharmacology, clinical pharmacology and clinical colleagues is mostly missing.

The ICMR’s initiative in identifying leads from its institutes, other national institutes and academia and investing in product development is a welcome initiative in this context, which has the potential to give dividends in near future.

Way forward

Drug development is time, cost and labour intensive, with chemists at one end and clinicians at the other and operates through stipulated regulatory guidelines. The development of a new drug has a long gestational period (about 10-12 yr) and may cost around ₹ 0.2-0.5 billion if marketed only in India; international development costs around ₹ 2 to 3 billion28,29. Government therefore should encourage Academia - Industry collaborations with liberal funding for translational efforts as was done during COVID-19 vaccine development. While regular funding is critical, training in the fundamentals of drug development for basic science researchers is also necessary. Further, to avoid wastage of resources, and to ensure fast track development, early proactive involvement of toxicologists, pharmacokinetics (PK) and pharmacodynamics (PD) study experts and clinical pharmacologist and interaction with clinicians from relevant speciality appears crucial. This will help in choosing apropriate animal model, adopting proper study design, working with likely safe and effective dose of target product profile, with much shortened go/no-go decision making time.

In order to promote product development in academic institutions, the method of assessing research work conducted by the scientists in these institutes needs to be changed. A template outlining research impact specified as short term (publications, citations, dissemination, knowledge transfer, capacity building, training, leadership, collaboration and data sharing), medium term (impact on guidelines, practice, policy and collaboration with industry) and long term (patents, economic impact, income from patents and evidence-based practice) would be helpful30. A large majority of basic science projects are projects on in vitro and in silico studies. Promising ones need to be taken forward by collaborating with other institutions/researchers with expertise in animal studies, and establishing proof of concept. There is a need to develop such a mechanism to connect basic science to translational development, pharmacology and clinical pharmacology expertise.