Size matters: Complex Conundrums of Biologics and their humble University origins

There is little value in new drugs that patients cannot afford — and there is no value in drugs that do not exist.¹

In a worldwide scenario of escalating drug prices, particularly of biopharmaceuticals or biologics, it is a global imperative to not only raise arguments against the justification of exorbitant drug prices by pharma companies but also to explore the possibilities of finding new avenues to foster fundamental research for future drug discovery. Academic-industrial collaboration during the drug discovery and development process will assume a lot of significance in this context. A significant portion of studies in the United States indicates the heavy involvement of academia as well as the public sector research institutions (PSRIs) in the research and development of biologic products.^2,3,4,5 PSRIs defined as universities, research hospitals, research foundations and federal laboratories have had a great impact on the commercialization of new drugs. The US National Institutes of Health is the largest source of biomedical research funding in the United States, which contributes more than 80% of its funding to more than 2,500 universities and research institutions. Studies have established that the US National Institutes of Health (NIH) Intramural Research Program (IRP) and other US PSRIs have contributed inventions that have had a disproportionately greater impact on the overall number of products produced, drugs granted orphan status and drugs granted priority review.

Biologics are life-saving, essential medicines and complex, challenging, pricey pharmaceuticals

Everything about Biologics is large and complex and by nature they defy definition. The inherent complexity of these systems lies in the fact that biologics are produced through biotechnology in a living system, such as microorganisms, plant cells or animal cells. The Food and Drug Administration (FDA) considers a biologic to be any therapeutic serum, toxin, antitoxin, vaccine, virus, blood, blood component or derivative, allergenic product, analogous product, or derivatives applicable to the prevention, treatment, or cure of injuries or disease of man. Major kinds of biologics include: Blood factors (Factor VIII and Factor IX), Thrombolytic agents (tissue plasminogen activator), Hormones (insulin, glucagon, growth hormone, gonadotrophins), Haematopoietic growth factors (Erythropoietin, colony stimulating factors), Interferons (Interferons- α, -β, -γ). Interleukin-based products (Interleukin- 2) Vaccines (Hepatitis B surface antigen), Monoclonal antibodies (Various). The challenges inherent to such systems (size >5000Da) are aplenty; which are non-existent in the development of small molecules (<500Da). Owing to their large size, hurdles in manufacturing as well as in quality control and obtaining the regulatory approvals, biologicals are notorious for their prolonged incubation periods as opposed to the small molecules. Challenges are also with respect to the generic versions of the drugs and the regulatory aspects. In comparison to their counterparts, the small molecule drugs, the characterization of biologics are complicated by the cell system in which they are produced, the fermentation media and/or operating conditions. Their susceptibility to microbial contamination as well as to heat sensitivity etc. can pose challenges in manufacture, contributing to the overall increased complexity as well as R&D expenditure, further contributing to the high drug prices. Given the high failure rate in each step of the R&D, prior to its regulatory review, the expected return on investment for successful biologic drug products are abnormally high, since the return must also compensate for the failed drug candidates.

Notwithstanding any of the complexities and hurdles, biologics have taken over the pharmaceutical world and have been instrumental in successful treatment of many serious and chronic illnesses. In fact, biologics have replaced the small molecules from the top drugs list and have emerged as blockbuster drugs with annual sales of at least $1 billion.⁶ However, the high R&D spend, the high expectations of the investors on return of investments (ROI) and the consequent rise in the drug prices and decrease in the affordability by common man remain a concern since it raises questions about the long-term sustainability of the industry’s R&D model. The strategies to increase the R&D efficiency includes building up of the right core competency for R&D both internally as well as by building external networks with academic/university partners and service providers. ⁷

Biologics and public funded R&D

Academia and universities have long served as the cradles for innovation and the baby steps of most biologics can be mapped to university research. In fact, the prelude for the fantastic opera of recombinant DNA technology-based biologics lies in the dingy labs and adept hands of university researchers and graduate students. According to the conventional R&D model, universities conducted the upstream research which elucidates the underlying mechanism of disease and identifies the promising points of intervention whereas the downstream research which results in the discovery and development of drugs for the treatment of diseases was done by corporate sector. For example, the basic R&D that resulted in the most successful biotech drug, Erythropoietin, which is used in the management of anaemia in chronic renal failure, in certain haematological diseases like myelodysplastic syndrome (MDS) and anaemia of chronic disease was conducted in universities before the knowledge transfer was done to a top pharmaceutical company, Amgen. A considerable amount of change in the scenario came in with the enactment of the Bayh-Dole Act of 1980,⁸ in the United States. The enactment of this legislation led universities and government laboratories such as those within National Institute of Health (NIH) to acquire a legal right and ownership in the invention made from federal research grants, enabling commercialization of the inventions. The repercussions of such commercialization are both positive and negative and are still felt to this day. While the positive effects include ownership for their invention and the revenue generation for further research, the negative effects were in possible side-lining of the public interest in such inventions and in stunting the growth of an open knowledge base⁹ Universities are now adopting newer models of technology transfer such as university start-ups which support the entrepreneurial efforts of the faculty by partnering with local business incubators and capital investors.¹⁰

Protection and Utilization of Public Funded Intellectual Property Bill, 2008 is an attempt to introduce an Indian version of Bayh Dole Act. However, this bill attracted strong criticism, questioning the viability of the act in current Indian socio-economic environment, ¹¹ for its lack of conceptual understanding of ground realities of publicly-funded research in India, the modes of appropriation and dissemination of results of such research and the industry nexus, ¹² The wisdom in touting patents as innovation metrics in the journey of Council of Scientific and Industrial Research (CSIR), an Indian version of National Institute of Health, from dissemination of research to hoarder of patents with very little commercial significance and value, was questioned and criticized. ¹³ Recommendations such as establishing university start-ups and open (royalty-free) licensing of patents to start-ups, fostering accountability, innovation and further research instead of hoarding of frivolous patents, were made to rectify the current university R&D scenario. University starts ups channelize the intellectual value that researchers can offer into commercial value by creating avenues for tech transfer within a nurturing atmosphere with small local investors. Open licensing of technically relevant patents without royalty to start-ups during the initial stages of research will build on the existing knowledge and the entrepreneurs can benefit from the collective scientific knowledge and the scientific networking of the universities where conferences and seminars take place on the latest research in the fields of interest.

It is an undeniable fact that the universities have the necessary intellectual resources to create knowledge. While patenting is one way of tech transfer, there are more avenues to perform research in collaboration and transfer the knowledge thus obtained to create commercially viable products which benefit the innovator as well as the society, the case at hand being biopharmaceuticals. Support from the government in the form of funding of the start-ups and in encouraging innovation can go a long way in decentralizing the entrepreneurial and investment burden. Since the investment in research is distributed in the university research model, as opposed to the R&D of pharmaceutical companies, it can translate into lower costs of investment, thus resulting in affordable medicine.