Drug discovery research in India - an overview

Pharmaceutical scientists within the industry work together for years and spend millions to piece together the basic causes of disease at the level of genes, proteins and cells. It can take up to 15 years to develop one new medicine from the earliest stages of discovery to the time it is available for treating patients. The average cost to research and develop each successful drug is estimated to be $800 million to $1 billion. This number includes the cost of the thousands of failures: For every 5,000-10,000 compounds that enter the research and development (R&D) pipeline, ultimately only one receives approval.

A decade ago, India started to market itself as the next big destination for pharmaceutical R&D because of its varied ethnic profile and inexpensive scientific work force. Even though the R&D outlay in the country has increased over the years, it is still far behind global peers. Only few of the top domestic companies have made any significant spending on R&D in 2011-12, the fast year for which such information is available.

Hence, opportunities definitely exist in the country; and for materializing these opportunities into successes, Academic institutions, Biopharmaceutical industry & Regulatory systems, together which constitutes the three major & essential components for an ecosystem of Innovations has to work together. Since Indian pharmaceutical industry has started taking only baby steps towards Innovation, it's essential to point out and fill the many knowledge gaps that may be existing in the current scenario, among these so that a thriving ecosystem is built.

Despite all the challenges, advances in technology and innovation process do present the industry with opportunities to push forward and prosper. Exploring these future opportunities to leverage India advantages should be the center of focus for the Indian Pharmaceutical Industry.

It is the mission of pharmaceutical research companies to take the path from understanding a disease to bringing a safe and effective new treatment to patients. Scientists work to piece together the basic causes of disease at the level of genes, proteins and cells. Out of this understanding emerge "targets," which potential new drugs might be able to affect.

There are many stakeholders in the drug discovery and development industry such as the regulatory bodies, public research institutes, universities, hospitals, small biotech companies, specialized R&D firms, domestic pharmaceutical companies, the multinational firms, CROs, the doctors, the patients, NGOs and the media. Each stakeholder represents different interests and priorities.

However, through it all they have some common objectives: they want the patients to lead better and fuller lives because of their innovations; they want the firms to make reasonable profits so that they can survive and continue to invest in innovations; and they want the government to set the right tone for the industry, act as a watchdog and protect public interest while providing the right incentives and partnering with the stakeholders in the industry.

Scientists/Researchers work to:

• validate these targets,
• discover the right molecule (potential drug) to interact with the target chosen,
• test the new compound in the lab and clinic for safety and efficacy and
• gain approval and get the new drug into the hands of doctors and patients.

This whole process takes an average of 10-17 years
a) it is well known that de novo drug discovery and development is 10-17 year process from idea to marketed drug
b) Drug repositioning offers the possibility of reduced time and risk as several phases common to de novo drug discovery and development can be bypassed because repositioning candidates have frequently been through several phases of development for their original indication.

It can take up to fifteen years to develop one new medicine from the earliest stages of discovery to the time it is available for treating patients. Many of the drugs coming to the market in 2007 were in the early stages of discovery fifteen years ago, in 1992.

The average cost to research and develop each successful drug is estimated to be $800 million to $1 billion. This number includes the cost of the thousands of failures: For every 5,000-10,000 compounds that enter the research and development (R&D) pipeline, ultimately only one receives approval.

In the current scenario, where the sustainability of traditional pharmaceutical Research & Development model is being questioned with changing market dynamics, emerging markets and saturating growth rates in developed markets, and when the complex and long development cycles and challenges in complying with regulatory and quality standards, different business models of Research & Development must be developed, tested and implemented.

Story of Indian pharmaceutical industry
While in the 1950s and 60s, the pharmaceutical industry in India produced only low level active pharmaceutical ingredients (APIs), by the 1980s, India had grown its generic pharmaceutical Industry and was manufacturing more prominent APIs. And in the mid-1980s, the industry became globalized as Indian companies began to interact with the U.S. market and drug companies.

However, real change in the industry did not arrive until the mid-1990s, when India signed the World Trade Organization (WTO) TRIPS agreement {Trade-Related Aspects of Intellectual Property Rights). In signing that agreement, India agreed to recognize innovator patents and enforce intellectual property rights in accordance with WTO guidelines. As a result of signing this agreement, India began its own serious innovative research in medicinal chemistry. In addition to conceptual changes about intellectual property, Indian science also benefited from amazing advances in the available infrastructure.

Global transformation of the pharmaceutical industry has given rise to new business opportunities in drug discovery for India. India has become a preferred location for clinical trials. In the last few years there has been a growth in the number of pre-clinical research collaborations as well. Indian companies have transitioned effectively from providing a "cost and speed" based value proposition in the clinical trials part of the enterprise, and R&D support services to the drug discovery enterprise, into more value added areas.

Indian Pharmaceutical Industry in R&D - A mixed bag of gains & losses
Outsourcing to Indian firms has happened for some time now. Indian firms started with functional outsourcing in areas such as process chemistry and the manufacture of intermediates. They moved to value added areas and began an emphasis on doing more biology. Pre-clinical development in the private sector (mostly rodents) was then established to match some of the work being done in governmental laboratories and universities. Soon thereafter some firms began to get intellectual property (IP) critical projects while the API and formulation businesses began to grow. This was followed by a growth in the synthesis business and lead optimization. Work on functional biology was started by the industry with toxicity and medicinal chemistry capabilities being developed. In the last two years or so licensing at preclinical stage and Phase I have occurred and we are beginning to see partnerships with developmental rights.

A decade ago, India started to market itself as the next big destination for pharmaceutical R&D because of its varied ethnic profile and inexpensive scientific workforce. Back then, it created ripples when Advinus announced that it was possible to develop a new drug in India for less than $ 100 million when globally the cost were spiraling to beyond $1 billion. At that time, several Indian companies launched themselves into new drug discovery.

Further, as drug pipelines dry up and finding new treatments for diseases afflicting the developing world remains a challenge, governments, drugs companies, research institutes and donors are forging partnerships to boost drug discovery. In recent years western businesses have turned to Indian CROs(contract research organization) and bio-pharma companies in search of affordable and effective research and development (R&D).

Below are few of such headlines from last couple of years, in this front-

• In 2009, Zydus Cadila inks deal with the US-based Eli Lilly for discovery and development of cardiovascular drugs, under which it was to receive milestone payments up to $300 million.
• In 2011, in a first-ever deal of a novel biologic molecule developed in India, Glenmark Pharma entered into a licensing agreement with global major Sanofi to develop and commercialize a monoclonal antibody, GBR 500. This could involve potential payments of $613 million over a period of five years if commercialized.
• Further, in 2012, Japanese pharma giant Takeda Pharmaceutical Company Limited (Takeda) and Indian pharma research company Advinus Therapeutics Ltd (Advinus) announced that they had entered into an agreement for a three-year discovery collaboration focused on novel targets for major therapeutic areas including inflammation, CNS, and metabolic diseases.
• In 2012, India-based CRO TCG Life sciences announced that it has delivered a molecule to Pfizer as part of their collaboration.
• Again, in the same year, Jubilant Biosys Ltd, an arm of Jubilant Life Sciences Ltd, and US-based Endo Pharmaceuticals, collaborating together in drug development programs, identified a new molecule to be developed as a possible candidate to treat cancer.
• In early 2013, GVK Biosciences, leading contract research and development organization and US-based biopharma company, Onconova Therapeutics, announced that they have entered into a partnership to develop new drugs for cancer.
• And then in June 06th 2013, came the biggest announcement in the Indian drug innovation until now - Cadila Healthcare's new chemical entity (NCE), Lipaglyn, the world's first drug for treating diabetic dyslipidemia and combines lipid- and glucose-lowering effects in a single molecule. This drug is the first glitazar to be approved anywhere in the world and the first Indian NCE.

However the success of all these and earlier ventures is unclear. The enthusiasm did get dampened when some of the high profile out-licensing deals went sour.

In 2003, global drug major, Novo Nordisk decided to dump Dr Reddy's insulin sensitizer compound Ragaglitazar after tumours were found in one mouse in its animal studies. In 2011, Merck cut ties to Ranbaxy and Lilly has ended its joint-venture with Jubilant Life Sciences.

Indian contribution to Patent claims - a relatively poor show
In 2010 a group of researchers studied all the US patents that have an Indian inventor to assess innovation in biopharma outsourcing. Ofthe4,094 US patents with at least one Indian inventor, 20 met the researchers' criteria. Each of these patents was assigned to a US or European biopharma company but invented, atleast in part, by an Indian CRO or academic group. Isolating this subsection of the US patent data gives a crude picture of the level of innovation handled by Indian partners.

The researchers acknowledge the data is 'imperfect' but think it is nonetheless of importance to the future of drug discovery in India. "If creative skills in the drug discovery process are not being honed, the prospects of original drug discovery in India are poor", the researchers wrote.

The patents are concentrated at two companies, Genzyme and Millennium Pharmaceuticals, which own more than three-quarters of the intellectual property generated by India-based partners. Basilea Pharmaceutica, Abbott Laboratories, and Servier account for the rest of the patents.

All of the patents relate to chemistry, a traditional strength in India, and none to biology. This fits with the overall picture for Indian biopharma companies' US patents, 95 percent of which are for chemistry inventions, the researcher's wrote. None of the patents were filed in the last three years of the study, from 2006 to 2009.

However, it's worth noting that, at this time many Western biopharma companies, such as Wyeth and Eli Lilly, formed joint-ventures with their Indian counterparts and that these partnerships could have filed patents after the study's cut-off date.

The Supreme Court's recent rejection of a patent for Novartis drug Glivecin India has now paved way to the many possible patent litigations and has thus opened up a high demand of patent experts from the country. It's highly suggested that the both the pharma industry and the government accept this sea of change and open the huge job opportunities for the nation's youngsters.

Current pharmaceutical R&D productivity in India
It's a known fact that despite dramatic advances in biological knowledge, the rate of new drugs applications and new drug approvals has remained relatively constant for several decades. While the output of new drugs has remained constant, total R&D investment by industry in drug discovery and development have grown exponentially, in inflation-adjusted terms (see figure below). As a result, the amortized R&D cost per newly approved drug has continued to grow.

Even though the R&D outlay in the country has increased over the years, it is still far behind global peers. According' to industry estimates, India attracted merely $0.7 billion into pharmaceutical research in 2010 and $0.8 billion in 2011. In contrast, $38.5 billion was spent in the US and $36 billion in Europe on drug R&D in 2011.

Reddy's Laboratories, Glenmark and Piramal Healthcare made any significant spending on R&D in 2011-12, the last year for which such information is available.

Dr Reddy's had the biggest R&D budget amongst Indian pharmaceutical companies- Rs 595.20 crore, or 6.10 per cent of net sales. And while Sun Pharma spent Rs 473 crore on R&D in nine months ending December 2012,Glenmark and Piramal spent Rs 291.62 crore and Rs 233.13 crore respectively.

Of the other domestic companies, Orchid Chemicals spent Rs. 69.33 crore on R&D, or 3.7 per cent of its total sales, whereas Alembic Pharma's expenditure invested Rs58.58 crore, or 3.99 percent of its total sales. Surprisingly, multinational corporations which spend large sums of money on R&D abroad too fared poorly in the country.

According to Capita line, an industry research body, among the top multinationals investing in India, only Fresenius Kabi Oncology, the German drug maker which acquired Dabur's pharma business in 2008, had a substantial budget of over 12 per cent of sales for R&D in 2011-12 at Rs. 65.69 crore.

All other major foreign players with noteworthy commercial operations in India such as Bristol-Myers Squibb, Pfizer, Merck, Novartis and Abbott spent either nothing or small amounts. Bristol-Myers Squibb, Abbott, Merck Sharp and Dohme, and Eli Lilly did not give details of their India investments. Swiss multinational Novartis, which spent $ 9 billion on R&D in 2012 globally, does not do any R&D in lndia.

Ecosystem required for Innovative Medicines
Medical & pharmaceutical progress through innovations depends on a successful partnership among various stakeholders.

Innovations are always brought by a thriving ecosystem consisting of three major components:

• academic researchers who can unlock secrets of basic biology and reveal mechanisms that underlie disease;
• a robust bio-pharmaceutical industry, which has develops molecules to treat disease and conduct clinical trials to demonstrate their efficacy; and
• Government regulators, who balance the benefits and risks that are inherent in any medical innovation.

Others including physicians, pharmacists, and consumer groups also play crucial roles in such ventures.

Key challenges affecting this ecosystem
There are many critical areas related to drug discovery and development that must be addressed to advance innovation:

(1) Resource deficiency
The main constraint lies in a lack of resources. Sources of high risk funding are not easily accessible in India. Skills and trained personnel are also in short supply. Assets such as specialized equipment are, unavailable, inaccessible or underutilized and poorly maintained. Indian firms do not have a long history of being innovative in this industry and have not as yet been able to show results. There is limited cooperation between the public sphere and the private sphere. Parts of the industry and the regulatory system are also seen to be working at odds with each other due to historical habits which need changing.

(2) Orbit shift- from generics to new chemical entities
It's not unknown that drug discovery and development needs lots of efforts and takes long periods of at least 8-10 years to show results. Thus, Indian pharmaceutical industry, comprised of mostly generic manufacturers, though have begun their foray into new drug discovery research in recent times; the results of such R&D takes time to make its impact. This restricts a financially cautious Indian pharmaceutical industry to indulge in the same. In fact, most of the R&D expenditure in the country is actually diverted towards the development of mere generics.

Unless the industry shifts its focus from generics to the new chemical entities, and encourage innovations, the dream of having an own brand drug is very distant.

(3) Scientific knowledge gaps between basic research and commercial projects
A fundamental problem is that advances in basic biomedical knowledge have not yet been matched by similar increases in the science and technologies needed for drug development. Accelerating the translation of biological insights into new medicines requires developing powerful new scientific knowledge, methodology, and analytical tools. Academic scientists tend not to pursue such work, because it is seen as 'too applied' and because it often requires multi-disciplinary teams rather than individual academic labs. Companies tend to under-invest in such work because it is at least partially a 'public good'-that is, a single company financing the development of new foundational approaches to drug discovery cannot fully appropriate the fruits of the work, because much of it is disseminated to benefit all participants.

A strong scientific correlation and co-existence of the academic scientists along with the pharmaceutical scientists is essential to bridge this gap; and considering the need of the hour, it's crucial that such partnerships come up quick. Such an effective pathway is essential for the Indian pharmaceutical industry, which is comparatively naive in innovations, so as to reduce the otherwise high probability of failure. A strong academic-industry symbiotic relationship will certainly lead to specific, relevant and faster drug evaluation.

The key rate-limiting scientific knowledge gaps for medicinal innovation exist in drug evaluation and they are:

• predicting the efficacy and toxicity of candidate drugs, and
• validating the "druggable" targets in the human body.

In principle, the academicians, the regulatory and the pharmaceutical industry should work together to ensure that the country's people gain access as rapidly as possible to new drugs that are safe and effective, while confirming that they are protected as completely as possible from drugs that are not.

In practice, it is very difficult to strike this balance because our knowledge about safety and efficacy is often initially very limited and evolves overtime. Approving drugs with too little information runs the risk of exposing the public to dangerous side effects or ineffective treatments.

Whether a drug discovery and development project succeeds depends on the answer to key scientific questions, such as: Will a drug that inhibits a target protein be effective against the targeted disease? Will a specific chemical entity be safe? With the current state of knowledge, it is difficult to make accurate predictions and uncertainty is often resolved only late in the development process after the expenditure of considerable time and money. Because the success rate is very low, the true cost of making successful drugs must include amortization of the many failures.

(4) Inefficiency and uncertainty in clinical trials
The drug discovery and development process is extremely expensive, with the most expensive factor being the cost of clinical trials. Clinical trials are expensive for at least two reasons: (1) the current clinical trials system is inefficient and (2) current clinical trials often require large numbers of patients and long durations to provide adequate evidence of safety and efficacy to meet the standards for regulatory approval, especially for drugs with clinical impacts which are not dramatic or which occur over a long period of time.

Clinical trials constitute the largest single component of the R&D budget of the biopharmaceutical industry, at approximately $31.3 billion, representing nearly40 percent of the R&D budget of major companies. Unfortunately, there is broad agreement that our current clinical trials system is inefficient.

Currently, each clinical trial to test a new drug candidate is typically organized de novo, requiring substantial effort, cost, and time. Drug companies must identify clinical investigators and assemble multi-investigator teams. Protocols must be written and submitted to each of many institutions, and approval of these protocols can take several months without necessarily improving the ethics of the research or the protections afforded human subjects. Information technology is not standardized among trials. Navigating all of these requirements is challenging even for large pharmaceutical companies, and thus, can be daunting for comparatively smaller and naive Indian pharmaceutical firms. The long-run return on these investments further dampens their spirits. Even in the best cases, the complexities add considerable time to trials-subtracting time from a successful drug's eventual time on the market without competition.

Ultimately, the industry, the Federal Government, academic researchers, and the medical community would need to work collectively to fill such knowledge gaps and create efficient clinical trial networks and trial designs.

The nation would benefit from a coherent, high-level partnership that brings together high-level leadership from key stakeholders on a sustained basis to develop and help launch initiatives for shared scientific objectives, such as filling scientific knowledge gaps and building efficient clinical trial networks.

(5) Regulatory Uncertainty
Drug discovery and development projects always face many uncertainties. Some a re unavoidable, as unanticipated issues arise during drug development. However, among these the most significant and apt for the current scenario in the nation is the regulatory uncertainty.  Currently, though our regulatory body is undergoing changes and coming forward with revised guidelines, it is mandatory that they discuss these changes with the industry, NGOs, Physicians, Clinical Pharmacologists and also other regulators so that it can be ensured that the revisions that they come up with would not turn out to be the roadblocks to drug discovery and development. If done so, it would be considered as the steps towards the right direction for country's growth as a strong drug discovery and development force. The regulators and the government should work in minimizing the current uncertainties with clearer guidelines and more consistent communications with the industry. These uncertainties often surround the type of the study design and quality of evidence that will be necessary to demonstrate safety and efficacy. Regulatory uncertainties affect the costs and timelines of drug development and hence dampen the spirits of the investors.

Conclusion
Although drug discovery in India is a relatively new phenomenon and thus far very few compounds have really been discovered in India, the potential for success is high. Cost and speed have been the primary value proposition provided by Indian firms.

Investors and pharma business owners have adopted a wait and watch attitude ruminating on whether or not to make a long term commitment. Most Indian pharmaceutical companies have spent the past decade in identifying strengths and weaknesses and shaping their business portfolios. In doing so, the companies have indulged in many appropriate but diverse activities including bulk drugs, formulations, generics, novel drug delivery systems, new chemical entities and biotechnology products. The coming decade will see these companies focusing on their strengths and leveraging opportunities in selected areas of research and development.

While SWOT analyses and speculations have filled columns and discussion forums on whether or not India can produce novel drug targets, it is time to introspect, identify and fix the flaws and march forward.

And in fact, a failure to do so may pose a threat to the future of the pharmaceutical industry. Despite all the challenges, advances in technology and innovation process do present the industry with opportunities to push forward and prosper. Exploring these future opportunities to leverage India advantages should be the center of focus for the Indian pharmaceutical industry.