Drug Discovery and Development

Before embarking upon a discussion on the role of Indian pharmaceutical industry in the development of drugs for the world market, it might be beneficial to review the dilemma faced by leading pharmaceutical companies of the world. Companies like Merck were the darlings of Wall Street as well as the public at large. However, the scenario started changing in the mid 1990s and the industry has been reeling ever since. There are many forces that have contributed to the current scenario: (i) a series of product recalls (ii) continued increase in the prices of new drugs (iii) increased, perhaps unrealistic expectations regarding the safety of current and future drugs and (iv) decreased productivity despite heavy expenditure in the discovery and development of innovative drugs. Therefore, it is clear that a new strategy is required to discover and develop new drugs at a cost that allows major pharmaceutical companies to address unmet medical needs in a timely and cost-effective manner. India and China are seemingly at the forefront to offer such an opportunity.

Indian companies have often been referred to as manufacturers of copycat drugs. Scores of DMF filings, highest number of FDA approved manufacturing sites (outside the US) and a not so congenial patent law; all these have not exactly given a standing of a country vying for a spot in the chase for new drug targets. With such a checkered background, when and how did India gain a place in the challenging business of novel drug discovery?

The new millennium brought about drastic changes for the Indian pharmaceutical industry; not that the changes were unexpected. TRIPS-compliant patent regime was in the offing since India became a signatory to the WTO in 1995. The companies have quickly realised that reverse engineering alone will not provide durability, and thus, have evolved various models that could fit within their research and business scheme. Traditionally, Indian pharmaceutical companies have been investing about 2% of the turnover on R&D, which is way below the 12% mark of their Western counterparts. This paltry investment though, is bound to change in the coming years as evidenced by the emerging trend (Table 1). With robust activity at the R&D front, the Associated Chambers of Commerce and Industry of India (ASSOCHAM) has indicated that the R&D spending of the Indian pharmaceutical industry will reach about 8%-9% (of total sales volume) by the year 2010. Most of the Indian R&D has turned around and initiated drug discovery as one of the key focus areas. Taking up such a challenging path may be for many reasons, among which at least two seem to be striking: firstly, globally it is being realised that longterm success can be ensured only by inno vation and novel drug discovery. Secondly, patent reform has forced Indian pharma to rethink and realign its strategy, which is to innovate for long term sustenance. The high cost of drug development, a subject matter that has been discussed in many forums, is of key concern to the pharma industry. What used to be a US$ 0.5 million endeavour in the 1990s, reached a whopping US$ 800 million in the beginning of the millennium and reports put it at more than a billion as of today. There is great pressure, globally, to cut costs, eliminate redundancies and retain profit margins. The critical factors driving the global pharmaceutical industry to look for newer strategies are based on hard facts stemming from decade-long experiences. These may be one or more of the combinations as stated below:

•  High cost of drug development in the Western countries
•  Drying drug pipeline
•  Patent expiration of blockbuster drugs
•  Hurdles in carrying out clinical trials

In view of the increasing drug development costs, two to three different models have evolved in the past 5-10 years. In all these models, India along with China has shown immense promise due to its substantial pool of talent in reverse engineering and a sound base in pharma manufacturing. Following are the models:

(i) Contract research and development activities, where bigger pharma outsource specific tasks (e.g. pre-clinical studies, animal studies or clinical trials) in the drug development process to smaller speciality companies. A number of Indian companies have positioned themselves to cater to such needs wherein a portion of the drug development process can be handled satisfactorily and the results achieved in a timely fashion (e.g. GVK Bio- Sciences, TCG Life Sciences). Besides cost advantage, India scores big on ease in patient recruitment as compared to its Western counterparts where the trials stretch for years for want of patient population.

(ii) Cost-effectiveness and confidence in the available skill sets have propelled many global pharmaceutical companies to set up offshore activities which should gradually result in seamless integration with the parent company. The offshore activities that merely started as manufacturing hubs in India have in due course emerged into clinical research or basic R&D units. Examples of this model include Pfizer, Novartis and AstraZeneca. There is also the future possibility of a larger multinational acquiring an Indian pharmaceutical company and developing it into a stronger R&D base.

(iii) Larger Indian pharmaceuticals have taken the leap quite confidently into innovative research. Generics companies like Dr. Reddy’s Laboratories (DRL) and Ranbaxy have set their vision firmly on developing novel drugs, while Nicholas Piramal has always been a proponent of novel drug discovery approach. DRL, for example, well known for its reverse engineering and manufacturing capabilities, had redefined its motto in the early nineties as ‘discovery-led global pharmaceutical company’ and now has an impressive array of new drugs (Table 2).

In addition to the above listed frontrunners, there are a number of other players like Zydus Cadila, Torrent, Sun Pharma and Orchid that are gradually foraying into the field of novel drug discovery.

There are also specific examples of how a given R&D centre, in totality, can function more efficiently in an all- Indian set up. If critically analysed, Indian pharma has circumvented some of the deterrents most effectively. Nicholas Piramal’s example may be instructive here. Firstly, the company has a state-of-the-art R&D facility, second to none built at approximately 1/5th of what it would cost in the US or Europe. Secondly, it has set its goal on novel discovery approach right from the outset and thus boasts of a robust pipeline of drugs across disease areas that are at different stages of discovery. And lastly, the company has capitalised on the advantages India offers with regard to clinical trials—it has been successful in completing the duration of clinical trials in half the estimated time in any Western country.

An in depth analysis of the third model described above may shed light on how Indian pharmaceutical companies are taking the new challenge to the next level. The Indian strategy, to start with, has been to dig the pot for ‘me-too’ targets instead of going for an unprecedented one. It may be contested that ‘me-too’ cannot be a blockbuster as compared to its original molecule. However, this approach has been validated by the market success of drugs that have followed the novel molecule in the same class, for e.g., Pfizer’s Lipitor, which has become the best selling drug in the world. Moreover, it should be clearly understood here that identifying and developing a ‘metoo’ is not an ordinary feat, given the fact that the innovator would have made every effort to study and patent all the analogues. Thus, identifying a novel and active equivalent in a given class of molecules is in itself a daunting chore. At the same time the search for a ‘me-too’ definitely has its advantage as the family is well-researched and the mechanism of action is known, leading to reduced risk as compared to starting with a relatively unknown molecule.

It is almost certain that the immediate task for the Indian companies is to leverage the cost advantage in bringing new drugs to clinical trials. Thus, the companies’ focus may not be on taking the drug products themselves to the clinics and/or subsequently to the market. For example, DRL had outlicensed some of its anti-diabetic molecules to Novo Nordisk and an insulin sensitiser to Novartis. More successful of the lot is believed to be Glenmark, that has struck a deal with Forest Labs (New York, USA) for developing its GRC 3886 (PDE-4 inhibitor) for pulmonary diseases. By adapting this strategy, the smaller pharma could do away with huge uncertainties associated with the discovery process. Furthermore, the upfront and staggered (milestone) payments can facilitate the licensor tremendously in channelling the resources for allied activities. On the other hand, there is also this conscious effort to carry on at least early clinical trials in-house to gain expertise in clinical development arena, which may be lacking in a basic research set up. Added to that will be the benefit of greater value to the discoveries once they are licensed out at a later stage of development.

It should be appreciated that drug discovery is an arduous task that could be a decade-long effort and that success is not always guaranteed. Indian pharmaceutical industry’s attempts to discover new drug entities are no exception. Reddy’s have their failure story in anti-diabetic targets while Ranbaxy’s target for prostatic hyperplasia met with stumbling blocks in the early stages of development. But isn’t early or late trial failure a part and parcel of the game? Failure of alfimeprase (Nuvelo-Bayer partnership) as recent as the end of 2006 exposes the inherent risks involved in the drug development business. Moreover, these are precious failures (though not intended) and will be tremendous learning experiences for the future drug discovery efforts.

On the expertise front, the cost advantage and availability of postgraduates are repeatedly reiterated. These certainly are factors that may seem positive. However, it needs to be recognised that neither the Indian academia nor the pharma business houses have skilled personnel to lead novel drug discovery effort. A thorough understanding of the process from identification to having the drug in the market is absolutely essential. Even in the US and Europe, leaders who have ‘been there, done that’ are a rare find. Drug discovery is relatively new for the Indian scientific community. The search for the few leaders who could drive the crew efficiently will need a mammoth effort. While attracting trained personnel from across the shore is both feasible and a necessary option, training a whole lot of the younger generation methodically should be recognised as an urgent need. The second model of a multinational company with a proven record of drug discovery setting its own facility has a significant advantage in this respect. There is this much needed guidance from the parent company in terms of scientific inputs and business development. The only major concern in these circumstances is the challenge of bridging the distance (and time!) that may hamper the consistency to lead the discovery effort.

India is on the threshold of drug discovery research where the next few years are going to be critical in terms of delivery. 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 focussing 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.