"To provide drugs at affordable prices for the masses in India, the best option is to make our own drugs. The objective should be to make them in a cost-effective way". This was stated by Dr. K. Anji Reddy, Chairman, Dr. Reddy's Laboratories Ltd. He was delivering the 7th Dr. Yellapragada Subba Row Memorial Lecture organized by Hyderabad University. Dr. Subba Row, born in Bhimavaram in Coastal Andhra Pradesh, was the Father of Modern Medicine in India. His most prominent discoveries include a colorimetric method of estimation of phosphorus in biological fluids which is widely used even today all over the world, Phosphocreatine, Adenosine Triphosphate (ATP), the Chemical Energy reservoirs in the body, Folic acid (a B-Complex Vitamin), Hetrazan (for curing Filariasis) and Aureomycin, the world's first tetracycline antibiotic.

The subject title of the talk was: "Management of Science in Pharmaceutical Industry."

The extracts:

Dr. Yellapragada Subba Row's biochemistry and pharmaceutical research are quite well known. My knowledge of Subba Row's work is more anecdotal. I heard of his method of estimation of phosphorous from a Biochemist who said even though it is 60 or 70 years old method, it is still one of the most accurate methods. Later on I saw from literature that the paper in which this method was given, was the most cited paper for three decades from 60's to 80's. And then of course the Hetrazan (Diethyl Carbamazine Citrate) from Lederle for treating the filariasis about which I learnt in my pharmaceutical chemistry class in 1959. At IDPL, we used to produce folic acid which I learnt later was synthesized first by Subba Row's team in Lederle. Even in a relatively short lifespan and given the status of science in the pharma industry in those times, Dr. Yellapragada's contributions have been phenomenal and illustrative of the human spirit to achieve success against all odds.

The management of science in the pharmaceutical industry is a broad topic and I will confine my talk to drug discovery & development. This is because this is the area that will ultimately drive the transformation of the Indian pharmaceutical industry into a globally competitive entity. The management of science has evolved in tandem with drug discovery and development approaches.

Let us look back in time to trace the evolutionary course that the management of science has traversed to reach the current state.

1800-mid 1900s:

The drug discovery was based on natural products of botanical origin. The discovery of medicines was largely by chance observations and serendipity. Science was largely empirical and less applied. Yet a few accidental discoveries such as quinine, digitalis and cocaine were developed into authentic drugs for human use. The classic example of serendipitous discovery is the discovery of penicillin by Sir Alexander Fleming. It took nearly 15 years to obtain that penicillin in crystalline form. Usually, drug discovery was accomplished in modest laboratories with few researchers. With relatively limited knowledge of chemistry and pharmacology, quite a few synthetic drugs have been discovered and developed. In this era, the management of science in the pharma industry was largely focused on manufacturing such drugs for mass consumption.

Mid 1900s:

This was the era of microbiology, synthetic organic chemistry and evolving rational approaches to drug design. The 50's and 60's were regarded as the golden era of drug discovery based on mass screening programs. Major classes of antibiotics such as Beta lactams comprising penicillins and cephalosporins, aminoglycosides and macrolides have been discovered in these decades. Sir James Black at ICI demonstrated the first mechanism-based biochemical approach to drug discovery with the discovery of a betablocker propranolol in the 60's. This was followed by yet another brilliant discovery of Cimetidine in a focused research aimed at developing H2 receptor antagonists in the 70's. Following these path-breaking discoveries based on rational screens and its advances in molecular pharmacology, receptors, enzymes and ion channels came to be regarded as targets for drug intervention. Coupled with the analog synthesis approach, there has been a dramatic shift in the way drug discovery was done in pharma industry. This approach has proven to be most successful in bringing out superior second and third generation molecules based on the parent drug (H2 receptor antagonist ranitidine, DNA gyrase inhibitor ciprofloxacin, ACE inhibitor enalapril, HMGCoA reductase inhibitor Simvastatin etc.) In this era, drug discovery was left much less to chance observations. It was guided by rational thinking and sustained / focussed research driven by organic chemistry and medicinal chemistry.

The management of science was focussed on

Ø Co-ordination of mutidisciplinary research teams

Ø Clinical development of drugs in accordance with regulator guidelines

Late 1900s:

The uprecedented advances in the area of biological sciences like cellular & molecular biology and genetics provided new insights to researchers. Increasingly biology came to drive the drug discovery process.

Current trends:

Rapid advances in technology have revolutionized the drug discovery and development process. If genomics and proteomics have set the stage for the next level of biology, combichem and HTS provide unprecedented capability to synthesize and screen new compounds. The challenge of sifting through voluminous data to identify the useful information is facilitated through tools like Bio-informatics. Technology is, in fact, the latest addition to the gamut of multidisciplinary elements in drug discovery and development. With the increasing complexity of the drug discovery and development approaches, proper management of the complex, interrelated processes of drug discovery & development has become crucial to success.

Let us now examine some important elements of management that may be used to maximize the chances of success of a scientific pursuit, in pharmaceutical industry.

Portfolio Planning

This is the first step that will determine the areas in which science will be deployed. The R & D strategy guides the manner in which the various resources are to be deployed to achieve the R & D mission. The choice of the therapeutic areas in which to deploy the available resources should be guided by both.

Ø Internal factors like available infrastructure, internal R & D expertise and

Ø External factors such as unmet medical need, market potential, etc.

As uncertainty is inherent to drug discovery it is better to deploy the available resources in a few therapeutic areas where the organization can be competitive globally. In addition, the portfolio should have a mix of projects with long and short development cycles (e.g. According to CSDD (Center for Study of Drug Development), it takes an average of 9-10 years to develop a CNS drug and about 5-6 years to develop an anti-bacterial drug.)

Research Approach:

The choice of the research approach is a strategic decision that will determine

Ø The level of science & technology

Ø Risk of operation

For instance, analog research, pursued so far at Dr. Reddy's requires comparatively less degree of automation. This approach relies on medicinal chemistry & biological screening and is relatively less risky than a first-in-class project as the analogs are based on a known discovery that our Atlanta research facility is pursuing, deploys more cutting edge approaches like genomics, proteomics etc. This approach is far more risky but potentially more rewarding.

Technology Management:

The choice of technologies is contingent upon the research approach. For analog research, the technologies required would be relatively simpler as compared to those required for new target-based research. The key elements of technology management include

Ø Acquisition of appropriate technologies

Ø Deployment of the technologies

Ø Modification / replacement of technologies as may be required

For instance, at Dr. Reddy's we have recently set up a team in the area of molecular modeling & drug design. While we have successfully undertaken analogy research in the past, we felt that this capability would bring a higher degree of rationality to our approach.

In recent times, the greatest impact of technology has been to provide capability for

Ø Thy synthesis of millions of compounds (Combichem)

Ø Rapid screening of tens of thousands of compounds (HTS). Merck for instance screened about 250,000 compounds in 60 years (1934-94). However, from 1995-98, using Combichem and HTS approaches they screened more than 4.5 million compounds.

Ø Data management (bio-informatics)

Ø Data integration (LIMS-Laboratory Information Management Systems that network the various analytical instruments in laboratories)

Ø Databased creation & management (e.g. ISIS)

Ø Electronic archival of experimental data for regulatory submission (Nugenesis) Intellectual Property Management

This aspect is gaining importance in virtually every knowledge-based industry. The intellectual property rights reward the inventor by allowing exclusive use of his inventions for a limited period of time. This is critical for drug discovery and development considering

Ø Increasing cost of drug discovery & development (802 million US$ to bring an NCE to market)

Ø High failure rate of NCEs in the clinic

Ø Only 30% of commercialized NCEs recoup their R & D costs

Ø Increasing competition

Ø Long gestation period (10-12 years to bring an NCE to Market) Intellectual property management addresses issue like

* Identification of research areas where opportunities for IP generation exist

* What inventions to secure, by patents

* When to file patents

* Patent protection from infringement

* Abandoning unviable patents

Drug Development Strategy

This is crucial not only because it involves considerable amounts of money but also because it involves testing experimental drugs in humans. Drug development may be achieved through a licensee(s), with a co-development partner(s), or in-house with progressively increasing management effort & allocation of resources.

1) Fledgling companies that do not have the expertise/financial capability to undertake drug development may undertake out-licensing. This approach ensures that the compound progresses in the clinic while providing some financial returns in the short term (based on the deal structure). It is also a risk mitigation technique that shields a company from the losses if the drug were to fail in the clinic.

2) Companies that wish to ultimately evolve into companies that can do the "molecule to market" may undertake co-development. While this approach involves greater risk and financial expenditure, it provides a company the experience of clinical development and if the drug were to reach the market, the upside would be significantly higher. In both these cases, alliance management either with the licensee or the co-developing partner is also crucial.

3) The third approach is to develop the compound on one's own. This approach involves the greatest risk and of course is potentially most rewarding. This approach is ideal for large well established companies.

Project Management

Research is a potentially unending process with boundless possibilities that may be explored. However, for a successful problem solving approach, it is essential that the limits of research be specified through finite projects with predefined timelines. Project selection should be based on a thorough evaluation of a project's feasibility and its potential for fulfilling the pre-determined strategic goals of the organization. The activities, timelines and resource requirements of each project should be clearly stated prior to implementation to facilitate an objective evaluation of its progress and to suitably amend the design / implementation if warranted at any stage. The key stages of a project form the bases for fixing go / no go decision points that are used in progressing a project from one stage to another. Such predefined decision points will facilitate the early termination of weak / unviable projects.

R & D Review & Control

The review of the R & D effort should be both internal as well as external to ensure objectivity Internal review may be undertaken through informal and formal meetings. Periodical internal review may be done through progress review of individual projects for go / no go decisions. The external review of the R & D effort should be performed by scientific advisors and scientific thought leaders. The review of the R & D activities facilitates control via modification / change of research plans, research inputs or implementation processes as may be required for achieving the desired output.

Performance Indicators

The following indicators may be used for assessing the overall productivity of the R & D program.

1. timely execution of projects : This indicates capability for project management and for evolving the correct scientific approach to the problem at hand.

2. Research publications : These represent the quality of science as the publications in scientific journals are made pursuant to peer review.

3. Patents : These indicate capability for generating intellectual property.

4. New Chemical Entities (NCEs) in the clinic : These represent intellectual property that has great potential for commercialization.

5. Out-licensing deals : These are the ultimate test of quality of research as they are an indication that the internal R & D effort has met / surpassed the quality criteria set by the external partner. These criteria tend to be very stringent, as the licensee would make a conscious and vigorous effort to minimize the chances of in-licensing a weak or unviable drug candidate.

Human Resources

However, one cannot ignore the equally important factor of human resource. In fact I would like to share with you that the philosophy of R & D at Dr. Reddy's was to bring together good people, invest in good science with the hope that good medicines would follow. It may not be out of context to mention that the alumni of this University have made a significant contribution to drug discovery at Dr. Reddy's. In fact, our present Chief Scientific Officer, Dr. Uday Saxena, is from the University of Hyderabad. We have strived to attract, retain and nurture the right talent. Sharing the profits of research with the scientists is in fact a great motivating factor that also helps retain the top talent.

Alliances

The drug discovery and development process is expensive and a complex process. According to the most recent estimate of the Tuft's Center for the Study of Drug Development (CSDD), it takes $ 802 million to bring a molecule to market. Also, the highly multidisciplinary nature of the effort necessitates partnering with external organizations in furthering the scientific program. The key alliances in drug discovery & development include

Ø Research partner(s)

Ø Licensee(s)

Ø Licensor(s)

Ø Co-development partner(s)

Ø Consultant(s)

Ø Contract Research Organization(s)

Attitude of the Top Management

In my own experience, I have found that in managing science, especially drug discovery, one needs to temper the commercial imperative with scientific wisdom. Infact, when I was planning to set up the drug discovery facility, I was advised by well-meaning friends not to embark on a losing proposition. I went back to my scientists and told them that if we are not able to discover new drugs we will definitely publish research papers in reputed journals. To me, the single most important factor for the success of the drug discovery at Dr. Reddy's would perhaps be the management of science to ensure the quality of the bench science without being too consumed about the commercial outcomes, as uncertainty is inherent to the process.

In summary, I believe that successful management of science especially in drug discovery & development requires as much patience as perseverance.