Challenges & opportunities
There is a need for systematic, integrated approach to fill in the gaps existing between the country’s offering and customers’ requirements, says Dr M D Nair
The challenges confronting the domestic pharmaceutical industry from globalisation, WTO’s advent, TRIPs commitments and the increasing non-tariff trade barriers call for new strategies to retain the last three decades’ growth momentum.
While a Mckinsey report estimates the domestic market growing 400 fold to US dollar 25 bn (Rs 112500 crore) by 2010, it is quite conceivable generic drugs exports (bulk drugs and formulations ) exceeding the domestic sales. However, to be a competitor in the global market, several other approaches which differentiates the Indian industry are required to be in place, where the country has unique opportunities and skills to offer.
To understand why contract research and development could be an area of strength for India, it is important to analyse the strengths and weaknesses of Indian expertise in drug development. Broadly, discovery and development of drugs can be classified under three major phases, namely 1) discovery of candidate molecules through synthesis and screening for activity for specific therapeutic areas 2) pre-clinical studies for determining efficacy and safety (toxicology) in-vitro or in experimental animals 3) generation of pharmaco-kinetic and limited metabolism data 4) clinical studies, phases I to III and marketing and post – marketing surveillance to check on efficacy and safety in patients under field conditions of usage.
Of these, various activities, the discovery of candidate molecules are generally carried out in-house by R&D-based companies, since the right to IPR generated rests with this stage. Therefore, for commercial reasons of retaining exclusivity for the final product, this phase is hardly ever contracted out to third parties. Possibilities for contract research for Indian companies and institutions, therefore rest with the following activities.
- R&D for discovery & development of new drugs for diseases of the developing world on which there is little investment in the West due to high costs of drug discovery and development and the relatively low returns on investments.
- R&D on new drugs for life-style related diseases for which, even though the markets are global, the lucrative ones are in the affluent West.
- Development of combinatorial libraries based on known scaffolds as well development of cell lines and molecular targets based on genomics and proteomics.
- Development of formulations of the conventional solid, liquid and parenteral dosage forms.
- Development of scientifically validated medicines based on traditional knowledge in India and on the Indian systems of medicine.
- Development of new (non-infringing) processes for marketed products for companies interested in early entry into the generic markets on patent expiry.
- Development and scale-up of viable eco-friendly processes for products which are in the development pipeline.
- Custom production at the laboratory/pilot plant scale for products in the development phase for carrying out pre-clinical (toxicology) and clinical investigations.
- Clinical Research including Phases I to III and Post-marketing surveillance studies.
- Drug stability and bioequivalence and Bioavailability studies in animals, healthy volunteers and patients required for regulatory submissions. – Preparation of Dossiers for submission for DMFs, ANDAs and NDAs for various regulatory agencies as per their individual and specific requirements.
Why has it not flourished in India?
While the need for contract research in some of these areas is quite clear, in order to ensure that India can be a major player, there are some pre-requisites such as 1) necessary skills, manpower, financial resources and infrastructure 2) adequate protection systems for intellectual property and undisclosed information 3) credibility that contractor can deliver as agreed with respect to the scope, schedules etc 4) costs advantages for the agreed activities 5) negotiating strengths to finalise the agreement.
Chemicals synthesis, process technology development
Indian capabilities to synthesise new molecules and develop new processes including non-infringing processes for existing or new drugs are excellent and India has the opportunity to enter into contractual agreements based on customer requirements. The terms of the contract including rights on intellectual property should be clearly defined. Indian strengths in synthetic chemistry and the availability of large numbers of high quality synthetic chemists makes synthesis and supply of new molecules not covered by patents, a very fertile area for contract research.
With the advent of High Throughput Screening (HTS), where as many as even 100,000 molecules in chemical libraries can be screened in one day, there is increasing demand from contract laboratories to supply such libraries The new processes which are developed under contract for existing drugs or for candidate drugs in the pipeline of development, need to be cost-effective, viable for scale up and should use eco-friendly raw materials and reagents and hazard and safety analysis as well as standards and specifications for all intermediates and final products and the SOPS for ensuring cGMP standards should be clearly spelt out in the ’Process Package.’
India produces all the conventional solid, liquid, parenteral and aerosol formulations needed in the country. In spite of the occasional claims made by some, India’s expertise in new drug delivery systems (NDDS) based formulations is rather limited. In fact as far as NDDS formulations are concerned, the only one indigenously developed has been the liposome based Amphotericin. The once-a-day Ciprofloxacin and some of the other innovative slow release forms for which patents are pending are yet to reach the market in India or abroad. None of the transdermals, drug implants, oros, McAb tagged oncology products, nano-particles or microsphere based targeted drugs are being made in India out of indigenous technology and hence there is very little scope for contract research in these areas.
Screening for primary & secondary pharmacological data
Whether in in-vitro or in-vivo disease models, screening of molecules at the first level of identifying a potentially useful product can be carried out in the Indian laboratories, even though there is much improvement needed to be carried out if they are to meet international GLP standards. On the other hand, such data could be considered as leads and confirmatory pharmacology can be conducted in laboratories accredited for GLP in India or abroad.
Generally Indian companies, barring a few exceptions, have very little strengths in screening in animals whether rodents or mammals. However, this is an area which is commercially very attractive since such pre-clinical data generation is extremely expensive in the West. The same is the case of toxicology studies, particularly, sub-acute and chronic toxicity data generation as well gross and specific histopathology, teratology and carcinogenicity. Most R&D based Indian companies are themselves contracting this work to external laboratories to ensure that their data is accepted by the strict regulatory standards of FDA in USA.
Pharmaco-kinetics & metabolism studies
Around a dozen laboratories in the country carry out bioequivalence and bioavailability studies for known and new molecules which are being accepted by the regulatory agencies in India and abroad. The capability to study detailed metabolic studies in animals, humans (volunteers or patients) is limited to very few laboratories and certainly India, as of now is not fully equipped to conduct contract research in this area. Detailed studies on metabolic patterns of the drug is not necessarily a pre-requisite for submission of an NDA to most regulatory agencies.
The Indian advantages here are:
- the largest available patient population with diverse diseases which gives a tremendous advantage in terms of access to patients for the trials, faster completion of the trials and resultant savings
- the fact that the per centage of the patient population who are naïve is perhaps the highest in the world
- the availability of Western trained (mostly in U.S. and Europe) clinicians – English as the language of medicine
- well laid out regulatory standards for control of the trials
- excellent capabilities in documentation and analysis(including bio-statistical analysis) of data
- convenient time zones with respect to US and Europe
- good communication services.
A number of companies have in recent years set up clinical research facilities in India, including Pfizer. The current market for clinical research in India is estimated to be $50 mn, with the bulk of the work being done by a few MNCs and CROs. Some analysts believe that clinical studies market could grow in India to at least USD 300-500 mn by 2010. The costs of clinical studies in India are slated to be around half of that in the developed countries.
Just like Pfizer, the largest CRO in the world, Quintiles Transnational Corporation, is very active in India. Quintiles have carried out a few dozen trials whose results have been used for international regulatory approvals. Around six other Indian companies carry out human clinical trials in various phases and with the advent of around 10 new INDs for molecules discovered by Ranbaxy, Dabur, Reddy’s, Torrent, Wockhardt, Glenmark and others a flurry of Phase I studies on molecules hither-to-fore not used in humans will be started in many hospital centres under leading investigators.
A model CRO should provide a whole package of services which should include development of protocols, clinical trial planning, selection of centers and investigators, clinical trial monitoring, site management, quality assurance, supply of samples and overall project management. All investigations should meet the global GCP standards as well as follow the ICH guidelines if the data is to be pooled with other trial data.
There are, however, some concerns in the minds of many companies which want to entrust clinical studies to Indian CROs. Apart from the difficulties in conducting concurrent studies, the problem of lack of legal protection of data generated and/or submitted from use by third parties (Data Exclusivity) is a matter of concern.
It is obvious that with the skills already available in India in the area of contract research for drug development activities and the need for a system which ensures cost-effective, assured quality, speedy trials in the international context of drug development, India could offer a major advantage in taking over contract research which can earn revenues equal to the turnover of the Indian pharmaceutical industry by 2020 or even earlier. For that to happen there needs a systematic, integrated approach to fill in the gaps existing between what the country can offer and what the customers need.
The writer is Chennai-based pharma consultant. E-mail: firstname.lastname@example.org