South Asia is often referred to as the Indian Subcontinent because its land mass broke away from the southern part of Africa more than 65 million years ago, drifted north, and “collided” with the Asian land mass to become part of Asia. The upheaval along the lines of the collision that occurred over millions of years (and is still continuing) led to the formation of the world’s tallest mountain range – the Himalayas. The volcanic activity that occurred on the subcontinent during its northward drift is linked to the extinction of 98% of the species on earth at that time, including the dinosaurs, and resulted in the formation of the Deccan plateau – among the largest igneous regions of the world covering most of peninsular India.

Aboriginal and tribal populations lived in India long before recorded history, which begins with archeological evidence of the Dravidian civilization dating through the 3rd to the 2nd millennium BC. Aryan tribes drifted into the subcontinent in the 2nd millennium from the region of the Caspian Sea, bringing with them Vedic traditions, the Hindu religion, and Sanskrit – a language of the Indo-European group that has common roots with early Persian and Latin. India was a patchwork of monarchies and republics in the 7th century BC when Siddhartha was born in one of the royal families and went on to become the Buddha – founder of the Buddhist religion that is followed in many parts of Asia.

Most of the country was united under one administration for the first time during the Maurya period that reached its zenith under Ashoka in the 3rd century BC. The first half of the 1st millennium AD was a period of relative peace, prosperity, and economic achievement when India accounted for about a third of world GDP. The country assimilated waves of Muslim invaders and immigrants from the north and northwest during the latter part of the 1st millennium AD and well into the 2nd. The last of these were the Moghuls who ruled large parts of the country from the 16th to the 18th century, bringing variety and leaving behind indelible influences on myriad aspects of social and civic life, from language and religion to the arts, handicrafts, and architecture. Trade, industry, and commerce did well and India was still the world’s single largest economy in the early part of the 18th century, accounting for 20-25% of world GDP.

The British, together with other Europeans, began as traders in India in the 17th century and ended up ruling and administering the country. The 190 years of British occupation helped the country integrate through nationwide railways and telecommunications, national institutions such as the judiciary, postal services, national armed forces, administrative services, and the national movement for independence. Many of the national institutions today remain a legacy of the British administration, in some instances with little change over the years. However, British rule did ruin the economy – the country was unable to keep pace with the rest of the world and accounted for merely 4% of world GDP at the time of Independence in 1947.

British rule ended disastrously, with the partition of the country. Independent India, although secular and democratic, struggled to kick-start the economy. The government invested heavily in industry while inadvertently stifling private enterprise in its endeavor to redistribute wealth. The country was perceived to be pro-communist during the cold war and leaned more heavily leftward in the 1960s and 70s. Nationalization, the opposite of privatization, resulted in the government taking over and monopolizing large domains of economic activity including mining,insurance, and the banking system. Product patents for chemicals and pharmaceuticals were abolished in a bid to bring down prices and make drugs affordable for the poor – a move that eventually succeeded beyond expectation. Price controls were also introduced on essential drugs irrespective of whether these were imported or locally produced. Curbs on private enterprise led to the “License-Permit Raj” – big government, and an enormous bureaucracy. Although public investments made from international borrowing, and the ingenuity of private entrepreneurs in adverse circumstances ensured that the economy kept growing, even if at a “Hindu pace”, India’s share of the world economy had fallen to 3% by 1973.

A balance-of-payments crisis in 1991 led to the first wave of purposeful liberalization. The ill-conceived policies of previous decades were reversed and the economy gathered momentum. Signing the GATT/WTO Agreement in the mid-1990s brought the country into the era of globalization, helped along by the coming of age of telecommunications and the Internet. Government investments in higher education made in the 1950s and 60s began to pay off at last as information technology boomed. Liberalization unleashed latent entrepreneurial instincts and led to the growth of start-ups in the new economy. The GDP growth rate picked up to 10.4% in the last quarter of 2003, beating China for the first time in a long time. WTO-led lifting of quota restrictions, intellectual property protection for chemicals and pharmaceuticals, a demographic dividend, and further doses of fiscal and macroeconomic liberalization are expected to generate sustained growth and rise in income levels. By the mid-twenties India is expected to be the third largest economy after China and the United States.

Over the last decade, we have witnessed a significant growth in clinical research activities outside of the traditional countries – US and Western Europe. This growth reflects a trend towards globalization of research and is a result of two major drivers.

Pressures on R & D Productivity – faced by pharmaceutical companies, this is reflected in widening of the gap between R & D investments and average NCE approvals per year with resultant cost pressures on development of new drugs.

Regulatory Standardization – ICH and initiatives for regulatory harmonization have acted as major triggers for globalization of clinical development by defining norms for global acceptance of data.

These changes in clinical research environment are driving the growing internationalization of research activities in emerging countries like Latin America, Eastern Europe and Asia.

In India pharmaceuticals are governed by the Drugs & Cosmetics Act and the Rules framed to implement the provisions in the Act. New chemical entities may not be administered to human subjects in a clinical trial without permission from the Drugs Controller General of India (DCGI). Such permission may be obtained by submitting to the DCGI an application for a clinical trial (CTA). A CTA package must include a protocol for the study, a draft of the Informed Consent Document, a list of proposed investigators who have agreed to participate in the study, and background information about the drug in accordance with Schedule Y of the Drugs & Cosmetics Rules. The latter may be submitted in the form of an Investigators’ Brochure. It takes approximately 12 weeks to obtain permission for a clinical trial for most investigational drugs. The duration may be longer for drugs with special significance to the healthcare concerns of the country or those that may be considered controversial since these are liable to be referred to the Indian Council of Medical Research for comments. Ethic Committee approval is not a necessary precondition for regulatory permission to conduct a clinical trial provided the applicant submits an undertaking that the study will not be initiated at individual sites without prior EC approval. If clinical supplies are to be imported, a “Test-Import License” must be applied for. This is done using the format provided in Form 12 of the Drugs & Cosmetics Rules. Import and manufacture of clinical trial supplies is governed by Rules 33 & 34 and provisions contained in Part X-A of the rules.

Imported clinical supplies do not attract any import duties. However, imports must be accompanied by an invoice bearing the value of the goods being imported and by a certificate of analysis attesting to the nature and quality of the products.

Adverse drug reactions occurring during the course of a clinical trial need to be submitted to the DCGI within 14 days if these are unexpected or serious and causally related or result in death. All other serious adverse events need to be submitted along with periodic progress reports. Compliance with GCP guidelines issued by the CDSCO is recommended although this does not have statutory status at the present time. A report on the status of the study with details of enrollment and safety issues needs to be submitted annually and on completion of the study.

Registration of new drugs for marketing in India requires submission of data generated on Indian patients. A 100-patient non-comparative open-label study on patients treated for the primary indication is sufficient. For drugs that treat rare conditions, a lower sample size is usually negotiable. Submission of India-specific data culled from one or more multi-country studies is often acceptable as a substitute for an India-specific study. Thus, Indian participation in the global development program can reduce registration timelines and enable an early launch in India. In addition to local data, the NDA must include various other items of information listed in Schedule Y of the Drugs & Cosmetics Rules.

Importation of commercial supplies requires registration of the overseas manufacturing site. The site where the last manufacturing activity for the product is completed is considered as the location to be registered. Import registration requires the submission of additional documents as listed in the schedules D-I and D-II of the Drugs and Cosmetics Rule, including a plant master file, a drug master file, a CPP and power-of-attorney from the exporting party. Import registration entitles the importer to apply for an import license authorizing unlimited imports.

Samples of the product from the first commercial consignment imported into the country will usually be sent by the port authorities for testing at the Central Drugs Laboratory before the consignment is cleared for distribution and sale.
Data from prospective post-marketing surveillance is usually required to be submitted to the CDSCO within 2 years of approval of a product. PMS data is considered a prerequisite for renewal of the import license on expiration of validity 3 years from the date of issue.

Local manufacture of bulk actives and formulations, including local repackaging, requires a manufacturing license from the state Food and Drugs Administration. The latter must be accompanied with manufacturing information and stability data. For new drugs, an approval from the CDSCO is a prerequisite.

At about US$ 4 billion, the Indian pharmaceutical market accounts for about 1% of global sales of drugs and pharmaceuticals. Yet by volume it is said to account for about 8% – average prices being among the lowest in the world. Abrogation of product patents in 1970 led to the growth of the local generics industry. There are currently about 20,000 registered pharmaceutical companies in India, the vast majority very small or non-operational. About 250 can be said to be large or medium-sized, manufacturing multiple products and operating on a regional or national scale. At the top of this pyramid are the Indian subsidiaries of multinational research-based pharmaceutical companies and the large Indian generic companies operating globally. For some of the latter, the revenue from overseas operations now exceeds domestic sales.

In addition to formulation sales, many companies manufacture and sell bulk drugs. Hyderabad is a key location for the bulk drug manufacturing industry with a majority of units located in and around this city in the south central part of the country.

The biotechnology sector has seen rapid growth in the last decade. Biotech companies manufacture and sell generic products synthesized using recombinant DNA technology licensed in from overseas partners. Biotech products are sold locally as well as exported.

The distribution channel for pharmaceuticals consists of a large number of individual wholesale stockists and retail drug stores. A license is required to stock and sell pharmaceutical products in India.

Growth of the generic industry in India meant continuous evolution of synthetic process development and formulation development skills within the industry. Till about 1995 much of the research undertaken by pharmaceutical companies in India related to process and formulation development and bioavailability/bioequivalence studies to support the latter, although a few multinational companies possessed research facilities in India that had a wider scope.

India’s signing of the GATT/WTO – TRIPS agreement resulted in large generic companies investing in major R&D facilities as part of the realignment of their long-term business model and strategy. Several companies across the traditional and new biotech sectors of the industry now have sizable research facilities involved in drug discovery and early development, and many of these companies have a small pipeline of products in development although no Indian discovery has yet completed development for worldwide commercialization as a result of these endeavors. Some companies have preferred to out-license partially developed products to larger multinationals for further development rather than risk the necessary investments for full development and commercialization.

Another interesting development has been Indian involvement in the global drug development process for multinational companies. Available human resource capabilities for clinical research in India, together with advantages in study start-up time, recruitment speed, comparable quality, and the availability of the requisite physical and electronic infrastructure has resulted in some multinational companies leveraging these to the advantage of the drug development effort through their Indian subsidiaries. Participation in drug development programs has also helped Indian subsidiaries speed up new drug introductions in India besides leading to refinements in local research capabilities and infrastructure that is expected to be of benefit to the growth of the pharmaceutical and healthcare sectors in the country.

More recently the landscape has undergone dramatic change with the emergence of CROs on the scene. There is now a wide selection of CROs with a variety of capabilities and core competence ranging from clinical trial monitoring, site management and data operations, to discovery sciences, toxicology, pharmacokinetics, genomics, and bioinformatics. Many of the CROs with clinical monitoring and data operations capabilities are Indian subsidiaries of larger organizations operating internationally.

South Asia is often referred to as the Indian Subcontinent because its land mass broke away from the southern part of Africa more than 65 million years ago, drifted north, and “collided” with the Asian land mass to become part of Asia. The upheaval along the lines of the collision that occurred over millions of years (and is still continuing) led to the formation of the world’s tallest mountain range – the Himalayas. The volcanic activity that occurred on the subcontinent during its northward drift is linked to the extinction of 98% of the species on earth at that time, including the dinosaurs, and resulted in the formation of the Deccan plateau – among the largest igneous regions of the world covering most of peninsular India.

Aboriginal and tribal populations lived in India long before recorded history, which begins with archeological evidence of the Dravidian civilization dating through the 3rd to the 2nd millennium BC. Aryan tribes drifted into the subcontinent in the 2nd millennium from the region of the Caspian Sea, bringing with them Vedic traditions, the Hindu religion, and Sanskrit – a language of the Indo-European group that has common roots with early Persian and Latin. India was a patchwork of monarchies and republics in the 7th century BC when Siddhartha was born in one of the royal families and went on to become the Buddha – founder of the Buddhist religion that is followed in many parts of Asia.

Most of the country was united under one administration for the first time during the Maurya period that reached its zenith under Ashoka in the 3rd century BC. The first half of the 1st millennium AD was a period of relative peace, prosperity, and economic achievement when India accounted for about a third of world GDP. The country assimilated waves of Muslim invaders and immigrants from the north and northwest during the latter part of the 1st millennium AD and well into the 2nd. The last of these were the Moghuls who ruled large parts of the country from the 16th to the 18th century, bringing variety and leaving behind indelible influences on myriad aspects of social and civic life, from language and religion to the arts, handicrafts, and architecture. Trade, industry, and commerce did well and India was still the world’s single largest economy in the early part of the 18th century, accounting for 20-25% of world GDP.

The British, together with other Europeans, began as traders in India in the 17th century and ended up ruling and administering the country. The 190 years of British occupation helped the country integrate through nationwide railways and telecommunications, national institutions such as the judiciary, postal services, national armed forces, administrative services, and the national movement for independence. Many of the national institutions today remain a legacy of the British administration, in some instances with little change over the years. However, British rule did ruin the economy – the country was unable to keep pace with the rest of the world and accounted for merely 4% of world GDP at the time of Independence in 1947.

British rule ended disastrously, with the partition of the country. Independent India, although secular and democratic, struggled to kick-start the economy. The government invested heavily in industry while inadvertently stifling private enterprise in its endeavor to redistribute wealth. The country was perceived to be pro-communist during the cold war and leaned more heavily leftward in the 1960s and 70s. Nationalization, the opposite of privatization, resulted in the government taking over and monopolizing large domains of economic activity including mining,insurance, and the banking system. Product patents for chemicals and pharmaceuticals were abolished in a bid to bring down prices and make drugs affordable for the poor – a move that eventually succeeded beyond expectation. Price controls were also introduced on essential drugs irrespective of whether these were imported or locally produced. Curbs on private enterprise led to the “License-Permit Raj” – big government, and an enormous bureaucracy. Although public investments made from international borrowing, and the ingenuity of private entrepreneurs in adverse circumstances ensured that the economy kept growing, even if at a “Hindu pace”, India’s share of the world economy had fallen to 3% by 1973.

A balance-of-payments crisis in 1991 led to the first wave of purposeful liberalization. The ill-conceived policies of previous decades were reversed and the economy gathered momentum. Signing the GATT/WTO Agreement in the mid-1990s brought the country into the era of globalization, helped along by the coming of age of telecommunications and the Internet. Government investments in higher education made in the 1950s and 60s began to pay off at last as information technology boomed. Liberalization unleashed latent entrepreneurial instincts and led to the growth of start-ups in the new economy. The GDP growth rate picked up to 10.4% in the last quarter of 2003, beating China for the first time in a long time. WTO-led lifting of quota restrictions, intellectual property protection for chemicals and pharmaceuticals, a demographic dividend, and further doses of fiscal and macroeconomic liberalization are expected to generate sustained growth and rise in income levels. By the mid-twenties India is expected to be the third largest economy after China and the United States.