Role of CROs in new drug development
India and China offer a great potential for a low cost drug development process and faster recruitment but the questions about data protection and informed consent remain, says Dr Krishan Maggon
India’s current share of GCP trials is negligible and will remain in this range unless an open regulatory system of checks, IP protection, responsibility, accountability and balance is operational. The Indian media coverage about some recent controversial trials involving Johns Hopkins/RCC cancer study, citalopram, letrozole, streptokinase trials in patient populations with high mortality, a new diabetic drug trials on poor and uneducated patients, payments to subjects in trials is a positive development of democracy by disclosures and helps DCGI and regulatory system.
It is a misconception to think that the developing world including India is becoming a favoured destination for clinical trials. There are headlines in Indian press and media including Express Pharma Pulse that India is fast becoming a ‘hot-bed’ for the clinical trials and apprehensions that Indians would be made guinea pigs in clinical studies.
The cost of drug development has reached astronomic proportions and the 2003 figure for a new drug is estimated at $1.7 billion and a major share of all drug developments cost are spent on clinical phase II, III, and IV. To produce it in a GMP facility costs an additional $500 million. An average drug file NDA for registration includes data on over 5000 patients enrolled in 80-100 clinical studies over a seven-ten year period.
The development of a new drug typically takes 7-12 years, and clinical trials for a new vaccine require 12,000-45,000 individuals enrolled in a 2:1 ratio in the treatment and placebo groups. Glaxo Smith Kline Rotarix vaccine to protect children from severe gastroenteritis has been studied in 30,000 patients and the current global phase III trial in 60,000 children is ongoing.
The Rotarix NDA when submitted in 2005 may contain data on 90,000 completed patients, a historic record. Merck has just published results of a ten-year treatment with Fosamax in patients with osteoporosis in JAMA. With such progression both in the duration of treatment and number of patients, the new drug development will be beyond the reach of small and mid-size companies and will be limited to big pharmaceutical companies.
Bulk of clinical research is carried out in USA, Europe and Japan in line with the market size. The pharmaceutical industry spend $50 billions on R&D in 2003 on over 5,100 development projects. The CRO share was $8 billion for central laboratory, clinical, toxicology and screening services and investigators grants an additional $10 billion. Active investigational new drug (IND) applications with FDA in 2003 were 4,000, the number of subjects per NDA currently exceeds 5,300 from only 3,300 in the 80s, and approximately 80,000 clinical trials are ongoing in the United States alone.
Center Watch estimated that in USA about 80,000 clinical trials with over 4,000 new drugs enrolled 20 million subjects and patients in 2003. The total number of trials in Europe is around 100,000 with the number of patients enrolled reaching 25 million. In Western Europe there are about 2,500 multicentric phase II and phase III trials per year requiring central laboratory services. Thus 95 per cent of the GCP clinical trials are carried out in USA, Europe and Japan. The rest of the world shares the remaining 5% mainly Eastern Europe, Latin America China and South Africa.
About 30 per cent of these studies are contracted out to CRO. A top ten CRO enrolls around 150,000 patients per year in clinical studies and had revenues touching $300-500 million in 2003. For a CRO early stage phase I studies are more profitable then the later phase II-III studies. The top 20 pharma companies all spent over $1 billion in R&D with over 100 projects each (Pfizer $7.1 billion, J&J, GSK $4 billion each).
The global CRO have become copies of big pharma. Qunitiles contract income is estimated to be over $2 billion in 2003. The advantage of using CRO offers flexibility to the industry to have faster recruitment, additional capacity or expertise in different therapeutic areas.
The disadvantages or inefficiencies come in data handling and edit queries on CRFs, protocol design, and legal responsibility, contract, budget and grants payment and loss of direct contact with the investigator who may use and champion the drug. Several companies, NGO and WHO have taken the drug development process to Eastern Europe (Russia, Hungary, Czech Republic, Poland), Asia (China, South Korea, Malaysia), India, Africa (mainly South Africa), Latin America (Brazil, Argentina, Chile, Mexico), Israel and Australia.
India and China offer a great potential for a low cost drug development process, faster recruitment but the questions about data protection and informed consent remain. Clinical trials in India cost one-third to half of the cost of trials in US or Europe. Once GCP framework is strictly followed, the cost advantage will disappear as it has happened with South Africa and Eastern Europe. The total number of ongoing clinical trials in India is a very small fraction of GCP studies done in Russia and China.
Ernst and Young estimated the total market value of clinical research performed in India between 1999-01 at $70-80 million and in 2001 at $25 million. The investigation covered 100 institutions/centers in India that had been engaged in clinical research. A majority of these were local non GCP studies. Center Watch 2002 estimate of Indian clinical trial market was 30-35 million and estimate of international GCP studies was 45-50. The number of investigators trained in GCP was 200-250 only.
India offers significant opportunities for global clinical research and development through a strong medical infrastructure and a large patient base in the world impacted by lifestyle-related illnesses like cancer, diabetes, and cardiovascular disease and are mostly without prior therapies.
Growth of CROs
There are about 1,000 of CROs operating worldwide employing nearly 100,000 professionals. In 1992, estimated CRO market size was $1 billion while in 2003 that number is over $8 billion and growing. CROs provide independent product development services primarily for the pharmaceutical, biotechnology and medical device industries. Companies in these industries outsource product development services to CROs in order to manage the product development process more efficiently and cost-effectively, and to maximise the benefits in time and profit of patient-protected products. CROs contribute to a large percentage of all products developed worldwide.
Their continued success is reliant on high ethical and professional standards, and compliance with Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) guidelines as prescribed by the regulatory authorities.
The markets for contract research organisations (CROs), which are companies that perform research services for pharmaceutical, biotechnology, and medical device industries, are strong. Continued growth in R&D expenditures, increases in the complexity of the drug development process, and the growing number of global developments are driving the CRO markets. R&D expenditures are increasing opportunities for CROs. Because of the demand for more efficient and expedient drug development processes, CRO outsourcing has grown exponentially during the past two decades.
The top ten CRO in the world, to maintain strong CRO market presence continuously: diversifying services beyond clinical trials to both front-end research and back-end development to sales and marketing. In addition, successfully establishing a global presence and offering both domestic and global service by mergers and acquisitions. CROs exemplify accelerating change in drug development.
In the past, most sponsors were large pharmaceutical companies and these companies did the vast majority of their drug development work in-house Today, 22 percent of drug development work—worth an estimated $6-8 billion annually—is outsourced to CROs and other independent providers. CROs are involved in two-thirds of all Phase II-III clinical projects.
CROs in India
The CRO companies were absent until recently from India due to lack of drug discovery and drug development activities. In addition, lack of patent protection for drugs in development kept multinationals out of India. There were two small Indian CROs in 1995 with 2-3 persons coordinating clinical trials for a fee.
The Central Drug Research Institute CDRI, Lucknow has conducted drug development studies with 8-10 new drugs, mostly herbals, discovered in its laboratories. These drugs were not patented and the data generated will not be acceptable in the Western World. Since 1995 when the first GCP trial was carried out to the year 2002, less then 50 GCP studies were carried out with the participation of 15,000 patients. This works out to about 2500 patients per year.
During the past three years the number of GCP trials has increased with the arrival of international CROs and it was reported that over 250 trials were ongoing at the end of 2003. Most Indian registration trials are of low cost and non-GCP quality. Companies developing a new chemical entity (NCE), conduct low cost non-GCP or paper GCP clinical trials to obtain data used for licensing their NCE. Costs of a GCP trial are invariably several times higher than for a non-GCP study. Although Qunitiles ventured into India, other major CRO like PPD, MDS Pharma, Ingenix, Parexel, ClinTrials and Kendle have stayed away.
SRL Specialty Ranbaxy Laboratory is the only central laboratory functioning in India and has filled a major need for GCP clinical study. For many GCP studies, central laboratories in Europe and USA are used.
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