For the global pharmaceutical industry, the year 2006 had very many special features. Every component of this life-line industrial sector, be it R&D, Manufacturing, Distribution, Marketing or Post-Marketing events had its own problems which affected all the major stake holders, the investors, the medical profession, national and international policy planners and most importantly the ultimate consumers, the patients. On the healthcare side, several new diseases surfaced particularly of bacterial and viral etiology in different parts of the World. Overall increase in life expectancy and increased emphasis on curtailing population growth through the use of contraceptives has led to changing demographic patterns with disproportionate increase of the ageing population in most societies. Managing the geriatric population and ensuring an acceptable quality of life for them has posed enormous challenges in most countries. The relentless pursuit for better medicaments continued, the main objective being to discover and develop more effective and safer medicines for diseases for which currently available drugs are unsuitable or unacceptable. Drugs and prophylactics for newly emerged diseases which if uncontrolled would reach epidemic proportions need to be discovered and developed expeditiously. For all these to be achieved it is essential that we understand the disease processes including their aetiology, role of vectors, transmission pathways and molecular pathways that impact on the progression of the disease. While attempts are being made to follow these approaches, they are yet to fructify into tangible solutions.
Nature of research on R&D
To ensure the launch of a new drug there are several distinct phases in the total developmental cascade. They include the discovery phase, the pre-clinical (in-vitro & in-vivo screening) phase, safety evaluation (toxicity and pharmacokinetics in animals) phase, entry into humans (for clinical evaluation of safety and efficacy), marketing of the drug after all regulatory approvals are obtained and continuous monitoring of the drug used by large populations in different countries for their efficacy and tolerability (post marketing surveillance). Ever since the advent of chemotherapy, which started the modern medicine revolution, the overall responsibility of carrying out all these activities rested with the R&D based pharmaceutical companies primarily based in USA, Western Europe and Japan. All the other countries whether developed or developing had only marginal contributions to make in these efforts.
The model of drug discovery used since the second half of last century needs a basic change if cost effective new drugs are to be discovered and developed for use by humans and animals. Currently available therapeutic products address issues related to symptoms of diseases and are largely palliative in character. In spite of all diligent care and scientific evaluation, followed by careful scrutiny by the most stringent Regulatory Control Agencies, many drugs fail when introduced for use in large populations. Serious side effects or even fatalities have occurred when drugs approved for human use based on limited and controlled clinical trials were extensively used by large populations. That is primarily because clinical trials necessarily have to be restricted to representative samples with respect to age groups, genders, ethnic backgrounds and time frames for evaluations.
Purely in terms of new drug approvals, 2006 was a relatively barren year with only 18 new drugs approved. During the previous 6 years, the average number of drugs approved per year was 26. Moreover most of these new drugs were me-too variations of existing drugs.
Pfizer and Merck had two each, the largest for any company. Of these Sutent (cancer) and Januvia (diabetes) could be considered major advances in medicine. The former attacks stomach and kidney tumours by choking blood supply to them and works in cases where patients are intolerant or resistant to the wonder drug Gleevec, primarily indicated for Chronic Myeloid Leukaemia. Januvia of Merck represents a new class of antidiabetic therapy which improves body's ability to lower blood sugar.
Costs of drug R&D
Considering that R&D expenditure in the US went up from $ 16 bio in 1993 to $ 40 bio in 2004 indicates that the cost per every new drug discovered and developed for the global markets has reached an all-time high of around $ 2 bio. Even assuming that a fair quantum of this amount is spent on initial promotional and marketing efforts, even then the expenditure on new drugs R&D is unaffordable even for the large MNCs. The worlds largest pharmaceutical company, Pfizer spends over $ 7 bio an year for this activity, equivalent to the turn-over of the Indian pharmaceutical industry catering to the needs of over a billion people.
Such escalating and unaffordable costs are unlikely to come down in the coming years. Apart from the very low innovation levels, even the drug approval process is getting to be more stringent and time consuming. To keep pace with such costs and ensure adequate returns on investments the top companies need to launch at least five new drugs every year. To recover such high costs, each drug launched need to have an annual turnover of at least $ 400 - 500 mio. Today these tops twenty research based companies on an average are launching not more than 2 drugs per year. Consequently Pharmaceutical companies are forced to include in their R&D portfolio only those therapeutic areas which has the potential sales of that order of magnitude. Diseases of the poor countries do not fall under such a category and therefore from purely economic considerations will not be targeted for drug discovery efforts.
The withdrawal of the blockbuster drug Vioxx by Merck based on reports of serious risks on the cardiovascular system and increasing shadows on many other major drugs have raised serious criticism of the FDA's standards of safety evaluation of new drugs. There is every chance that henceforth there will be further delays in drug approvals resulting in further escalation of costs. One days delay for the launch of a blockbuster drug can cost a company as much as $ 2 million in addition to the social costs of the drugs not being available early to the needy patients.
The large number of drugs going off patents during the next three years have added to the woes of the R&D based Pharmaceutical industry. The drug Lipitor which had sales of $ 13 billion and contributed 40% of Pfizer's profits in 2005, is losing market share even before patents run out in many countries.
Historically, drug discovery research has relied on identification of a candidate molecule from a synthetic or natural product source, establishing its pharmacological activity through available in-vitro and in-vivo screening models for the disease and their development through a long cascade of pre-clinical and clinical evaluation. While looking for new chemical entities, the current synthetic approaches offer chemical libraries with very little diversity and in addition have poor structure activity correlation with respect to their pharmacokinetic parameters such as absorption, distribution, metabolism and excretion (ADME) patterns. The in-vitro results cannot be extrapolated routinely to in-vivo activity once again due to the differential nature of animal species, vis-à-vis in-vitro systems. Even in in-vivo screening, many of the animal models do not truly simulate the disease condition or the way it progresses in humans. The recent approaches of use of molecular drug targets are also deficient since most of them have not been validated and in turn their relevance to the disease model has not been established. One analysis of the reasons for drug candidates' failures point out that over half of the drugs which pass the rigorous pre-clinical screening fail later due to their poor pharmacokinetic characteristics, which include solubility and ADME parameters. Around 30 % end up having unacceptable toxicity profiles in animal studies and Adverse Drug Reactions (ADRs) when introduced for human use.
The case of diabetes
Let us take the case of just one disease for discussion on developments in 2006. Among all the diseases which afflict mankind, apart from the several infectious diseases of bacterial and viral origin , one disease which influences the incidence of a whole lot of other diseases is Diabetes Mellitus. The impact of this disease on a variety of tissues and organs of the human body and the overall poor prognosis from conditions of debilities affecting the heart, liver, kidney, eyes and the peripheral and central nervous system are well-known, but not well understood. Its relevance to India has also been emphasized since the much 'cliched' statement that India is indeed the 'Diabetic Capital' of the World with its > 20 mio diagnosed diabetic patients and perhaps an equal number of undiagnosed ones has gained currency the world over. Another unique feature of the Indian diabetic scene is the emergence of MODY (Maturity Onset Diabetes in the Young) at a rate faster than in any other part of the World. The number of asymptomatic cases with Impaired Glucose Tolerance (IGT), a fair number of whom will progress to full blown diabetes is also a matter of concern.
It is therefore interesting to look at the developments in 2006 in this therapeutic area to understand the approaches followed by many of the leading research groups to tackle this disease and evolve both preventive and therapeutic strategies for the future.
It is obvious that for Maturity Onset Diabetes Mellitus, early detection and slowing down the progression of the disease through appropriate diet and adequate exercise has proved to be an efficient approach and is highly recommended.
However important this approach is, it cannot by any means minimise the importance of therapeutic interventions. The overall objective of any anti-diabetic treatment is the reduction in blood glucose levels as well as reduction in the levels of glycosylated haemoglobin below 7. These are achieved by the use of insulin through subcutaneous administration in titrated doses as well as through the use of one or more of the pletthora of oral hypoglycaemic agent available today. While use of insulin was the ultimate gold standard for glycemic control ever since its discovery by Banting and Best at McGill University in Canada in 1921, even after 85 years, the basic handicap of having to use Insulin as an injectable still remains. That is, if the new inhaled insulin (Exubera) recently approved by US FDA does'nt turn out to be the preferred dosage form. That this product got approved through a fast track route five months after the FDA's Endocrinological and Metabolic Drugs Advisory Committee recommended it, is probably an indication of its perceived importance in the management of diabetes.
At best, it may be better than short acting insulins, but at its worst variations in absorption from the pulmonary tissue, pulmonary toxicity profiles and of course costs of treatment could be matters of concern. Based on a clinical study on 2500 patients, it was observed that peak levels were reached in 49 minutes after administration, compared to 105 minutes for short acting insulin. Clinical studies on buccal and nasal as well as oral insulins continue.
In October 2006, FDA approved sitagliptin (Januvia), the first dipeptidyl peptidase (DDP-4) inhibitor. The drug was investigated in > 2700 patients and is recommended for use alone or in combination with metformin or a PPAR agonist such as pioglitazone or rosiglitazone.
While there was much promise of islet cell transplants, only 5 out of the 36 patients who received the transplants two years ago were free from the need for external insulin in Type 1 diabetic patients. However majority of these patients maintained lower levels of HbA1c.
In phase 2 studies, the drug liraglutide an injectable drug candidate reduced HbA1c levels and resulted in significant weight loss, two important requirements for any novel anti-diabetic therapy. Liraglutide is an analog of glucagon like peptide - 1 (GLP-1), a hormone released from the GI tract on ingestion of food.
All in all like in most therapeutic areas, progress in R&D in the area of diabetes in 2006 has been marginal and the major issue of how to control and slow down the development of Syndrome X affecting many tissues and organs of the human body in chronic Diabetic patients still remain unanswered.
In India while all the major research institutions have programmes for the discovery and development of new therapeutic agents for diabetes and there have been a few success stories leading up to advanced phases of clinical trials, most of them are analogs of existing drug molecules. At the same time the possibility of finding and developing new anti diabetic agents which will answer some of the unanswered questions by the Indian research groups cannot be totally ruled out.
(The author is a senior research scientist and industry observer. He can be reached at mdnair@vsnl.com)