A recent article on the above subject (Hindu July 7th, 2005) prompts me to put the issues raised in a broader perspective. While it is true that there are unscrupulous elements and practices prevailing in the clinical research field, which includes doctors, the pharmaceutical companies, the regulatory agencies and the healthcare establishments, by and large, clinical trials are by no means a doctored game, since they are carefully planned and designed research tools to establish efficacy and safety of drugs potentially useful for treatment of diseases in human beings and animals. Doctoring them has not only disastrous consequences on the patients, but also not in the interest of R&D based pharmaceutical companies. The negative impact of doctoring ultimately affects not only the company’s credibility, but also affects its business since it is a well-known paradigm, particularly in a sensitive segment like the healthcare industry, that ‘the only good business is ethical business’. According to the article, supported by a large number of anecdotal references including from prestigious authors and Editors of journals such as the New England Journal of Medicine, British Medical Journal and others, none of the parties involved which includes the Companies, the Clinicians, the prestigious Medical and Scientific Journals or even the reviewers who are peers in their own right are above board and are part of the nexus to promote commercial interests at all costs. That indeed is a very serious indictment on modern practices in drug discovery and development.

There are basically three levels of criticisms leveled against the current practices in drug discovery, development and marketing. First, that too many ‘Me-too drugs’ are developed and marketed with little or no real benefits over the available ones, primarily to exploit the market rather than for meeting true medical needs. Second, data at the pre-clinical and clinical phases of drug development are manipulated including of vital negative data to procure appropriate approvals from the Drug Control Agencies and impress the clinicians on their benefits vis-à-vis existing therapy. Third, adequate and unambiguous evidence of efficacy and safety is not garnered before launching a product, and consequently many disasters or near disasters occur in the market place, as in the case of Sulfonamide Elixir, Thalidomide, Benoxaprofen, Troglitazone, Rofecoxib and many others. Then there are a number of drugs on which the shadow of doubt of their safety persists even after years of use, such as Clioquinol, Phenformin, Lomotil, Nimesulide, Cisapride, Celecoxib etc. There are other criticisms, some of them valid, of off-label use of drugs for indications where their usefulness has not been established and exaggerated claims of additional indications for the drug by industry representatives during detailing to physicians based on questionable and ambiguous evidence.

As far as the “Me-Too” drugs are concerned, there have been outstanding improvements through this model of developing and screening analogs of the first break-through molecule. Newer generations of Beta blockers, Calcium Channel Blockers, ACE Inhibitors (all drugs for hypertension and cardiac related diseases), Sulphonyl Ureas, Biguanides, Glitazones and Glinides (All Anti-Diabetics), the Statins (Anti-hyper-lipidemics), H-2 Receptor Antagonists – Cimetidine Ranitidine, Famotidine etc (Anti-Ulcer Drugs), Proton Pump Inhibitors – Omeprazole, Lansoprazole, Pantoprazole etc (Anti-Ulcer drugs), Nitroimidazoles – Metronidazole, Tinidazole etc (Anti-Amoebic Drugs), Beta lactam, Macrolide and aminoglycoside antibiotics, quinolones (all anti-bacterials) are all excellent examples where molecular manipulation has resulted in drugs with much better pharmacological profiles, better safety and efficacy and selective and targeted action.

Data manipulation

Regarding manipulation of data at the pre-clinical and clinical stages of drug development, no enlightened company will dare to push a drug with questionable safety profile into the market, since resultant liability suits could land the company into bankruptcy and result in serious credibility and image problems. It is possible, certainly not justifiable, that some results which in the opinion of the sponsor are not significant are not highlighted during the promotional phase. More and more companies realising this lacuna in the present system have started bringing an additional degree of transparency by publishing clinical trial results through the electronic media. It is at the same time important that unwarranted panic is created among the public through such publications. For example, even now if one reads the package inserts of drugs, it will be obvious that enough frightening references are made to side effects and contra-indications which overall may not have much relevance to the usefulness of the drug or on its safety of efficacy.

Claims of better efficacy compared to earlier marketed drugs is a grey area at times and hence are sometimes exaggerated to gain marketing advantage. Over-enthusiastic medical representatives from the industry often times promote drugs for use in indications which have not been scientifically established. Similarly, physicians too dispense medicines for conditions for which the drugs have not been approved for use by the Regulatory Agencies, generally referred to as ‘off-label’ use of drugs. These practices are clearly unethical, even though in the long run if these claims are not sustainable in the market, they will neither advance therapeutic utility or sales.

The stringent regulatory standards prescribed by FDA and almost all other national agencies had their origin on the Kefauver-Harris Amendments to US FDA’s Drug Regulations in 1962 after a major global tragedy resulted from the use of the sedative, Thalidomide in the birth of over 10,000 malformed babies.

However, even with the best available knowledge base, the most stringent pre-clinical and clinical experimentation including using all known models for determining toxicological parameters, such as acute, sub-acute and chronic toxicity, teratogenicity, genotoxicity, mutagenicity & carcinogenic studies, absolute safety of a drug can never be guaranteed when introduced as treatment for large populations. The reasons are 1) most of the experimental animal screening models do not simulate human disease conditions and hence do not guarantee similar effects in humans 2) the metabolic and pharmacokinetic patterns which determine the fate of the drug are dissimilar in animals and human beings and sometimes even within human beings and 3) clinical results from limited population samples do not reflect the final outcomes when extended to large populations of patients with different genetic, ethnic and physical attributes, not to speak of varying life styles and the differing human psyche between people. Due to all these reasons, new drugs which are researched and results evaluated at various levels including by the leading experts in the field will still fail in the market with respect to their efficacy, safety or both. Modern approaches to drug discovery and development including the application of combinatorial libraries, high throughput screening, genomics or proteomics are unlikely to change the scenario of uncertainity which prevails even after years after the launch of a drug.

While the model currently used for drug discovery and development is by no means perfect and will never be, in the absence of a better model, there are very few options to guarantee better drugs. However the track record to date of the pharmaceutical industry in the discovery of new drugs has been impressive. While commercial considerations will always continue to be a major factor in the pursuit of drug discovery and development; they are never going to be the only or even the primary deciding factor while deploying research efforts for discovery, development and marketing of new drugs, since ultimately only better and safer drugs will survive in the market. What is needed is due diligence on the part of the companies, the Regulatory Agencies and the medical profession, a high degree of transparency while disclosing information on pre-clinical and clinical results and a commitment that the most stringent standards available for determining safety and efficacy of new drugs are followed not only during discovery and development but also post-marketing. What is required is to educate and enlighten all the stake-holders involved with healthcare of their responsibility to the Society whose welfare and good will they are dependent on for their own survival and growth.

(The author is a senior research scientist and industry observer.) email: mdnair@vsnl.com