Ever since the advent of modern chemotherapy, until recently, attempts at new drug discovery were based on a process of trial and error, screening large number of   organic molecules against  animal models deemed to simulate  human disease conditions. While most of the drugs available to the patients emanated from such an approach, it had increasingly become evident  that such an approach was very unlikely to lead to useful medicines and in addition would be extremely cost-ineffective.

With better understanding of the disease processes and of vectors which transmit diseases,  biochemical approaches were developed primarily working with enzyme inhibitors which worked on blocking essential disease causing pathways. Considering the variety of alternate pathways available, these approaches also had their own limitations. With the  elucidation of the structure of the vital element of life, the DNA and its role in life’s processes and the deciphering of the human genome, the importance of functional genes and the proteins they express as vital links to understanding health and diseases was realised.  This is particularly so in the case of diseases which have a genetic aetiology. Using the science of genomics and  proteomics, efforts are now directed to utilise the new knowledge and tools to discover and develop drugs to meet the challenges of treating individual patients rather than diseases or their symptoms.

Drug discovery  at cross roads
New drugs, ever since the advent of chemotherapy, have been discovered from two major sources- synthetic chemicals and natural products including plants, animals and microbes. The development of recombinant DNA technology as a source for a variety of new biotechnology based products has opened up yet another promising source of new drugs. While these sources are still the major ones, there has been a paradigm shift in the  ways candidate products are identified and developed through pre-clinical and clinical studies.

Drug discovery programmes of the 50’s to 70’s started in the medicinal chemistry laboratories where a large number of new chemical entities were synthesised, isolated from natural products or produced by the fermentation process and screened for their biological activity in various iv-vitro (where relevant) and in-vivo animal models. Even though the selection of chemical entities was in some cases based on established drugs or leads from traditional use, in most cases all new molecules synthesised by chemists were routinely subjected to random screening against  available models.

During the early days of research, the approach practiced by all the major R&D-based companies  for almost three to four decades was to a large extent a numbers game with a heavy element of chance and luck  contributing to success. Serendipitous discoveries also played a role. There was very little rationale  for the  selection of a chemical class, a plant, or a micro-organism at the beginning of the programme,  even though once a lead molecule which may not be a candidate for development was identified,  techniques of Quantitative Structure Activity Relationships (QSAR) studies were deployed with successful outcomes.

Rational  approaches to  drug  discovery
The compulsions to rationalise drug discovery approaches stemmed from the following imperatives.

• Better  drugs with a higher therapeutic ratio (efficacy to safety)  and therapeutic rationale were needed for most disease conditions
• the time required for the discovery and development of new drugs needed to be  shortened
• overall   costs   needed   to   be reduced to contain escalating costs on drugs as a component of healthcare costs and  
• companies had to have products with unique properties to gain competitive advantages and market share. While all these objectives are highly desirable, the fact remains that the costs of discovery and development of new drugs are ever escalating and success rates dwindling to unacceptable levels. Overall benefits to patients have also not increased in any substantial way with many diseases still remaining unconquered. High costs of drugs have made them unaffordable to the majority of world’s population.

End of blockbuster era?
During the last five decades, leading R&D-based pharmaceutical  companies had targeted bulk of their research efforts at markets which  had the potential to achieve  blockbuster status (annual sale of a single brand > $ 1 billion). That means that research efforts were concentrated in areas which had  high market needs and the largest number of patients who could afford the latest version of drugs. With the large number of failures  during the development phase as well as post – marketing, large number of patent expiries, increasing popularity of generic drugs substituting patented products and consequent loss of revenues to the innovating companies, there is a trend to  move away from strategies to discover blockbusters to developing larger number of niche products catering to the needs of fewer patients. In other words the era of personalised medicine is emerging.

The most recent  approaches  to new drug discovery, including the use of genomics and proteomics  are all leading to personalised medicines useful for meeting the genetic deficiencies and medical needs which are highly individualised in terms of medical conditions and needs. Since the ‘OMICS’ model which relies on genomics and proteomics will lead to better, more specific, effective and safer drugs, drug research efforts  by the large pharmaceutical  companies are moving from the blockbuster model to the personalised medicine model.

Personalised medicines
It is being increasingly realised that  drugs which have been used in therapy and continue to be used  act differently in different individuals ranging from varying degrees of effectiveness to being even totally ineffective in certain population types.  Such variations in response to drugs are attributed to gene variability and to a lesser extent on life style and environment. In other words the expectation that  a   drug which has been validated for activity in animal models and have undergone clinical trials with favourable positive outcomes (in limited patient populations) will be effective for all patients having the same disease with perhaps multiple aetiology or intensity has turned to be a myth. In drug discovery, the concept of ‘one size fits all’  a premise which has been followed over decades is now realised as invalid. While prescribing a drug to a patient, it is essential  that the patient gets the right & effective drug at the right time and  in the right dosage so that optimal results are  ensured . Subjecting patients to treatment with a drug which is ineffective has several negative connotations. Apart from not benefiting from the use of the drug, the patient also will be subjected to unwanted side effects in addition to the economic burden that therapy entails without any benefit.  Already a number of cancer drugs have  been shown to be beneficial only for patients with well defined pharmacogenetic features. For example in breast tumours only those tumours which over express HER 2 associated with a bad prognosis responds to Trastuzumab. It is now standard practice to carry out some pharmacogenomics studies before starting treatment with many monoclonal based oncology products  to establish the usefulness of the drug for the patient concerned. There is now evidence that  even many common drugs which have been used across populations are not effective to large numbers of patients.

The National Institutes of Health and FDA, U.S.A together are drawing up detailed guidelines based on a common vision to ensure that the patients who are treated with a drug  belong to the sub type for whom the drug is effective. In order to do that, it is essential to identify the genetic markers which have most clinical significance and correlate the genetic make-up of the patient  with drug response. Already these agencies are working on  developing a more integrated pathway that connects therapeutic targets with therapeutic utility of the drug. It is expected that  in the coming days such information will have to be provided to the regulatory agencies when submitting New Drug Applications (NDAs).

Future attempts are to develop new personalised therapies either through development of targeted drugs or through correlation with relevant biomarkers and thereby even salvage abandoned or failed drugs and drug candidates. This involves developing standards and evidence needed to use genetic information in drug discovery and development to gain early knowledge as to which population types the drug will be effective in.  From a practical point of view, accurate diagnostic tests to identify patient populations who  are likely to benefit from the drug, need to be developed. In  future, more and more   drugs will be prescribed to the patient only after establishing the benefit that will accrue   to that patient, based on pharmaco-diagnostic testing. Such personalised treatments  will be based on carrying out diagnostic tests  using biomarkers before prescribing  for therapeutic use.

The question to be answered is whether these new developments  in the area of personalised medicines will make medical interventions using pharmaceuticals more complex, cumbersome and  expensive, even if they would result in  better treatment outcomes . How can such diagnostic tests be developed which are simple, fast and inexpensive for the large number of diseases? A wider , but important question is whether the shift to personalised medicines in fact will further escalate  costs of healthcare and make  drugs less accessible and affordable to the majority of the world’s population living in developing countries.