Birth- "How is a drug born and how long does it take?"

In the hands of the doctor the new drug must be a beneficial tool in terms of efficacy, safety and usefulness.
The long path leading from the initial idea to the availability of the drug to the doctor seldom takes less than 10-15 years and almost always involves assessment of the properties of many thousands of chemical compounds, the selection of a more limited number of these, the choice of few final candidates for clinical assessment, and finally the identification of the new drug.

Research - "The need for a drug"

The original idea must derive from a medical need. Traditionally the drug used to be identified taking inspiration from natural products or existing drugs which were however of low efficacy or safety; or observing the side effects of other drugs; or finally through serendipity.
This procedure, besides being rather haphazard and not very selective in terms of the biological target, generally takes a very long time (4-5 years or more) to produce a compound which will then have to be optimised for efficacy e safety. High investments now allow Menarini Ricerche to use the most recent techniques of automation and miniaturisation for assaying the biological activity of the test compounds.

The latter in turn are obtained in numbers which are several orders of greatness higher than in the past, with the use of combinatorial chemistry or parallel synthesis. Thus tens or hundreds of thousands of compounds are assayed over few months for each selected biological target. Our Research however favours a rationalised selection of the compounds based on the features of the target biolgical system, rather than the "brute force" approach, which consists of indiscriminately assaying what may be millions of compounds.

An important role is in this case played by biotechnologies. This stage of basic research lasts about 2-3 years and takes up about 10% of the total investment.

Biotechnologies

The biotechnology department applies methods of DNA chemistry to material of genetic origin, and by means of cell engineering techniques transfers these products into host cells. These cells will thus produce the required proteins, which can have therapeutic or research applications.The proteins produced for therapeutic purposes pass through processes of fermentation, isolation and purification in order to obtain a drug.

The research applications allow Research and Development to increase their efficacy considerably. In Research, for example, engineered receptors or enzymes allow sure identification of the mechanism of action of a new substance while reducing the number of experimental animals involved. Moreover they allow selection right from the start of potential drugs endowed with high selectivity. In Development considerable advantages may be obtained in increasing the scale of synthesis of the products.

Preclinical Development - "Can it become a drug?"

When one or more chemical compounds deriving from the base research phase have shown significant biological activity on the target considered, a series of chemical/biological trials ensues to determine the selectivity of action (hence reduction of side effects), bioavailability, toxicity*, metabolic behaviour as well as the possibility of synthesising it on an adequate scale and the development of suitable pharmaceutical forms.

Before verifying the in vivo behaviour of a substance on man in the subsequent phase of Clinical Development, it is indispensable to assess the behaviour of the substance in the animal, according to international norms and in compliance with clearly-defined, strict ethical criteria. The Preclinical Development phase requires another 2-3 years and takes up 30% of the total investment.

*Toxicity
The aspects of toxicity which are assessed for a drug are related to the effects immediately following its administration ("acute toxicity"), and those originating from a prolonged use ("chronic toxicity"). Genotoxic, teratogenic, carcinogeni effects must also be assessed.

Clinical Development - "Confirmation: it will be a good drug"

If the outcome of the assessments carried out in the previous phase of Preclinical Development is positive, the efficacy and safety of the candidate drug must be demonstrated in humans.
The Clinical Development phase is the longest and costliest of the whole experimental process (it takes up 60% of the total investment by itself). It is conducted in three phases according to strict laws and with the assent and control of the Health Authorities, using approved trial protocols.
In Stage I, which generally lasts about a year, with the administration to a small number of healthy volunteers it is possible to determine safety, metabolic effects and optimum dose.

In the context of Menarini research, a current example may be found in the antitumoral agent SABARUBICIN, which will be tested in this stage in various types of tumour such as ovary carcinoma, non-small cell lung tumour, sarcoma, gastric carcinoma, prostate carcinoma, small-cell lung tumour and breast tumour.
During Stage II, lasting from 6 months to 2 years, the substance will be administered to a suitable number of volunteers affected with the pathology for which the drug will be proposed. Thus the most effective and at the same time best-tolerated dose will be identified. Menarini has for example a thrombolytic agent, Amediplase, at this stage.
It is currently being assessed in post heart-attack patients with the aim of discovering its capacity for reopening the heart arteries which have been closed by a thrombus (the cause of the heart attack).

In Stage III efficacy, therapeutic benefits and less common side effectsare assessed significantly on a large patient population. The results of the clinical trials are examined by experts who evaluate them against strict clinical criteria to be able to pronounce whether the drug is "effective and safe". This stage lasts at least 2-3 years.

Regulatory - "I guarantee that it is a safe, effective drug"

When the therapeutically innovative drug has been identified, the next step is its registration. In this stage the name by which the drug will be identified by doctor and patient is assigned and inserted into the lists of available medicinal products.
During these administrative procedures the local and international Health Authorities verify the good quality of the trials conducted and certify that the new drug can be marketed. The body of clinical and preclinical information which will serve as a guide to the use of the drug are recorded, in agreement with the Health Authorities , on the technical data sheet of the product, whose content is summarised and simplified in the information leaflet (Patient Package Insert) which accompanies the drug.

The research and development of a drug thus constitute a process which runs a high risk of failure and is long and costly.
Only one synthesised molecule out of 10,000 succeeds in reaching the Clinical Development stage, and only one out of 10 manages to pass all the clinical development stages and reach the patient. At best, 9 years will have passed from the creation to the marketing of the drug, with about 500 billion Italian Lira of costs; in the more difficult cases almost 13 years and almost 1000 billion Italian Lira.
Furthermore, the original structure is patented at the moment of its identification, so that at the moment of marketing only 7-11 years of patent coverage remain (though they can be prolonged for a maximum of another 5 years with a supplementary protection certificate) to get an economic return for the investments made.
Examples from Menarini research which have successfully completed this long course and are now marketed in all Europe are the analgesic Dexketoprofen and the anti-hypertensive agent Zofenopril, each of whose development took about 10 years.