The Medicines Price Paradox
Patients may be missing out on innovative therapies. After having worked for many years in the design and development of novel active ingredients, this is a difficult fact to accept, but a fact, nevertheless.
In the beginning of modern pharmaceutical industry, towards the end of the 19th century, practitioners made decisions regarding the use of drugs, and cost was never a concern. The situation in the 21st century is completely different. Right now, there is an enormous pressure to reduce the healthcare expenditure. There is not a single reason why this change has taken place, but there are a couple of events that occurred in the second half of the 20th century that probably mark an inflexion point in this tendency: on the one hand the thalidomide disaster, which led to tighter regulatory controls, which subsequently led to higher attrition rates, longer timelines and significant increase of development costs. On the other hand, the introduction of legislation to set a fixed period of exclusivity, which led to the appearance of generic companies and the need for pharmaceutical companies to recover part of their investment and make their profit quicker.
Both these events have contributed to the increasing costs of new medicines, making them inaccessible to many patients around the world. So, while the cost of drug development has increased owing to tighter regulatory controls and higher attrition rates, there is pressure from insurers and medicine agencies to bring down the price of new medicines. This is what I call the Medicines Price Paradox. This situation is not sustainable in the long term and because of this, innovation is likely to suffer. As industry professionals in the healthcare industry, we have the moral obligation to do whatever we can to reduce the cost of developing new therapies.
The Cost of Failure
The cost of development of new candidate drugs is estimated to be ~$2.6 billion dollars per approved new drug. This takes into consideration not only the increase in development times derived from stricter regulatory and safety controls, but also the cost of failure. Out of the drug candidates entering clinical development only ~10% is likely to reach commercial authorization. In a very simple calculation, if we can reduce the failure rate from 90% to 80%, we would double the success rate and half the cost per new approval. This is a massive saving opportunity!
The high attrition rate is often due to their suboptimal physicochemical and biopharmaceutical attributes, poor safety profile and poor efficacy. In this scenario, the industry can benefit enormously form the collaborative efforts of the discovery and development teams working together. The knowledge acquired during the development phase feeds directly back into the design of the new chemical entities (NCEs) more apt to face the preclinical and clinical development challenges, thus shortening the timelines and increasing the chances of success, and consequently, reducing the overall cost of development.
In this context, an assessment of the developability of a compound, which typically involves a thorough physicochemical characterization, the selection of the solid form displaying the best properties for development (depending on the intended application) an assessment of the potential challenges that the compound may face during early development and the preparation of robust formulations for PK, tox and efficacy screens in preclinical animal species. This data package will allow for the appropriate selection of candidates with a greater chance of success. Alternatively, it will provide us with enough evidence to de-prioritize or completely bring a project to a halt, which otherwise would be unlikely to survive the stringent selection process, before we enter the significantly more expensive clinical phases of development. Either way, a good developability assessment program should lead to reduction in cash invested in the new drug candidates.
Developability Assessment Program
A key factor for a successful Developability Assessment Program (DAP) is the existence of a strong cross-functional collaboration between medicinal chemists, biologists, pharmacologists, formulation teams and clinicians. In some organizations in which some of these functions are not present, there are well positioned contract service companies that can take in the lacking functions and act as strategic partners. This is often an efficient way to incorporate these functions into your own organization, without the need to increase overheads or the additional costs of infrastructure and headcount.
There are typically two strategies that the DAP can use. On the one hand, the appropriate physicochemical attributes are built into the design of the NCE (e.g. pKa, logP/D, solubility, stability, etc.), solid forms susceptible of being developed for the intended application for which these were designed are identified (e.g. salts, cocrystals, polymorph, etc.) or the optimal delivery strategy is chosen (e.g. route of administration and formulation principles). Alternatively, strategies aimed at increasing solubility and bioavailability (for parenteral and oral delivery), modifying the release of the drug (i.e. immediate or slow release, to improve therapeutic index) or target drug delivery (local, site of infection, etc.) are implemented. If both strategies lead to unsatisfactory results, it is probably wise to consider bringing the project to a halt. This is a great mechanism to mitigate risks and prioritize the development of candidate drugs with greater chances of success, before incurring in much higher expenditure.