Throughout my three plus decades working in pharmaceutical research and development, the industry followed a standard and relatively reliable formula for success:
Focus on developing blockbuster therapeutics and then use the profits from those major wins to finance the search for the next big hit. This approach has been responsible for scores of breakthrough drugs benefiting millions of patients.
But today that approach is outdated, as therapies that work well for most people become more elusive and unmet patient needs become more apparent.
Our collective focus on identifying the most effective medicines for the majority of patients, which can potentially yield the blockbuster drugs that have sustained past innovation, does not take into account our growing understanding of human biology and the nature and progression of disease. Through a combination of new insights into genomic and phenomic sciences, made available by high-powered analytical and informatics technologies that are advancing just as rapidly, we are developing a more nuanced view of how and why patients with the same disease may respond differently to the same treatments.
We now know the success of a therapeutic is determined by far more than the molecular make-up of the drug itself. It is the interaction of several factors, including a patient’s genetic composition, his or her proteomic, metabolomic and environmental status, the specific pathology of the disease and the delivery mechanism for the medication.
These complexities are not well accounted for in much of our traditional drug discovery and development processes. It is thus no surprise that 70% of therapeutics fail in Phase III clinical trials. And it is even less surprising perhaps that a significant number of patients are not seeing the outcomes they want – even when approved, prescribed drugs have demonstrated effectiveness in controlled settings.
My role with Waters has provided me an opportunity to take a broader view of research and development and speak with many of our customers and partners in industry, academia and the contract research communities. I increasingly see more targeted and personalised approaches to the discovery, development and evaluation of new therapies. It is a shift that will benefit drug developers and the patients their work aims to serve.
More specificity, from discovery to delivery
The shift toward a more efficient and targeted approach to therapeutics – one that seeks to create more consistently effective products for a smaller but more appropriate group of patients – is taking place throughout the drug discovery and development enterprise.
In discovery, the changes that are taking place are not large in the source content for new drugs, but in the way we analyse them to identify candidate therapies. Pharmaceutical organisations are looking back at synthetic chemical libraries and taking a fresh look at a whole host of natural products. Thought leaders with unique insights into the biomarker activity of synthetic, plant and marine substances are working together, leveraging developments in mass spectrometry and informatics technologies.
The roles for high-throughput chemical synthesis, medicinal chemistry, process chemistry in drug discovery are evolving as we gain ability to control specifications and critical quality attributes. Likewise as we are seeing the success of next-generation biologics, organisations are also applying new understandings to the interactions of small and large molecule classes in therapeutic opportunities such as antibodydrug conjugates.
Meanwhile, in development, where I have spent a majority of my career, we are seeing a growing emphasis on efficiency, productivity and specificity. The average time from drug discovery to completed development is 12 years, which puts extra pressure on companies to produce blockbuster therapies and capitalise on their patents. It also keeps patients waiting long periods for solutions they urgently need.
Researchers are working to move candidate therapies more quickly from preclinical to clinical research. Advances in analytical chemistry are allowing scientists to evaluate and produce more quickly and precisely the molecules needed for clinical studies. This work is aided by in vitro studies and a better understanding of systems biology and the factors that may trigger or accelerate disease in certain patients.
There is progress to be made as you go deeper into development. Focusing on the right-first-time design of formulations can lead to quicker commercialisation of products. The shift to Quality by Design will lead to better understood and more robust processes.
There are also imminent changes to the manufacturing of drugs. Pharmaceutical processing in manufacturing is synonymous with batch processing in which each unit dosage form is identified by a unique batch. This has been the way of the pharmaceutical industry for many years, but the industry is now following the approach taken by petrochemical, chemical, polymer and food manufacturers that have moved to continuous processing technologies driven mainly by cost and quality considerations. Much of our success in employing this new manufacturing process will depend on the delivery of new technologies that allow analysis in real time.
Scaling the Phase III barrier
The process for testing and validating new drugs is also quickly evolving, and that is good news given our low success rate historically. There are countless promising drugs that have advanced to Phase III clinical trials, but have failed to demonstrate effectiveness in large groups of people. In some cases, the molecule was not effective enough or had too many side-effects to warrant approval.
However, there are a number of instances where drugs have been tested in ‘average patients’, when they are likely effective only for patients with particular characteristics or a specific subset of a given disease. And that is a problem we can fix through better trial design. If drug companies focus on smaller populations based on phenotypically augmented data, the chances for clinical success will be greater. Adaptive trials also can help investigators and their clinical partners make smarter real-time adjustments in medication dosing and delivery, based on how patients are responding.
The growing development of companion diagnostics is helping this effort. Coupled with more-informed patient selection for trial participation, our ability to predict who might benefit from a therapy is growing. This also means there is promise for revisiting some therapies that previously failed and examine them in a more focused and targeted way.
Our more complex understanding of the interaction between diseases and therapeutics has put us in position for a renaissance in drug discovery and development. The key is to eschew the onesize- fits-all strategy that harms both consumers and the industry and find more targeted, effective solutions for smaller groups of patients.