The Problem: The pharmaceutical industry develops drugs to cure and treat diseases. R&D productivity has gone down in the last decades, while R&D spending has increased. The number of new drugs brought to market per year has stayed constant at best. Pharmaceutical companies need to change the ways in which they discover, develop, test and market new drugs. What are the ‘game changing’ innovations that the pharma industry needs to adopt in order to continue delivering therapies that improve lives?
Introduction to the Problem
The pharma industry is combing through the obvious sources of solutions to find the one game changing innovation that will turn the industry around. Currently it is focused on incremental improvements such as new technologies for drug discovery such as new in-silico modeling approaches, new biological sources or screens. Will there be one ‘next big thing’ technology that enables discovery of better drug candidates, molecular targets or biomarkers? Can clinical trials be revamped to provide faster and more cost effective results?
The industry has been down the technology road long enough to know there will not be a single magic answer for drug discovery. We passed through combinatorial chemistry, microarrays, the Human Genome Project, and most recently the Next Generation Sequencing phase. Each one is a tool that helps understand and characterize disease states and drug candidates, but the vast amount of treasure expended on new technologies has not led to higher numbers of approved drugs. What is missing?
For decades, the pharma industry has attempted to drive down the cost of drug failure in time and money. It has understood that a failure at Step One is far faster and cheaper than failure of a Phase III clinical trial. Each company closely monitors how many candidates fail at what step, and attempts to implement strategies for identifying the failures faster. Why is it getting more difficult?
• Rising Medical Expectations. New drugs must be more efficacious than available (and generic) drugs to justify a higher cost to third party payers. The end result must lower the cost of treating the patient, including lower mortality and shorter hospital stays. The introduction of statins decreased both morbidity and mortality to the point where greater reductions are not likely. Statins clearly improved the health of unhealthy populations. To have an even greater effect, therapies must improve the health of normal (assumed healthy) populations – a significantly higher barrier created by the industry’s own past success.
• Increasing Regulatory Burden. The FDA is caught in a bind: Prevent medical disasters without delaying medical advances, all on a shrinking budget. Patient privacy concerns have created the need for new security safeguards.
• Rising Financial Expectations. In order to accelerate profits, drugs must be more successful than previous offerings. This has led to the Blockbuster Drug concept. Reality is driving pharma towards personalized medicine, where each drug is efficacious for a smaller population. That in turn increases the number of required trials and decreases the potential reward per drug.
• New Technologies. In the 1990s the Human Genome Project, combinatorial chemistry, and microarrays aimed to revolutionize medicine. As a result, crucial medical insights were made but this did not translate to lower drug development costs. Today, novel technologies include digital PCR and Next Generation Sequencing. These too will speed basic discovery and enable new approaches. Yet they too will not lower the cost of drug development to any significant extent. The greatest directly medical technology developments appear in the bioengineering field, improving the healthcare options available but not helping the pharma industry directly.
The industry is aware of game-changing technologies such as PCR, yet the entire biomedical industry is aware of how its use was limited by high royalties and other barriers. In a Forbes article, Roche’s drug approval rate is in the middle of the pack. Clearly, owning the rights to PCR did not provide the game-changing advantage. What went wrong?
• The Druggable Target. The concept and description of the druggable target has been in use by the pharma industry for decades, and examines the characteristics of biomedical targets against which drugs, whether small molecules or larger biomolecules, may be directed. It is recognized that a single target at a time is unlikely to cure diseases, especially not multigenic ones.
• Solved Problems Become Unsolved. The antibiotic Wonder Drugs introduced since 1945 increased worldwide life expectancy by over 20 years. Today, however, bacteria including TB, MRSA and gonorrhea have mutated into drug-resistant forms that reduce or eliminate known treatment options.
The Solution does not currently exist, and may best be described as the application of statistical design of experiments (DOE) to drug development and patient care. While the computational tools and concepts of DOE are not new, and in fact are used within the pharma industry for limited purposes, these are not applied to cells, organs, and patients due to a series of barriers that must be overcome.
DOE, or Experimental Design, consists of a family of design types including full factorial, Plackett-Burman, Taguchi, Box-Behnken, Central Composite Designs (CCD), and many others. The art of DOE as currently practiced includes determining the appropriateness of analysis strategies. The proposed Solution includes development of new analysis strategies that may better serve applications to living organisms, as well as outlines of changes needed in the drug discovery world to make such DOE applications feasible and desired – both medically and financially.
The Solution is not likely to be or use a single game-changing technology, but a game-changing approach by the pharma industry. This approach will use newly developed tools, each of which may be (temporarily) claimed as the ‘game-changer’ for a while. There are changes that can be instituted by the pharma industry itself, either in existing companies or in new companies. Other changes must come from outside, whether from government agencies or academia. Below are some important components of the overall Solution.
• Adapt and Implement DOE Methods to Drug Discovery. The goal is attempting to solve a global medical problem rather than a single problem. That is, ‘global’ in the sense of a complete living entity rather than an allegedly isolated biological subsystem. The aerospace industry does not test thousands of airplanes for each component, yet we entrust our lives to the results. Aerospace recognizes that complex machinery consists of interacting components that must be simultaneously optimized. The same is true of the complex human and its health maintenance. The concept may be extended to initial screening methods for medicinal chemistry candidate compounds. It is understood that current DOE methods are effective in cases where input can be controlled and quantitated. This includes temperature, pH, salt concentrations, and other such factors. The innovation required by the Solution will be adaptation of mathematical concepts to biological systems that may be less amenable to quantitation – for practical or ethical reasons.
• Implementation is best done by a central entity that acquires drug candidates from individual pharma companies. This may be possible in an academic setting. The Solution involves the use of multiple interacting components, very likely manufactured by multiple vendors that compete in the marketplace. Implementation of the Solution may require development of situations under which the disparate drugs can be accessed reliably.
• Include Generics. Currently, pharma seeks only therapies that are or can be patent protected. Therapies for such infections as HIV do include cocktails, but there is currently a strong dis-incentive to consider combination of any new drug with older, particularly generic, drugs. Clinical trials do include currently standard therapies, and require the new therapy demonstrate an added benefit above that Standard of Care. Yet drug development is not focused on inclusion of multiple drugs starting at initial screening.
• Re-Evaluate Active Ingredient Purification. Traditional medicines are seen as a refuge of quackery and fraud, often rightly so. Yet some effective ingredients from natural products have been isolated and used. Others appear to lose potency when purified. In how many cases is the desired medical benefit a result of interacting components? There are at least two examples of natural products known in India for thousands of years – yet patented by entities in the West.
The University of Mississippi patented the use of turmeric for wound healing until India pointed out prior art that stretches back to ancient Vedic texts (see http://www1.american.edu/ted/turmeric.htm). Also in the 1990s WR Grace patented a biopesticide made from the neem tree (see http://www.actionbioscience.org/genomic/crg.html and http://news.bbc.co.uk/2/hi/science/nature/745028.stm).
In the case of turmeric, the active ingredient (Curcumin) was isolated yet did not retain its expected efficacy. Re-introduction of the removed (and assumed inactive) ingredients increased potency, which indicated the presence of component interactions that lie at the heart of the DOE analysis methods.
• Cure the Disease, Don’t Treat the Patient. A cynical view of the pharmaceutical industry states that Pharma does not seek to cure, since a cure would be taken only a small number of times. Instead, pharma seeks to invent new medicines for heart disease, cancer, and diabetes. The goal is to ‘manage’ a patient with repeated doses over long periods of time if not the patient’s entire life. At some point the industry will have optimized treatment of symptoms without treating the cause, even of multigenic diseases and conditions. This is avoided not only because of the financial incentive to provide a long-term treatment rather than a one-shot cure. A single cure is out of the realm of medical understanding for many conditions. Yet there is currently a financial dis-incentive to develop cures that involve a single or small number of inexpensive dosings.
• Generalize Target Approaches. Many diseases are becoming resistant to antibiotics. The industry is financially dis-incentivized from seeking more efficacious replacements. Yet even if programs cranked out succeeding generations of antibiotics, would that simply trigger a never-ending arms race? Bacterial infections may need treatments akin to cocktail treatments of HIV. An adaptation of DOE principles may determine the optimal drug cocktail components and proportions. This may be particularly effective in chemotherapy applications.
• Reconsider Discarded Approaches. It has already been suggested by others that the dwindling utility of antibiotics be replaced with an approach demonstrated in 1915: therapeutic use of bacteriophages. This is surely not the only instance of a once promising approach set aside for a later time. The main barrier may be lack of patent protection, and is not a generalized approach. The point emphasized here is the openness to using partial solutions from the past as elements of more efficacious new solutions.
• Alter the IP Landscape. Currently the pharma industry considers only novel drugs that can be patent protected. Many of the promising approaches, including examples mentioned above, are overlooked since there will be no patent protection for any expended effort. Although the pharma industry cannot directly fix this, it can advocate a restructured arrangement with the Patent Office and other relevant agencies.
• Active Pursuit of Side Effects. Drugs may fail in clinical trials or wait until market entry to display detrimental or even fatal side effects. A more global approach to the cellular, organ, and human patient level will attempt to balance the entire biological system and determine how maintain balance. Fundamentally, an application of DOE methods to medical issues seeks to see disease as in fact the underlying dis-ease of the patient. A successful application of DOE will end the current Whack-a-Mole attempt by medicine to solve one problem – while possibly causing another to pop up elsewhere as a side effect.
The Solution includes development of analysis methods capable of handling complex input variables and multifaceted outputs that can model the complex interacting components of a living organism. The Solution must be accompanied by changes in the drug development environment that allow incentives for inclusion of novel and legacy drugs as long as the desired medical and financial outcomes can be achieved. These changes assume continued development of novel technologies that will be included in drug development, such as Next Generation Sequencing (NGS).
It is not clear at this time if the Solution will be a development of currently available statistical analysis tools far beyond those now in use, or if DOE serves chiefly as an analogy for completely different methods applicable to living organisms.
There are many books and computer programs for DOE, some far more complex (and expensive) than others. One example for an elementary text is:
Understanding Industrial Designed Experiments, Third Edition, SR Schmidt and RG Launsby. Air Academy Press, Colorado Springs, CO, 1992.
The authors also offer software including DOE Pro XL, which provides a macro for use with Microsoft Excel.
At the other extreme are the SAS Institute and others that provide high-powered statistical analyses mainly aimed at clinical research data and clinical trials assessments.