Providers of personalized medicine often describe their service as “stratified” or “precision” medicine because they claim to customize and target client care based on an individual’s genetic make-up. The term ‘P4 medicine’, coined by Leroy Hood, MD, PhD, is gaining traction to characterize a personalized, predictive, preventative and participatory method of treatment. A study published recently by Misu et al. in Nature Medicine explains the possible molecular basis behind differential response to exercise in humans. The interplay between anti-oxidative hepatokine selenoprotein P (SeP) and the muscle low-density lipoprotein receptor–related protein 1 (LRP1) decides how well a response to exercise could be. Circulating levels of SeP could be a guiding parameter to determine the level of ‘exercise resistance’. Be it response to exercise or response to a drug for cancer, there has been accumulating evidence for differential response among humans to a drug or treatment.
The potential of P4 medicine is multi-faceted. With the tremendous advancements in genomics, metabolomics, and proteomics technologies in the post-human-genome-sequencing era, targeted therapies could revolutionize healthcare contingent upon their use and their strategies. And that could help propel providers of P4 medicine in the market. A recent review evaluates the development and use of tailored precision medicine in the oncology field based on molecular-pattern recognition in cancer utilizing omics and bioinformatics platforms.
A 2015 report published by the Academy of Medical Sciences in collaboration with Medical Research Council, Science Europe and the University of Southampton suggests that obstacles to the future development of P4 medicine could be contemporary lower pricing for companion diagnostics, underestimation of P4 medicine value due to volume-based pricing models, and a knowledge gap in the comprehensive understanding of genomics. In addition, a dearth of sufficient awareness among people about the prospects of an individualized and tailored medical approach further fuels the problem. Therefore, a knowledge-based initiative is required from both clinicians and researchers to promote adoption of tailor-made personalized medicines among patients. A study by Hood and Friend suggests that a strategic collaboration among patients, patient-advocate groups, members of the health-care community including physicians could help overcome this technical and societal barrier towards the advancement of P4 medicine in the future.
Complex regulatory policies and reimbursement models further add to the growing challenge towards the clinical adoption of such therapies, the development of which relies on remarkable scientific innovation. Interestingly, the Peronalized Medicine Coalition published a recent report evaluating the opportunity, challenges and future of P4 medicine that suggests there has been a significant increase in FDA approval for personalized drug candidates. The proportion of P4 drugs approved by the FDA has escalated sharply from 5% in 2005 to 27% in 2016. Despite the potential challenges, this is promising! Over time, the FDA has been distilling its regulatory policies to encompass the complex regulatory considerations such as research methods to ensure safety, efficacy, and overall reliability of a personalized medical product. According to Pettit et al. in Pharmacy & Therapeutics, the 2012 FDA-approved drug Kalydeco (generic name: Ivacaftor) for Cystic Fibrosis (CF), specifically for patients carrying the mutation G551D, exemplifies the application of human genomics in the development of a personalized medicine tailored for 4% of the CF cases in the US who carry the mutation
Genetic heterogeneity lies at the crux of the evolution of personalized medicines. The variation in an individual’s response to a particular disease or to a therapy could be due to allelic variations or single nucleotide polymorphisms (SNPs) of the gene responsible for the disease. In simple words, alleles are different forms or versions of a particular gene. For example: the gene responsible for the color of eye could have allelic variants rendering differences in eye color in the human population. Figure 1 illustrates differential response to a drug in a population.
This emphasizes that a ‘one size fits all’ strategy may not work, and hence the ability of a drug to cure a specific disease relies on the specific genetic make-up of the individual. The randomness in selecting volunteers during clinical trials could contribute to this problem of imprecision. Eventually, according to an FDA report, several oncology drugs such as Vemurafinib and Debrafenib were developed to address genetic heterogeneity of specific tumors that differentiate one individual from another. It is interesting to note that differential responses of individuals to a particular disease or therapy has never been an obscure phenomenon. However, diagnosing the right reason has been an issue. New medical devices and diagnostics based on the application of human genomics have led to a renaissance in the development of predictive medicine. This could inevitably shift the balance more towards personalized patient-care through development of disease-specific therapies.
A key factor behind the exponential growth of genome-based predictive diagnostic tools was largely possible due to the significant drop in sequencing cost post-development of “next-generation sequencing.” The ability to rapidly generate millions of sequence reads enhancing the quality and coverage without the requirement of cloning fragments was a huge technological leap in sequencing technology (Figure 2).
Compared to Moore’s law (which observes that the number of transistors that fit on an integrated circuit doubles every two years), a commonly used reference to predict the success of a technology, the cost of next-generation sequencing (another technological success) has overtaken the law in terms of cost-metrics as early as 2008 (Figure 3). This has undoubtedly boosted the concurrent development and growth of the market for P4 medicines and associated predictive diagnostic tools. An insightful market study performed by Grand View Research suggests that the market value of personalized medicine that accounted for just over a trillion dollars in 2014 could potentially stretch to an estimated $2.45 trillion in 2022. This projection that accounts for a CAGR (Compound Annual Growth Rate) of 11.8% from 2014 to 2022 indicates a growing demand for genetic disease testing for predictive reasons and also future adoption of disease-specific precision therapeutics.
Inarguably, this has propelled considerable interest in the development of patient-centric medicine within the scientific community. However, there still seems to be a knowledge gap among public and medical providers. This is because, P4 medicine suffers from a marketing and awareness challenge: most people are unaware of its potential so adoption of P4 medicine lags far behind its potential.
The FDA is taking initiative to generate a platform to address the regulatory issues that could help ensure the accuracy of ‘big data’ (large number of sequence information) generated by the sequencing technologies that would lay the future foundation for precision medicines. Such oversight of next-generation sequencing to improve health-informatics through community outreach led to the development of a platform called precisionFDA. This promising initiative emphasizes the importance of accurate, high-quality informatics crucial to the expansion of precision medicine that could be safely marketable.
The market for precision medicine is segmented according to Grand View’s report, broadly on three aspects: 1. Product size [diagnostics, medical care, therapeutics and personalized nutrition and wellness]; 2. Region [North America, Europe, Asia-Pacific, Latin America, Middle East and Africa (predominantly South Africa)]; and 3. Competition among present share-holders of P4 medicine. A combinatorial approach integrating information technology with operations and workflow in hospitals is predicted to be a key driver to generate public awareness and increase market value for personalized medicine over a broad spectrum of diseases. The US personalized medicine market has been predicted to grow steadily over time generating much hope among patients who desire more tailored care (Figure 4).
In addition to the considerable cost reduction of next-generation sequencing, another key reason behind the advantageous positioning of North America (occupying the major market share from a global perspective) for the personalized medicine market is the rapid development of biomarkers, companion diagnostics and other therapeutic products through successful clinical research. The report from Grand View Research also suggests, that the market demand in Asia-Pacific has witnessed a sharp increase over the past few years and is poised to compete for the market share in the future due to the escalation of genetic tools and therapeutics in their healthcare network. The growing awareness among a significantly large population with unmet needs is further fueling this rise in the Asia-Pacific region.
In summary, despite the present challenges with the growing aging population and the birth of new diseases, the demand for individualized therapy will gradually accelerate in the years to come. A comprehensive evidence-based documentation of value-assessments through clinical research programs is essential to offset the costs of predictive molecular diagnostic tests and patient-centric interventions. Such a program could be achieved through various reimbursement policies such as insurance and government loans. One can only hope for such a day when health care providers will design tailored-care regimens for patients after comprehensive molecular diagnostic screening. This will lead to safe delivery of the most effective individualized treatment. That is when the economic impact of precision medicine will be truly reflected in the market.