President Obama, during his 2015 State of the Union Address, launched the Precision Medicine Initiative “to enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care.” The message given to the American people reinforced the critical need to implement precision medicine into health care: “Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatment as best as they can to individuals. You can match a blood transfusion to a blood type—that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?”
Although “personalized medicines” and diagnostic tests have been implemented in healthcare for over two decades, the precision medicine initiative established a cohesive network of regulators, industry and policy makers who are committed to replace the old paradigm of “one drug fits all” to a targeted approach. This new paradigm will allow physicians and researchers to more accurately predict the best treatment and prevention strategies to use for a specific disease in a given population of people. Over the last two years, advances in the fields of genomics, proteomics, metabolomics, bioinformatics, and other disciplines, combined with improved technologies and tools for biomedical analysis and large dataset handling, have driven the initiative which promises to improve patient outcomes. The result? Precision medicine approvals are on the rise. More than 20% of all new molecular entities (NMEs) approved by the US FDA between 2014–2016 have been classified as precision medicines, and overall 1 in 4 drugs approved during this period were classified as a precision medicine.
Strength in numbers
Nearly three years since the launch of the initiative, global regulatory agencies, the pharmaceutical industry, major research centers, patients, health care providers, diagnostics companies, payers, advocacy groups, and bioinformatics companies, have helped to advance precision medicine to deliver “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.” Furthermore, global alliances have been formed to move the precision medicine into clinical practice. For example, the Precision Medicine Initiative, involving the NIH and multiple research centers, will be implementing the All of Us Research Program in early 2018. This study will enroll at least 1 million volunteers from around the United States. As part of this program, researchers will use the data collected to study a range of diseases, with the goals of better predicting disease risk, understanding disease pathophysiology, and finding improved diagnosis and treatment strategies.
Precision dosing: a critical component of precision medicine
The cornerstone of precision dosing, which falls under the umbrella of precision medicine, is delivering the right dose, of the right drug, to the right patient, at the right time. Precision dosing will provide patients with the most efficacious medications with minimum probability of adverse events. Alarming US statistics provide compelling reasons to move towards a precision dosing platform:
- Drug-related problems in patients account for $177 billion in costs annually, with $20 billion contributing to preventable adverse drug reactions (ADRs), and 30-50% of these are due to dosing errors
- “One-size-fits-all” dosing contributes to the failure of approximately two-thirds of drugs across all indications moving from Phase 2 to 3, of which 50% of the failures are due to lack of efficacy; patient populations at greatest risk for developing ADRs include pediatrics, geriatrics, patients on polypharmacy, and those with end-organ dysfunction—groups not well represented in Phase 3 clinical trials
- Poor medication adherence—estimated in the US at $105 billion in avoidable costs
- Escalating drug development costs—estimated at $2.6 billion
Model-informed precision dosing—maximize therapeutic benefit while reducing risk
Modeling and simulation (M&S) has become a widely adopted and important part of the drug development process. This approach forms a crucial link between deciding on the precise dose and delivering it to the right patient population. Since being sworn in as commissioner of Food and Drug in May 2017, Dr. Scott Gottlieb has iterated the important role that model-informed drug development (MIDD) plays in the 21st Century Cures Act, the FDA’s new guidance for the industry for drug-drug interactions, and the FDA Reauthorization Act (FDARA).
Many quantitative tools are widely used to characterize drug disposition and effects, such as physiologically-based pharmacokinetic (PBPK) modeling, and non-linear mixed effects (NLME) population modeling. The application of PBPK modeling is used by regulatory agencies and the pharmaceutical industry across the drug discovery and development continuum, eg, predict drug-drug interactions, extrapolate to special populations, and optimize clinical trial designs. In particular, model-informed precision dosing (MIPD) allows the interpolation and extrapolation of dosage regimen with models of varying complexity.
PBPK modeling can predict an initial dose for new drugs in patients not studied in the pivotal trials by using prior knowledge of other drugs that have similar physiochemical and PK/PD characteristics to the drug in development. Using a systems pharmacology in silico approach, whole body virtual PBPK models can be used to account for the behavior of drugs in most tissues in the body.
MIPD technologies will yield the greatest return on investment in certain patient groups, diseases and drugs:
- Patients who belong to vulnerable groups, or those where minimal or no data is available to determine optimal dosing, eg, pediatrics, neonates and infants, geriatrics, pregnant women, those with rare diseases, oncology patients, and patients with either impaired organ function or are immunocompromised
- Diseases that have high unmet medical needs with validated biomarkers for diagnostics
- Drugs that are well-characterized, have a narrow therapeutic index and a wide interpatient PK/PD variability, and impose financial burden on patients, payers, and providers due to high costs
Looking to the future—removing barriers for widespread adoption of MIPD
Several challenges remain to be overcome for MIPD to realize its promise to improve clinical outcomes by optimizing dosing for individual patients. These include establishing a network of interdisciplinary collaborations, more evidence-based efficacy, and determination of a cost-benefit analysis in healthcare. Greater engagement and education of clinicians, development of intuitive tools, harmonization and standardization of pharmacokinetic data collection, analysis and reporting, and effective communication by modelers to healthcare sponsors, providers, approvers, payers, and patient groups on the values of MIPD will help to eliminate the barriers for bringing MIPD into more widespread clinical use.
MIPD has the potential to revolutionize healthcare by reducing the incidence of ADRs related to suboptimal dosing and increasing patient adherence. Continued support by regulatory agencies and the pharmaceutical industry to develop, validate, and implement precision dosing models will facilitate applying this approach.
To learn more about how PBPK models and IVIVE can be used as tools for precision dosing, please watch this webinar by my colleague, Dr. Devendra Pade.