August 1, 2016 PAP-Q03-16-CL-004
Pharma’s next blockbuster is increasingly hard to find and that’s shifting the emphasis of R&D spending and the traditional direction of innovation. According to Tufts Center for the Study of Drug Development, industry leaders will spend $2.5 billion to get a drug from conception to approval.1 That’s an expensive proposition, especially if the new drug disappoints in the marketplace. For many of pharma’s top companies, R&D spend is already shifting away from high-risk blockbuster gambles to more patient-centric product strategies focused on improving the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of drugs in their portfolios. To extend patent protection and market lives of their products, as well as generate better patient outcomes, drug developers are optimizing drug formulation, dose frequency, dose form, and simplifying administration and delivery to remove barriers to achieving the desired results.
Tufts finds that companies spend an additional ~$300 million in post-approval studies to test new indications, new formulations, new dosage strengths and regimens, the latter associated with studying what are termed a drug’s real-world “pharmionic” traits.1 Waiting until post-approval is risky; therefore, drug developers must begin to study pharmionics during development to better understand actual patient use and caregiver dynamics so that the real-world experience matches the results from the controlled clinical studies. To get there, pharma’s supply chain is collaborating in new ways to address the issues and risk associated with dose adherence in support of safer, more effective drugs that economically deliver better health care to society.
Researchers and leading companies in the supply chain are doing their part to advance the science of drug adherence. According to the 2012 Ascertaining Barriers to Compliance (ABC) paper “A new taxonomy for describing and defining adherence to medications,” there was little agreement on a common vocabulary — necessary to accurately study the issue.2 Searching popular life-science databases, the group studied 40 years of literature to identify all the different terms used to describe medication-taking behavior and outline the evolution of the lexicon associated with the field. As a result, ABC proposed the term pharmionics, which labels and describes the study of dose adherence behavior. An understanding of pharmionics is expected to help the industry more accurately predict and mitigate the consequences of correct versus incorrect dosing and the harmful effects of specific adherence errors in patient populations.
Measuring the elements of adherence (initiation, implementation and discontinuation) and understanding the consequences of correct versus incorrect dosing followed by quantitative analysis helps drug developers to design a product that will deliver health outcomes closer to those predicted from the clinical trials. Failure to do this can be commercially disastrous. In the US, more than 50% of prescribed medicines are taken incorrectly or not at all, which can reduce the efficacy of the treatment, cause severe negative health effects and ultimately, the failure of the drug in the marketplace.3
Because patients don’t consistently take medicine as prescribed, society isn’t gaining all it can from the time and effort it puts into creating better pharmaceuticals. According to the US Congressional Budget Office, a 1% increase in prescription fills by beneficiaries would also cause Medicare spending on services to fall by a statistically significant amount.4 The support for value-based outcomes and other models of healthcare financing are mounting and it is expected the pharmaceutical sector will soon be prompted to enter into risk-sharing arrangements with payers predicated on the therapeutic performance of their products.
It’s clear the patients, payers and regulators are less willing to tolerate medications and therapies with poor PK and PD actions. Conversely, drug developers are exploring these factors internally, as well as collaborating with their supply chain partners to engineer better pharmionic performance into their products. With product strategies now more often tied to strategic contract manufacturing and development partners over the long-term, a pharmionics-focused development path will help manage risk both pre- and post-approval.
As cited by Drug Development & Delivery’s 2015 Global Formulation Report, and referenced in the Q2 issue of Pharma’s Almanac in the article, “Dose and Form Matter: Future of Care Demands Optimal Drug Delivery,” while the Humira formulation has remained for the most part unchanged since its launch, AbbVie has consistently developed pharmionic improvements to the drug / device configuration to better match outpatient needs.5,6 Launched with a vial presentation, the study notes a mid-year switch in 2004 to prefilled syringes. In 2006, the company launched a single-use disposable pen presentation. It’s clear that post-approval study revealed opportunities to improve the drug’s pharmionics and the company acted, adopting new approaches and technology to consistently improve the patient experience. In spite of a twice-monthly maintenance dosing, patient self-injection has not affected the sales of Humira or its ascent as a top selling biologic.
On the other side, poor pharmionic data may have contributed to the failure associated with Duract (Bromfenac), a drug which caused four deaths and prompted eight liver transplants and twelve cases of severe liver damage. Developed by Wyeth-Ayerst Laboratories in the 1990s, Duract was labeled for a maximum use of 10 days, but patients often received / took more than 10 days’ worth of pills. According to a 1996 Wall Street Journal report, the first liver transplant occurred on a patient who was misusing Duract.7 The 36-year-old patient had been taking the drug for osteoarthritis, a condition the label said the drug wasn’t meant to treat — and for two months, much longer than the label suggested. Duract, introduced in July 1997, was withdrawn June 26, 1998. The adverse reaction was deemed “undetectable” by Wyeth researchers, but perhaps the drug’s potential negative outcomes would have been different if, in clinical trial, the study showed that the drug was most effective and safer dispensed only in 10-day quantities with individual doses clearly marked to stress dose adherence and contraindications.
Drug developers are increasingly aware that products that fail to address distasteful or harmful side effects, or to mitigate dose / form / formulation issues, dosage or delivery complexity and other barriers like portability and price, will be challenged in the marketplace. Dr. Thomas Hein, Senior Vice President of Commercial and Regulatory Affairs at Hermes Pharma, cited a 2014 Spiegel Institute survey that revealed that roughly half of the population has difficulty in swallowing tablets and capsules.8 This issue is prevalent across all demographics, and taste and texture also cause adherence issues and consumer complaints. Hein cited the study to set the stage for his discussion of dose form issues and innovation: “Companies are responding by tackling these difficulties from new angles in the pursuit of innovative solutions.” For all of these solutions, he said, a core strategy points to putting consumers directly at the center of the business.
Technologies that support easy-to-use dosage and packaging forms are readily available and CDMOs like Unither Pharmaceuticals have been innovating solutions successfully for their customers for years. Specializing in the development and contract manufacturing of non-parenteral sterile and oral dose products, Unither offers a comprehensive range of single-use dosage forms and delivery systems that help mitigate pharmionic issues and support an effective patient-centric therapy. Unither has experience with many primary packaging forms including single-dose stick-packs and sterile blow-fill-seal containers. These forms are proven to be a convenient and affordable way to consume single doses of liquid and semi-liquid medicines, as well as patient friendly respiratory and orally-digestible dose (OGD) formulations. These and other innovations allow Unither to support its customers’ patient-centric drug development plans and simplify the lives of patients in real-world use.
Moving forward, patients and health care systems will not accept medicines that fail to conform to consumer preferences or deliver expected results in real-world use. Pharmaceutical companies unwilling to consider these imperatives earlier in development are likely to face mounting uncertainty and risk; less return on R&D investment; and products less able to meet the demands of regulators, government agencies, healthcare systems and patients. Above all, the industry must innovate, working collaboratively to apply the best pharmacokinetic, pharmacodynamic and pharmionic science to create the high-value, high-performing therapies and better health outcomes the world is demanding.