Program Details
Dr. John Urquhart, FRCPE, FRSE
Chief Scientist, AARDEX Ltd; Professor of Biopharmaceutical Sciences, UCSF, Emeritus Professor of Pharmaco-epidemiology, Maastricht University
The Usability of Prescription Pharmaceuticals—Some Paradoxes Revealed By Pharmionic Research
“Pharmionics” is the study of what patients do with the medicines they have been prescribed. It became possible to do such research after the incorporation of time-stamping microcircuitry into pharmaceutical packages, to capture data on when the maneuvers occur that are needed to remove a dose of the medicine from the package. This method, known as ‘electronic medication-event monitoring,’ captures reliable dosing histories in ambulatory patients – the 80% of prescription drug use, in which patients bear the responsibility for administering successive doses of medicine to themselves.
Such research had its origins in the mid-1970's with monitored eyedrop dispensers for glaucoma treatment, but gathered force when electronically monitored packages for tablets and capsules were introduced to clinical researchers as scientific products in 1988 by the pioneering company that I had the mixed pleasure and pain to found. Since then the costs of prescription pharmaceuticals have increased stiffly, and the number of medicines meant for long-term containment or prevention of disease has steadily risen. Now there are now over 400 peer-reviewed, published studies based on electronically captured dosing histories in various therapeutic fields. This body of work teaches several lessons:
- most patients discontinue medicines prescribed for long-term use within 1-2 years after the start of their use
- many written prescriptions never reach a pharmacy; some that do are never collected; some that are collected are never started; the incidence of these breaks in the chain vary by therapeutic field
- people are ~4X more likely to omit a scheduled dose than to take an extra dose
- doses scheduled for administration in the evening are more frequently omitted than morning doses
- doses are more frequently omitted on weekends than weekdays
- drug ‘holidays’ – runs of 3 or more days of consecutively omitted doses – recur, on average, semi-annually, with a range varying between monthly and never
- there is a pervasive lack of candor between patient and caregiver regarding how/when/whether prescribed medicines are being taken
- yet most patients not only accept but welcome an objective record of their dosing histories with medically important medicines
Four basic questions arise: (a) what are the reasons for such wide disparity between professional advice and patients’ execution of that advice? (b) what are the medical and economic consequences of the main types of deviation from professional advice re the execution of prescribed drug dosing regimens? (c) is it possible to achieve closer correspondence between prescription and execution than presently prevails? (d) how close must the correspondence be to achieve the therapeutic aim? The answers to (b) and (d) are specific to the medicine and clinical situation of the patient, subsumed in the vastly diverse field of therapeutics. The answer to (c) is that the advent of a reliable, essentially un-fudgeable dosing history permits the application of simple techniques of management, under the rubric of ‘measurement-guided medication management’ (MGMM). Like any effective management technique, MGMM (i) is grounded in a reliable, objective measure of performance against mutually agreed-upon objectives, (ii) is an imperfect tool, requiring individualization both in technique and frequency of repetition, but (iii) is clearly beneficial by standard statistical measures, especially in extending patients’ persistence in their use of medicines meant to be taken indefinitely.
The cost-effectiveness of MGMM is a moving target, heavily dependent, first, on manufacturing volume, as with any electronics-based product, and on the learning curve, as in anything new that humans undertake to put into routine use. Some answers to (a) may help increase the effectiveness of MGMM.
Presently, pharmionics is making the transition from a purely academic research topic to applied use in routine therapeutics, starting with MGMM of certain of the higher-cost medicines. There the medical and economic advantages of lengthened treatment are clearly evident to care-givers, care-payers, and drug manufacturers and can thus support the transition from low- to high-volume production of electronically monitored packages and the MGMM learning curve.
Curiously, these applications of MGMM are almost all occurring in Europe, not yet in the US. There has been also a long-running preponderance of pharmionic research in Europe over the US. Yet it was that quintessential American doctor, C. Everett Koop, who summed it all up by saying: “drugs don't work in people who don't take them.” Europeans seem to have taken the point more readily than their American cousins. Perhaps it is some kind of corollary to the much more rapid adoption of mobile phones and faster diversification of their uses in Europe than in North America.
Some Further Reading
- Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 353:487-97, 2005.
- Urquhart J. The odds of the three nons when an aptly prescribed medicine isn’t working: noncompliance, nonabsorption, nonresponse. Brit J Clin Pharmacol 54: 212-20, 2002.
About John Urquhart, FRCPE, FRSE
Chief Scientist, AARDEX Ltd; Professor of Biopharmaceutical Sciences, Center for Drug Development Science, UCSF, Emeritus Professor of Pharmaco-epidemiology, Maastricht University. He has a BA (Rice, 1955), an MD (Harvard, 1959), and was a Surgical House Officer at Massachusetts General Hospital (1959-61). His core scientific interest is the nonlinear dynamics of hormonal and drug actions.
He was Professor of Physiology (Pittsburgh, 1963-70), Professor of Biomedical Engineering (USC, 1970-1), and Research Director at ALZA Corp (1971-86), pioneer developer of drug delivery systems. Since 1986, he has focused on the clinical consequences of variable patient compliance with prescribed drug dosing regimens, pioneering electronic means to compile dosing histories in ambulatory patients, the premier method for obtaining such data. He co-founded the now-merged firms, APREX Corp and AARDEX Ltd,. that produce such products and supporting statistical methods. Time-variations in dosing, occurring for whatever reasons, create variations – always quantitative, sometimes qualitative – in drug actions. Sound pharmionic analyses convert this leading source of variance in drug response from noise into signal, integral in the learn-confirm paradigm of clinical drug development. He has co-authored 3 books, over 160 scientific papers, and is named as inventor on over 40 U.S. Patents. He and his wife, Joan, reside in Palo Alto, California. They have 3 children, 4 grandchildren, and 1 great-grandchild.
* FCRPE: Fellow of the Royal College of Physicians of Edinburgh
FRSE: Fellow of the Royal Society of Edinburgh