No Substitute for Better Study to Protect Patients


It’s baseball season so it seems timely to cry foul on the practice of therapeutic substitution, as well as a recent study encouraging its use. Every day, healthcare professionals observe first-hand how diagnostic and dispensing decisions are often influenced by external cost-control measures. Whether it is through a step therapy protocol, a fail first mandate, a prior authorization requirement or dispensing limits, both public and private payers have turned the U.S. healthcare delivery system into an enormous bureaucratic headache for practitioners.

These policies have led to more money being spent on billing and insurance-related paperwork (approx. $471 billion in 2012)  than on life saving biopharmaceuticals (approx. $425 billion in 2015). Payers promote these practices under the guise that they know better than the physician which treatment option is right for the physician’s patients; that individual patients are not so different from one another and do not actually need individualized care; that any one of the therapies approved for treatment of a certain disease from the same class of medicines is good enough to fix the patient’s condition.

Payers are saying that a handful of hired “experts” and the algorithms they develop from a corporate office building make better treatment decisions than the practitioner sitting in the exam room with their patient. It should come as no surprise that most patients and clinicians would dispute that.  After all, humans are not genetically identical and we know that genetics play an important role in health and disease.

Consequently, policy makers in search of ways to easily fix the healthcare cost challenge need to guard against all-encompassing strategies that make broad population-based assumptions which are based on poorly designed studies or data. A recent example of such over-simplification is the call by some for implementation of the aforementioned “therapeutic substitution” policy based on a study published last month in the Journal of the American Medical Association (JAMA).

Therapeutic substitution refers to the practice of switching a patient from one prescribed medicine to a different medication. The “switch” can take place before the prescription is initially filled, or it may take place after a patient has already been stabilized on a different medication. The alternate drug usually belongs to the same “therapeutic class”—essentially, medications that work in a similar way or treat the same health condition.

However, these switched medicines contain a different active ingredient or, in some cases, a different delivery mechanism; which may lead to important differences in the medicine’s safety, efficacy and outcomes, and even uses that may be contrary to the indications approved by the Food and Drug Administration (FDA). Therapeutic substitution should not be confused with generic substitution. Unlike therapeutic substitutions, generic substitutions involve drugs with the same active ingredients as determined by the FDA (or the equivalent government agency) as well as strength and dosage form that are therapeutically equivalent to the brand name drug.

In the above referenced JAMA study, the authors concluded that a certain percentage of the biopharmaceuticals used in some therapeutic classes had a so called “equivalent medicine” which was a generic. Thus the investigators concluded that substantial savings may be attained if those patients on a brand name medicine could be switched to the less costly generic alternative through a therapeutic substitution intervention.

Unfortunately, the published study has several flaws, beginning with its design. The researchers analyzed the data at a specific point of time (cross-sectional study) rather than employing a longitudinal study design that observes patterns of use over a period of time. As such, the investigators did not know whether patients in the study protocol had already taken a generic or any other drugs from the same class of medicines over their course of treatment. In addition, because the study did not look at overall healthcare utilization data and cost, the investigators could not determine whether utilization of more costly hospital or physician services was higher or lower for patients using the brand name medicines.

Most importantly, the study was devoid of any data regarding patient outcomes. The authors also did not disclose or discuss the fact that no published peer reviewed studies analyzing mass therapeutic substitution  policies have ever demonstrated a reduction in utilization of more expensive healthcare services such as additional physician interventions, hospitalizations, emergency room visits or impact on patient outcomes, quality of life and satisfaction. Interestingly, the authors did divulge that therapeutic substitution policies may lead to higher overall costs because patients need to be re-adjusted to their new therapies or may become non-compliant with their new therapies.

Despite these shortcomings, the authors of the study recommended mass therapeutic substitution. They even compared adoption of therapeutic substitution to generic substitution based on their research findings. Such poorly designed investigations are nothing new. Others have tried to advocate similar policies based on unsuitable studies.

If the authors had utilized a more appropriate study design investigating the prescribing patterns in the U.S., I believe they would have found different results which may have altered their policy recommendation.

Addressing rising healthcare costs in the U.S. is an important policy matter. However, policy recommendations based on inadequately designed studies that provide incomplete answers is a recipe for disaster.

Robert Popovian is the Senior Director of Pfizer U.S. Government Relations. 

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