As this issue is released in print, the American Association of Pharmaceutical Scientists’ National Biotechnology Conference (AAPS NBC) is convening in Boston, MA. This conference is one of the world leaders in bringing together experts to norm on the opinions and future trajectory for manufacturing, manufacturability, formulation, drug delivery, and other critical themes for pharmaceutical science and production. One of the main aspects of pharmaceutical formulation ultimately ends up being a question of what combination of pharmaceutical technologies, including excipients, tablet or capsule matrices, time-release components, parenteral co-factors, and so forth will produce a medicinal product that has a high degree of safety and demonstrable efficacy.

This is formulation, the process in which different chemical and/or biochemical substances, including the active drug, are combined to produce a final medicinal product. The word ‘formulation’ is often used in a way that includes not just the inputs and process of manufacturing the drug, but also the final product dosage form. The final product dosage form is what the patient ultimately experiences, and should encourage patients to be compliant with their dosing regimen. After all, as former Surgeon General C. Everett Koop had said, “drugs don’t work in patients who don’t take them.” We have plenty of evidence for t.i.d. dosing schedules—three times daily—producing more incidences of patients not following through on dosing properly—compared to q.i.d.—and ultimately giving up on their drug therapy.

In order to help patients as effectively as we can in our industry, we need to harness the best practices of human behavior when we think about how the drug products will actually be used. I’m going to list three of the top factors in this field as it pertains to formulation and its broad effects on pharmacocompliance.

Diseases are a disruption of lives
First, people like to be ‘treated.’ People feel much better after talking with others about their condition or symptoms. During the patient-physician encounter, being listened to and cared for provides a tremendous boost to wellbeing. But once a patient has received his or her physician visit and gotten the effective treatment, they do not want to be burdened by the continuous thought of their disease or disorder. So anything we can do to minimize the intertia of the drug therapy—the significance and weight it has on the patient’s cognitive load—and allow patients to live a life aside from their course of treatment, will definitively produce better results.

Form follows function, but function in our world includes form!
Second, the form of the dose makes a difference in how well-treated a patient feels. Whether it’s solid dosage formulations, injectables, sublinguals, transdermals, or parenterals, there are different patient perceptions for the different dose forms and, perhaps surprisingly, different reported treatment effects from one form to another. Certain dosage forms (e.g., transdermal instead of tablet, injectable instead of nebulizer) that a patient hasn’t experienced before or associates with better quality care can improve measurements of outcomes.

However, as more patients are exposed to more dosage forms, this will bring up its own issues. There will be a leveling of the playing field we are in now, where these novel dosage forms that become more ubiquitous throughout society will then produce less of a novelty, or placebo effect and can become more of a patient burden. Many patients take five, six, or more medications in pill form for their current conditions essentially in one mode of dosing. Having some of these span the range of more exotic formulations may end up backfiring and causing more patient dissatisfaction if some of their co-therapies are pills, some parenteral, some transdermal, etc., and lead to rejection of their medication compliance.

Economics is the Queen of social sciences
Third, the price of a drug therapy can have a substantial effect on placebo and the patient’s expectation and perception of the drug’s function.¹ On the periphery of formulation, is the topic of drug pricing, because when looked at holistically from afar, the price affects accessiblity and can influence patient-reported outcomes. So pricing could be considered a ‘behavioral economics component of formulation,’ ultimately influencing what the patient gleans from treatment. I recently participated in a moderated webinar debate for the AAPS on drug pricing, and this is one of the most contentious facets of the pharmaceutical industry at the moment.

Ultimately, drug formulation needs to take into account all of the aforementioned components, including final dosage form, in order to maximize patient compliance and pharmacoutility. When I’ve worked on developability lifecycle of biotherapeutics³, one of the things that most often comes up as a gaffe within organizations is that the entire development and formulation cycle is often not taken in totality of its parts, but is instead a process that’s plodded through one step at a time, where each step is almost entirely isolated from the antecedent and post-cedent steps (similar to how one-factor-at-a-time experimentation is inferior to Design of Experiments). This insulation from knowledge of the adjacent steps in the process has a negative effect on the whole development and formulation lifecycle. There are some companies who are just starting to do some of this holistic appraisal well, but many aren’t, and we still have a long way to go to move the industry forward in this respect. We owe it to our patients for the future of medicine.

Formulation isn’t just following a recipe to bake a cake. However, with that said, think about this: Top pastry chefs know that how a dessert is offered and displayed has a differential effect on enjoyment. 

References and Further Reading

• Espay AJ, Norris MM, Eliassen JC, et al. Placebo effect of medication cost in Parkinson disease: a randomized double-blind study. Neurology 28 January 2015.
• Locwin, B. (2016). Drug pricing: Market value. AAPS blog. https://aapsblog.aaps.org/2016/03/14/drug-pricing-market-value/
• Zurdo, J., Arnell, A., Obrezanova, O., Smith, N., Gallagher, T.R.A., Gomez de la Cuesta, R., Locwin, B. (2016). Developability of biotherapeutics: Computational Approaches. Boca Raton, FL: CRC Press (Taylor & Francis Group, LLC).
• Levitt, S.D. & Dubner, S. J. (2009). Freakonomics: A rogue economist explores the hidden side of everything. William Morrow.

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Ben Locwin

Ben Locwin, PhD, MBA, MS writes the Clinically Speaking column for Contract Pharma and is an author of a wide variety of scientific articles for books and magazines, as well as an acclaimed speaker. He is an expert media contact for the American Association of Pharmaceutical Scientists (AAPS) and a committee member for the American Statistical Association (ASA). He also provides advisement to many organizations and boards for a range of business, healthcare, clinical, and patient concerns. He can be reached at ben.locwin@healthcarescienceadvisors.com.