Aspects of a medication beyond the chemical composition can have an impact on patient outcomes. Consideration of these aspects when developing clinical pathways may result in particular formulations or delivery systems being specified on the pathway. However, greater specificity within the clinical pathway may raise concerns with regard to patient access. Balancing these considerations is key when determining the ideal level of specificity and can ensure that the right drug is prescribed to the right patient to produce the best possible outcome.
Clinical pathways differ greatly in their specificity from one pathways program to another, but those that simply note the class of medication recommended, rather than noting a specific medication within the class, may be the result of a belief that there are no important differences between medications within a class. The “best” medication may actually share the same mechanism of action (MOA) or be chemically the same as others within the medication class but differ in mode of delivery or other attributes. These “best” medications must be specified on clinical pathways and formularies in order to produce superior outcomes. Finding these differences among similar medications can be difficult because of the variety of nuances; however, identifying the right treatment for the right patient for placement on clinical pathways is critical to achieving the best possible outcomes.
There are many aspects of the same medication that can provide significantly different results for patients, such as formulation (topical ointment/cream, extended-release [ER] tablet), route of administration (topical, sublingual, intravenous), device (inhaler, insulin pen), or packaging.
For certain patient populations, swallowing pills is difficult, if not impossible. In older adult patients, dysphagia is common and prohibits the swallowing of pills. In pediatric patients, the fear of choking when swallowing oral medications is often observed. In institutionalized patients with mental illness, the practice of “cheeking”—hiding medications in one’s cheeks to avoid swallowing—often occurs. As a result, alternative formulations for medications are required. Oral formulations that can be crushed and sprinkled over foods are increasingly being developed. Sublingual formulations and orally-disintegrating tablets (ODTs) offer easier administration for patients with nausea or vomiting or who have difficulty swallowing. ODTs combine the advantages of liquid formulations with the administration convenience of a tablet for improved compliance. Topical formulations, such as ointments, creams, or gels, allow for direct application of a drug to where it is needed most (ie, site of skin irritation), avoiding systemic side effects, reducing pill burden, and preventing non-adherence.1
Drugs that may be administered through alternate delivery routes, including subcutaneous, intravenous, or rectal, may be appropriate for patients who cannot take oral medications; however, administering drugs through these routes is more difficult and may preclude self-administration.
Simplification of medication regimens and access to affordable medication in easy-to-use dosing formats are crucial to improve the treatment outcomes of patients, especially in the elderly population. Drug delivery customization can also be utilized to address the needs of those who require compliance support or disease management. Patient non-compliance due to unpleasant taste, inconvenience, and difficulty in administration combined results in an annual loss of $30 billion in revenue to the global pharmaceutical industry from medications not filled or re-filled. These factors are driving pharmaceutical companies to seek partnerships with drug delivery companies that have a proven track record in formulation expertise to adress unmet medical needs such that patients are more likely to be adherent.1
Physical disabilities often make it difficult or impossible for older adults to utilize devices such as inhalers or to self-administer medications such as insulin via a vial and syringe. To combat these physical limitations, a variety of novel devices have become available for medication delivery. These include innovative inhalers, prefilled insulin dial-up pens, and slow-release drug patches.
Taking the example of inhaler therapies for respiratory conditions, a number of novel inhaler devices have gained FDA approval within the last few years. Traditionally, patients were prescribed inhalers that were based on the pressurized inhaler or dry powder inhaler (DPI) technology. These inhaler mechanisms were packaged in various devices, such as Diskus™, metered-dose inhaler (MDI), Handihaler™, or aerolizer. However, over the past few years, various new devices have become available, including the soft-mist inhaler Ellipta™ and, most recently, Aerosphere™. Newer devices may carry certain advantages, such as decreasing the need for accurate coordination of device actuation and inhalation by the patient, which may be key for elderly patients or those with physical disabilities.2
For patients requiring around-the-clock drug effect, such as those with chronic pain or hypertension, patches may be an ideal form of drug delivery, as it bypasses the requirement for remembering to take medication and swallowing pills. Patches can also help minimize systemic side effects, such as in elderly patients treated with fentanyl patch for chronic pain, who may otherwise develop nausea/vomiting or constipation with oral fentanyl.
Given the availability of a wide variety of devices and formulations available, the patient must be educated and should clearly understand how to properly use their device or drug formulation in order to achieve the maximum benefit.
The FDA has called out opportunities for abuse-deterrent formulations as a need because opioid products are often manipulated for purposes of abuse by different routes of administration or through bypassing ER properties.1 Most abuse-deterrent technologies developed to date are intended to make manipulation more difficult or to make abuse of the manipulated product less attractive or less rewarding. It should be noted that these technologies have not yet proven successful at deterring the most common form of abuse—swallowing a number of intact capsules or tablets at one time. Moreover, the fact that a product has abuse-deterrent properties does not mean that there is no risk of abuse. It means, rather, that the risk of abuse is lower than it would be without such properties. Because opioid products must eventually be able to deliver the opioid to the patient, there may always be some abuse of these products. For purposes of this guidance, abuse-deterrent properties are defined as those properties shown to meaningfully deter abuse, even if they do not fully prevent abuse. The term abuse is defined as the intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desirable psychological or physiological effect. Abuse is not the same as misuse, which refers to the intentional therapeutic use of a drug product in an inappropriate way and specifically excludes the definition of abuse.
This FDA guidance uses the term abuse-deterrent rather than tamper-resistant because the latter term refers to, or is used in connection with, packaging requirements applicable to certain classes of drugs, devices, and cosmetics. The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving. Based on the evolving nature of the field, the FDA intends to take a flexible, adaptive approach to the evaluation and labeling of potentially abuse-deterrent products. As a result, clinical pathways and formularies may want to give preference to medications with unique formulation to improve individual and population health outcomes.
Surgeon General C Everett Koop said: “Drugs don’t work in patients who don’t take them.” Packaging of medications can support greater adherence, resulting in improved outcomes. Several medications are developing unique packaging or delivery through medication dispensing systems to improve outcomes. One type of adherence packaging that the FDA went on record supporting is unit-dose, or blister, packaging. In fact, there is a council dedicated to specialized compliance packaging.
As an example of successful compliance packaging, the Healthcare Compliance Packaging Council award winner from last year4 offered a number of compliance prompting features for patients. The product provides convenient daily blister units, with graphics clearly highlighting the morning and evening dosing requirements. Individual blister units are file packed into a weekly organizer carton, with individual days neatly arranged to illustrate the daily regimen. Dosing instructions are positioned to educate patients, reminding them to take the morning and evening doses 12 hours apart and to take their medicine with fat-containing foods. Four weekly packs are provided in a monthly carton, which contains graphics that further reinforce dosing instructions as well as the FDA-approved labeling. This type of packaging can have better results over the same product only available in vials.
There are even more sophisticated mechanical dispensing being used that can promote and track adherence. These systems can also be used to assure proper use of as-needed medication, which for many frail older adults have resulted in unintended overdoses because of forgetfulness. By preventing too frequent use of as-needed medications, improved outcomes through prevention of a potential adverse event can be realized. These delivery systems are another example of differences between chemically similar products that can result in significantly different outcomes.
Greater specificity within clinical pathways may raise concerns with regard to patient access. Although it is beneficial to delineate the “best” medication, based on criteria including formulation and delivery route, within the clinical pathway, it is also important to ensure that patients may access alternative versions of the same drug, given that there may be differences in how individual patients respond to particular treatments.
The Centers for Medicare and Medicaid Services (CMS) recognized that, for some drug classes, limiting access could harm patients.5 Initially, when Medicare Part D was implemented in 2006, CMS recognized differences within a class of medications and required that plans to ensure that “all or substantially all” Part D drugs within the following six protected drug classes are on a plan’s formulary to meet therapeutic needs: antineoplastics, anticonvulsants, antiretrovirals, antipsychotics, antidepressants, and immunosuppressants. CMS designated these as protected classes to ensure that beneficiaries who needed these life-saving therapies would not be discouraged from enrolling in certain Part D plans, as well as to mitigate any risks and complications associated with interrupting therapy or limiting access on a formulary or clinical pathway. These six classes have commonly become referred to as protected classes.
The Patient Protection and Affordable Care Act recently codified this existing policy, allowing CMS to outline criteria for identifying protected classes. However, the Medicare Payment Advisory Commission (MedPAC) recently recommended eliminating two protected drug classes—antidepressants and transplant medications.
Despite this shift in position, it is important for plan formularies and clinical pathways to assure access to the “best” medications not only for a population but also for individuals with specific needs to have access to the right treatment. Through thoughtful examination of the differences between medications that truly impact clinical outcomes, clinical pathways can be developed that assure the right drug is made available to the right patient in order to produce the best possible outcome.
1. Maalouf N. Developing patient-centric drug formulations to meet patient needs. Business Development & Licensing. 2013;20:1-4.
2. Respiratory Quality Improvement Group. Inhaler Devices Identification Chart. September 2013.
3. US Food and Drug Administration. Guidance for Industry: Abuse-deterrent opioids–evaluation and labeling. April 2015. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf
4. Healthcare Compliance Packaging Council. Healthcare Compliance Packaging Council (HCPC) Announces Compliance Packages of the Year. HCP Online Web Site. http://www.hcpconline.org/compliance-package-winner.html. Accessed June 6, 2016.
5. Stefanacci R. Weighing in on changes affecting Medicare Advantage. Annals of Long-Term Care: Clinical Care and Aging. 2014;22(2):38-39.
6. Moynihan H, Crean A. Physiochemical Bases of Pharmaceuticals. Ch 1. Oxford University Press; 2009.