Oral Oncolytics: Part 1-Financial, Adherence, and Management Challenges

Robert Mancini, PharmD, BCOP

Ali Mcbride, PharmD, MS

Mary Kruczynski

Timeline of the Introduction of Oral Oncolytics

The management of patients receiving treatment with oral oncolytics presents many challenges. Issues related to cost, adherence, monitoring of side effects and interactions, and safe handling create a vast web of complexity that makes the use of these agents far more challenging than the use of traditional intravenous oncolytics. Data are scarce on the management of oral chemotherapy patients, and the data that are available often only address a single issue related to the care of these patients. The fact is that each of the issues noted above creates a situation that is more complicated than has been depicted in most of the literature.

The Scope of the Problem

All of the above challenges are exacerbated-and made more urgent-by the changes that are occurring in anticancer drug development. If we look at the history of oral oncolytic drug approvals, we can see why the issues surrounding the use of oral anticancer agents are coming to the forefront of cancer care. After the first oral oncolytic was approved in 1953, the subsequent 50 years saw 27 oral agents approved for cancer treatment. This represents 1 new medication roughly every 2 years. Since 2004, 22 new oral agents have been approved in 9 years, indicating an approval rate of 1 new medication roughly every 5 months. If we look at just the last 5 years, there have been 15 new oral drugs approved, further increasing the average approval rate to 1 new drug every 4 months. New oral oncolytics are thus hitting the market 12 times faster than they were prior to 2003 (Figure). In addition, up to 35% of the agents in clinical trials are oral agents, making this an issue that will only grow in the future.[1] Although some of these agents are for more atypical or rarer forms of cancer, such as vandetanib for medullary thyroid cancer or vismodegib for advanced basal cell carcinoma, some are for very common diseases, such as abiraterone or enzalutamide for castration-resistant prostate cancer. In some cases, the new oral agents represent drugs that formerly were available only in IV formulations (ie, methotrexate, fludarabine, and etoposide); others of the new oral agents are new multi-targeted kinases or hormonal ­antagonists.

This proliferation of oral agents has resulted in increased monitoring and care of patients on oral chemotherapy. At St. Luke’s Mountain States Tumor Institute, we showed that the addition of abiraterone to our institutional formulary increased our healthcare providers’ workload by approximately 15%. If new agents are being approved at a rate of 1 every 4 months, that could lead to nearly a doubling of workload in 2 years’ time.[2] In order to keep up with workload requirements, institutions need to “work smarter”: they need to develop standard measures of care and monitoring that will enable them to optimize care of these patients.

It is our hope that this discussion of both the various challenges involved in managing patients receiving treatment with oral oncolytics, and possible solutions, will prove helpful. Next month, in a second article, we will discuss the ramifications of recent legislative activity both for patients receiving oral oncolytic therapy and for their physicians.

The Financial Challenge

Possibly the most significant day-to-day barrier to optimum management of oral oncolytics is the issue of cost. In 2009, oral oncology medication monthly out-of-pocket costs averaged $2,942, up 17% from 2008.[3] An Avalere Health study found that almost 10% of patients choose not to fill their initial prescriptions for oral anticancer medications due to the high rates of cost-sharing.[4] The literature reports primary nonadherence rates upwards of 20%, with the main reason given for nonadherence being cost.[5,6]

Most of the oral oncolytics currently available cost several thousand dollars per month (eg, lenalidomide, dasatinib, vemurafenib, to name a few), and the type or presence of insurance greatly influences the cost to patients and their likelihood of filling their prescription. Patients often fall into one of three financial categories: they are either uninsured or underinsured, they have private insurance, or they have government insurance (Medicare, Medicaid, Tricare, etc). Each of these groups presents unique obstacles to optimal fulfillment of oral oncolytic prescriptions. A working knowledge of the pathways associated with medication fulfillment can greatly reduce costs to the patients, the healthcare system, and the insurance companies. Patients who are uninsured can often get help directly from manufacturers, who can supply free medication for persons who qualify for medication assistance programs.[7] Patients with private insurance often have high copays, but copay cards from manufacturers can often help reduce the cost to the patient. Lastly, patients on government insurance can have a wide range of prescription drug benefits. Some patients have supplemental insurance plans that help with the coverage gap, making their medications easy to manage. Other patients without prescription drug insurance or supplemental insurance may have copays up to 20% of the drug cost or more. Unfortunately, being on government insurance automatically precludes patients from utilizing manufacturer-based copay assistance programs. However, many nonprofit copay assistance programs exist that can help this group of patients (Chronic Disease Fund, Partnership for Prescription Assistance [PPARX], Care Care, etc). Collaborations with such programs can be arranged more easily on site, where interactions between pharmacists and financial advocates or social workers can happen quickly. This process of collaboration has been shown to reduce nonfulfillment rates while saving the patient money and reducing medication write-offs for unpaid pharmacy bills.[8]

Dispensing Challenges

In a majority of cases, oral chemotherapy agents that are prescribed are issued by specialty pharmacies, and this may prevent patients from obtaining these medications at the time of diagnosis. In some cases, this problem can be overcome easily by having a discussion with the insurance company and getting on contract. However, some insurance companies only allow fills to go through a single mail-order pharmacy, in which case neither the patient nor the provider has any choice in how the patient obtains his or her medication. This is potentially problematic, since the direct lines of communication that exist between an internal pharmacy and the physician’s office do not exist with external pharmacies. In addition, if patients are required to use a mail-order pharmacy, they may never have the opportunity for direct interactions with the pharmacist, much less with a pharmacist who is a member of their healthcare team, and this may compromise optimal therapy.[9]

In a majority of cases, physicians like to see their patients on the day of or a few days prior to the start of their next cycle of chemotherapy. Programs with on-site dispensing can prepare prescriptions for patients to pick up at their physician’s office after their visit to initiate their subsequent chemotherapy cycle. Mail-order pharmacies often have to send scripts via mail to arrive on or before a patient’s Day One cycle visit with his or her prescriber. This can be potentially wasteful, since any change in the prescription or discontinuation of the medication-which typically occurs on what would have been Day One of a cycle-can leave the patient with thousands of dollars of unused drug that cannot be returned for credit (once a medication is dispensed and leaves pharmacy control, legally it cannot be reused for another patient). A 6-month assessment of this issue was conducted at our site, based on utilization of an on-site pharmacy to fill all prescriptions. In that 6-month analysis, 37 patients discontinued medication on the start date of their next cycle after seeing their physician. This resulted in a total of $103,567.33 worth of medication (based on average wholesale price) that was able to be returned for credit, thereby saving the insurance companies money as well as saving patients $13,850 in copay costs, compared with the costs these parties would have incurred if a mail-order pharmacy had been used. Further analysis of this type of cost savings can show a significant overall reduction in healthcare costs associated with on-site dispensing.

Problems With Adherence

The issue of adherence is serious for cancer patients. Poor medication adherence can lead to a number of complications, including unnecessary disease progression, complication of treatment, reduced functional abilities, lower quality of life, and premature death.[10] Adherence issues can arise because of complex dosing schedules or because of “pill fatigue,” where the sheer number of pills is overwhelming to patients. Despite the fact that a cancer patient’s survival and well-being may depend on accurate administration of oral medications, overuse, underuse, and misuse of prescription drugs remain highly problematic. It is estimated that as many as 80% of patients do not take oral oncology agents according to their doctor’s instructions.[11]

Many methods for measuring and improving patient adherence have been proposed, but no one method, by itself, has been proven to be complete enough or beneficial enough. The only approach that can increase adherence across all patient populations is involvement by a multidisciplinary group of providers who can assist patients on multiple levels. By keeping all aspects of patient care within a single unified system, patients have direct access to practitioners from multiple disciplines, including oncologists, nurses, pharmacists, advanced practitioners, social workers, dietitians, and other allied healthcare professionals who can assess and assist them on a case-by-case basis. If patients are obtaining their medications from elsewhere, it is very difficult for their oncologists to keep accurate track of when, or if, they are actually receiving the medications. However, if an on-site pharmacy is used, providers can assist with adherence by conducting frequent follow-up, giving specific instructions, issuing scripts for only one cycle at a time, and providing patients with dosing calendars to assist with timing. In addition, having the pharmacist on staff at the cancer center control refills, instead of refills by patient request, allows for assessment of adherence and symptom management, as well as prevention of late refills.[2]

Difficulties in Managing Adverse Effects and Drug Interactions

One of the biggest perceived benefits of oral chemotherapy is convenience. Patients are able to take their medications at home and avoid repeated visits to the infusion center for their treatments.[11] This seems great until one considers the fact that these oral oncolytics are not innocuous. These medications can have potentially serious adverse effects that may not be as easily observed by clinicians, since patients do not always get as much follow-up as patients receiving treatment intravenously.

Similar to the challenges presented by the potential adverse effects of oral agents are those raised by possible drug-drug and drug-food interactions, and by the dose adjustments needed for renal or hepatic dysfunction.[12] Many medications have drug interactions that require interventions. Several of these medications have cytochrome P450–based drug interactions that can be quite significant, and at least 14 oral oncolytics have moderate or greater interactions with grapefruit juice.[13,14] In addition, a handful of agents require acidic environments to be fully absorbed, and the use of acid suppressors can greatly reduce the efficacy of these medications as a result of poor absorption. Finally, some medications require that they be taken with food, some must be taken on an empty stomach, and for still others this does not matter. It is important that patients be aware of what the requirement is for their medications-and also that they understand why, so they can pay more attention to the correct protocol.

In an early analysis of 552 patients at our institution, 36 patients were found to have drug-drug interactions that required intervention by their oncologist, and 11 patients required dose adjustment because of organ dysfunction.[15] In an updated analysis of 700 patients, a total of 82 drug-drug interactions in 73 patients were found, and 24 dose adjustments were required for organ dysfunction. These data emphasize how common these issues can be. Our patients were fortunate in that their oral medications were dispensed on-site at our center. The benefits of the pharmacist being part of the health system included full access to lab values on the part of the pharmacist, a complete reconciled medication list in the patient’s electronic medical record, and the ability of the pharmacist to quickly and easily remedy any issues that arose with initial assessment of a prescription by simply walking down the hallway and talking to the prescriber. However, in settings where prescriptions are filled by a mail-order pharmacy, as is often the case with oral agents, managing incidents of drug interactions or needed dose adjustments due to organ dysfunction is much more problematic.

In order to address issues of potential adverse effects or drug-drug or drug-food interactions, many institutions have implemented more thorough weekly assessments via telephone. This allows someone to be in contact with patients more frequently without having to bring them in to the clinic as often.[15] One benefit of this type of program is that it ensures that all patients receive valuable, in-depth counseling on their medication, including dosing, food or drug interactions, and potential side effects (including preventive measures and self-treatment options). These telephone interactions are then documented in an electronic medical record that is accessible to all providers within the cancer center. In other cases, utilization of medication therapy management programs that employ Current Procedural Terminology (CPT) code claims has been found to increase adherence and promote patient understanding.[16] When prescriptions are handled by a mail-order pharmacy, and the mail-order pharmacy conducts the telephone counseling program, there can be no guarantee of the extent or quality of the counseling provided. Having a telephone counseling program both on-site and connected with an on-site pharmacy is the ideal, since it allows for more direct interventions that involve the patient’s oncologist. After a phone call with a patient, a pharmacist or nurse can talk directly with the physician in the clinic and get issues addressed quickly.

The Issue of Safe Handling

Proper handling of oral chemotherapy has become an important issue not only for patients, but for healthcare professionals as well. The translation of previous intravenous chemotherapy compounds to oral formulations has not lessened the potential of these agents to harm caregivers and healthcare professionals. Accidental exposures to these agents can occur during numerous stages of handling or waste disposal. Because of these risks, safe handling guidelines were developed.[17] Recently, newer consensus recommendations have been developed on storage, handling, disposal, and training for safe handling.[4,18-21] Whether patients receive oncolytic agents “on-site” at a cancer center, or at home, the center’s procedural policies must include continued provisions for the safe dispensing of these medications at a level commensurate with that of its policies for the handling of intravenous agents.

The authors’ personal experience in managing patients receiving treatment with oral oncolytics has shown how complex the care of these patients can be. Issues we continue to face on a day-to-day basis include those mentioned above, as well as others. However, we have found ways to optimize the care of these patients. One of the best ways to address the most issues in the most efficient way is to allow clinics to work with local dispensing specialty pharmacies or in-house pharmacies that have direct physical contact with the prescribing oncologists. This can allow issues such as adherence assessment, access to financial assistance, side-effect management, drug interactions, and dose adjustments to be handled quickly and efficiently, limiting unnecessary delays in access to the medications.

The content of ONCOLOGY’s Practice & Policy department represents a joint venture between the editors of ONCOLOGY and the Community Oncology Alliance. Articles featured in Practice & Policy are supplied by the COA as part of its mission to educate oncologists about the policy issues that affect the nation's cancer care delivery system. Practice & Policy features reflect the views of their authors and not necessarily those of the COA.

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