Pembrolizumab Flat Dosing Wastes Nearly $1 Billion Annually

Alexander M. Castellino, PhD

June 26, 2017

The new immunotherapies are expensive drugs, but a new study suggests that they are costing more than they need to because of flat, rather than personalized, dosing.

Using a flat dose of pembrolizumab (Keytruda, Merck &Co) for first-line treatment of lung cancer instead of personalizing the dose to the patient's body weight results in an excess of 25% in drug dose, and hence a 25% increase in drug costs, say a group of oncologists. They calculate that this excess could mount up to nearly $1 billion annually in the United States.

This estimate was reported in a poster presentation (abstract 9013) at the recent American Society of Clinical Oncology (ASCO) 2017 Annual Meeting, and the study was simultaneously published online June 3 in the Journal of the National Cancer Institute.

Daniel A. Goldstein, MD, from the Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel, and colleagues reported that patients with non-small cell lung cancer (NSCLC) receiving first-line pembrolizumab at the flat dose of 200 mg every 3 weeks (Q3W) results in an excess of 25% in drug dose, and therefore a 25% increase in drug cost, compared with the originally approved personalized dosing of 2 mg/kg Q3W.

"Using personalized dosing may reduce the budget impact by approximately 25%, thus increasing access and improving health outcomes," the authors concluded.

Medical oncologist and a critic of drug pricing, Leonard B. Saltz, MD, professor and chair of pharmacy and therapeutics committee at the Memorial Sloan Kettering Cancer Center (MSKCC), New York City,  agreed.

"Pembrolizumab is only sold in the United States in 100-mg vials. An average lung cancer patient weighing 75 kg would require 150 mg of pembrolizumab based on weight. Because the 50-mg vials are only marketed outside of the US, 50 mg of drug, at over $48 per milligram, must be wasted for each 75-kg American patient," Dr Saltz told Medscape Medical News. "If we don't share

vials between patients, that 50 mg goes in the trash, but we pay for it anyway. The flat dosing of 200 mg just means that we are dumping the additional 50 mg into the patient for no additional benefit," he added.

Pharmacoeconomic Analysis

Dr Goldstein and colleagues noted that pembrolizumab was initially approved at a dose of 2 mg/kg Q3W in patients with metastatic melanoma. The Keynote lung cancer studies (Keynote 001, 010) showed that response rates and toxicity were similar for pembrolizumab 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg every 2 weeks. Finally, an analysis of samples from patients in Keynote studies 001, 002, 006, 010, and 024 showed that the pharmacokinetics of pembrolizumab are consistent across weight-based and fixed-dose regimens and showed a flat exposure–response relationship.

When pembrolizumab was approved for the first-line treatment of patients with metastatic NSCLC overexpressing programmed cell death ligand 1, the approval was for the flat dose of 200 mg Q3W.

In a budget impact analysis from the US societal perspective, Dr Goldstein and colleagues compared costs associated with fixed dosing and personalized dosing.

For their analysis, the authors included 19,601 patients who were likely candidates for first-line pembrolizumab. On the basis of published data, the number of pembrolizumab cycles was 17.9; patient weight was 76 kg according to the average weight of a patient with lung cancer at Emory University in Atlanta, Georgia. Drug cost was based on Medicare pricing of $48.45/mg.

The authors' base-case model demonstrated that, in the United States, the total annual cost of pembrolizumab is $3,440,127,429 with fixed dosing and $2,614,496,846 with personalized dosing. Use of personalized dosing could therefore result in an annual saving of $0.825 billion.

Implications of Fixed Dosing, Large Vial Size

Dr Goldstein indicated that potential barriers to implementing personalized dosing includes prescriber agreement, ineffective vial sharing, oversized vials, and the current policy of payment for wastage being a disincentive for reducing wastage.

"There is no incentive for physicians at community centers to use less drug since they get paid for the amount of drug they use," Dr Goldstein said. "Flat dosing means that infusion centers do not have to share vials between patients," he continued. "Flat dosing increases the revenue for a drug company, with no additional clinical benefit," Dr Saltz added.

"The most appropriate first step to avoid waste is to change or add personalized dosing to the FDA [US Food and Drug Administration] label. If the FDA changes the label, clinicians and payers will be more comfortable prescribing and reimbursing personalized dosing," Dr Goldstein and colleagues write in their discussion.

"This analysis is picking up on an issue we previously addressed — that drug companies are increasing the amount of drug they are selling by packaging it in large vial sizes so that a considerable amount is wasted, but paid for, with each dose," Dr Saltz said. "In case of flat dosing, the waste is infused in the patient for no benefit; in case of weight-based dosing, it is dumped into the sink," he added.

Dr Saltz was referring to the article published in March 2016 (BMJ. 2016;352:i788), which was widely publicized and reported by Medscape Medical News at the time. This analysis of 20 cancer drugs showed that as a result of large vial sizes, leftover cancer drugs in vials cost $3 billion annually.

In that BMJ paper, outspoken critic of drug pricing Peter Bach, MD, professor and director of the Center for Health Policy and Outcomes at MSKCC, along with his colleagues (Dr Saltz included), argued that under the buy-and-bill system, practices and hospitals buy single-dose vials of drugs and then bill insurers or patients when they are used. "The bill includes a percentage-based mark-up which can vary widely, but even low percentages can equate to large amounts of money given that many of the drugs cost thousands of dollars per vial," they wrote.

Dr Bach and colleagues urged drug companies to provide drugs in multiple vial sizes. They cite the example of bendamustine (Treanda, Teva Oncology), which is available in a broad array of single-dose vials (25 mg, 45 mg, 100 mg, and 180 mg) that can be combined to reach the precise dose of 100 mg/m2. The availability of these vial sizes allows only 1% of the drug to be wasted.

Pembrolizumab was initially packaged in 50-mg and 100-mg vials in the United States. However, long before the approval of flat dosing, the 50-mg vial was discontinued and Merck marketed only the 100-mg vial.

Medscape Medical News reached out to Merck about pembrolizumab vial sizes because both vial sizes are indicated as available in the May 2017 KEYTRUDA Prescribing Information.

"In the US, when KEYTRUDA received initial approval (Sept 2014), we introduced a 50 mg lyophilized dose which required reconstitution and then quickly transitioned to the 100 mg liquid dose as planned, which was preferred by providers because it does not require reconstitution. KEYTRUDA currently is only available in the US in the ready-to-use, liquid formulation in the 100 mg vial size," Merck told Medscape Medical News.

However, both vials continue to be available in Europe, where the concept of a value framework exists. For example, the United Kingdom's National Institute for Health and Care Excellence provides a stamp of approval for drugs based on a cost-effective analysis, which needs to consider the amount of drug wasted, Dr Goldstein explained.

The FDA approves drugs on the basis of efficacy and safety. "If a drug is FDA-approved, Medicare has to provide the drug at the price set by the drug company. Medicare has no power to negotiate the price," Dr Goldstein said.

"In the US, there needs to be a step where someone assesses the value of a drug after it is approved and before Medicare agrees to pay for the drug," he explained.

"The FDA has no legal mandate, and appears to have no desire, to take on the issue of drug costs. As it stands now, no one can tell the drug companies how to package the drug," Dr Saltz told Medscape Medical News. "Once the FDA approves a drug for an indication, Medicare must pay for it at any price that the drug company chooses to set. If Medicare pays for the drug, others will," he added. "If drugs are priced higher, copays and Medicare payments increase," he said.

"Personalized dosing has the potential to decrease costs while maintaining efficacy," Dr Goldstein and colleagues write. "While personalized dosing should be encouraged, its rapid adoption and potential cost savings may be dependent on cooperation between the FDA, physicians, patients, payers, and manufacturers," they add.

Financial Toxicity, a Need for Transparency

Dr Goldstein explained that although the 200-mg flat dose of pembrolizumab is not associated with additional toxicity, it is associated with financial toxicity for the patient, who has a higher out-of-pocket cost when he or she receives a higher dose than is warranted. Financial toxicity can manifest as patients cutting back on daily needs, selling their homes, not adhering to treatment, or declaring personal bankruptcy to pay for cancer care.

"Understanding cost matters," Dr Saltz told Medscape Medical News. He advocates the need for transparency with respect to any drug costs. It is important to know the price of the drugs one is prescribing, and the price should factor into decision-making. "We should be discussing the cost of drugs we prescribe as openly as we discuss its risks, benefits, and other toxicities," he said.

Dr Saltz argued that it is incorrect to assume that physicians should be concerned only with immediate out-of-pocket costs and that societal costs are not relevant. "Societal costs are ultimately distributed across the population. We all eventually bear the burden of increased drug costs in terms of increased insurance premiums," he said.

He commented  further that physicians openly talk with their patients about the intimate and personal details of their lives. They ask patients about bowel function, bladder function, sexual function, depression, alcohol and illicit drug use, and other details that are outside of normal social discourse. "There was a time decades ago when we as a profession did not talk to patients about the presence of cancer or about prognosis, but all this has changed," he said. "In this context, it is inconsistent that any conversation about costs is taboo," he said.

Dr Saltz also noted that it is important and routine for people to make informed decisions about any goods and services they might choose to purchase, and to consider alternatives and value. "Healthcare should be no different," he added.

The discussion of value in healthcare is too often confused by how the word is used. For a meaningful discussion of "value," the word should be used as a noun. The value of something can be quantitated in terms of high- and low-value care. In this context, the value of a drug can be seen as a ratio of its objective positives and negatives, with high price being one of the negatives, Dr Saltz explained.

"For any drug with fixed benefits and adverse effects, the higher price means lower value and vice versa," he said. "Drug cost is simply one component of value," he pointed out.

However, using "value" as a verb obfuscates the issue, he explained. When we say that patients "value" the benefits of a drug, we can no longer quantify it. "The subjective nature of this sort of use of the word 'value' resists a correlation with price," Dr Saltz said. "This focus of 'value' as a verb distracts us from a meaningful discussion of what is high-value care, and more importantly, what is not," he added.

"There needs to be a transparency about true risks, benefits, and alternatives of treatment strategies being considered," Dr Saltz said. "As much as it would be wrong to exclude a consideration of physical toxicities of a drug, it would be equally wrong to exclude consideration of price or financial toxicity," he said.

Dr Saltz contends that there will come a day when academic publications will include the drug price, and future cost issues will be incorporated into study design, as well as review and approval processes. "When a trial is designed that increases the length of treatment or increases drug dose to higher than the standard, investigators must think about what the costs of those changes will be and must take them into consideration," he said.

Dr Goldstein has disclosed no relevant financial relationships. Dr Saltz reports grants from Taiho Pharmaceuticals.

American Society of Clinical Oncology (ASCO) 2017 Annual Meeting. Abstract 9013. Presented June 3, 2017.

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