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Medications in Single-Dose Vials: Implications of Discarded Drugs (2021)

Chapter: 2 Single-Dose Vials of Weight-Based Drugs

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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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2

Single-Dose Vials of Weight-Based Drugs

For most injectable or infusible medications, a measured amount of the drug is drawn from a container1 using calibrated syringes and then given to the patient. Some of these drugs are injected or infused in fixed amounts, with every patient receiving the same dose. However, the dosage of many injectable or infusible drugs, particularly cancer drugs, depends on a patient’s weight.2 In the United States, weight-based drugs are typically supplied in single-dose vials—that is, in vials that are intended to be used by a single patient because of various health-related concerns that arise if multiple patients share a vial. The vials may come in one or several sizes,3 and depending on size, a single patient may be treated with one or several vials in order to receive the correct dose.

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1 The container could be a glass or plastic bottle often used to store medication as liquids, powders, or capsules. Some containers could contain medication for injection or infusion for a single patient as a single administration at a single time. The remainder is disposed of after use because the vials do not contain preservatives to stop microbial growth. Such types are referred to as single-dose or single-use containers. They are usually supplied in ampules, small vials, and prefilled syringes. Vials have rubber stoppers that must be pierced with a needle, and their contents can be stored for a relatively short time once opened. Ampules do not have rubber stoppers and the glass neck must be broken; they must not be stored or reused after that. Other types of containers hold medications intended for multiple doses for injection or infusion and for more than one patient. They contain preservatives to stop bacterial growth but can still be contaminated if safe injection practices are not followed. They are usually referred to as multi-dose vials.

2 As noted in Chapter 1, for the purposes of this report, weight-based dosing includes dosing based on body surface area.

3 The phrase vial size used throughout this report refers to the volume per vial of a drug.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Generally, a certain amount of drug will be left over because the dose that the patient requires is not exactly equal to the amount of drug contained in one or multiple vials. Typically, the unused drug is discarded—thus, the “discarded drugs” specified in the committee’s Statement of Task. This chapter offers an overview of the factors in the U.S. biopharmaceutical supply chain that interact or compete to influence the amount of discarded drugs from weight-based dosing of medicines contained in single-dose vials including the drug discovery and development process, drug dosing approaches, vial sizes, guidance from federal and nongovernmental organizations, and clinician acquisition of and payment for drugs. The chapter concludes with an examination of patient safety and quality-of-care issues related to weight-based drugs.

DRUG DISCOVERY AND DEVELOPMENT PROCESS

Injectable and infusible drugs are delivered in weight-based doses for a variety of reasons, but among the most important is the establishment of this regimen during the drug development process.

The typical time line from drug discovery to development in the United States can be as long as 15 years, and it involves a series of stages, including discovery, preclinical trials, clinical trials, U.S. Food and Drug Administration (FDA) approval, and post-marketing surveillance (see Figure 2-1).

At the beginning of the discovery stage, researchers in academia, government agencies such as the National Institutes of Health, and the biopharmaceutical industry work to understand the underlying causes and potential treatments of a disease. They often test compounds in the laboratory and in animal models to determine which ones show some activity against the targeted disease and are safe enough for human testing. The analyses of the data from this testing must provide detailed information on dosing and toxicity levels. After animal testing and the accompanying analyses, if the drug manufacturer wishes to continue on to perform tests in humans, it must submit an investigational new drug (IND) application to FDA (2015a).4

Approval of the IND advances the potential drug to the clinical stage (known as clinical trials), where it is presumed safe to be tested in humans. The potential drug is tested in a clinical setting during three phases of trials, usually lasting 6 to 7 years. In Phase I trials, investigators gather information on safety, tolerability, drug metabolism and excretion, side effects, and mechanisms for determining the maximum tolerated dose.

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4 FDA does not develop drugs. Instead, it develops regulations for good laboratory practices and oversees each study to help ensure drug safety.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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FIGURE 2-1 A typical time line for drug discovery and development in the United States.
SOURCE: NASEM, 2018.
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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The drug formulation and method of administration may be refined continuously until, and even after, the drug’s final approval (FDA, 2018d).

In Phase II trials, investigators gather preliminary information about the potential drug’s long-term safety, determine if it has the intended effect in humans, and identify any side effects and any benefits beyond its intended effect (FDA, 2018d). Phase III trials represent the final step in determining if a potential drug is safe and effective (FDA, 2018d). The dosing regimen shown to be safe and effective in these pivotal studies5 will be the regimen that regulators approve for marketing. The drug manufacturer submits a new drug application to FDA to formally request approval for the drug to be sold and marketed in the United States and for doctors to prescribe it for patients. Typically, for the new drug to be sold in other countries, it would have to satisfy the regulatory requirements in those countries. After the drug is available on the market, further trials—referred to as Phase IV trials—may be carried out by the drug’s manufacturer; in some cases, FDA requires the manufacturer to carry out further evaluations of the drug’s safety or efficacy in order to obtain marketing approval, while in others the manufacturer chooses to carry out the studies to get more information about the drug such as looking for additional indications. Whether or not Phase IV trials are carried out, all drugs are monitored to identify new or delayed toxicity—a process described as post-marketing surveillance.

Drug manufacturers may further study the drug in different doses and specific populations, such as older adults or children, and may conduct more research to obtain FDA approval to use it in a new formulation or for another indication, such as another type of cancer. FDA does not make decisions on reimbursement or on how much a drug should cost.

Establishment of Weight-Based Dosing in the Drug Development Process

As noted above, drug doses are established during early clinical trials to demonstrate that the drug is both safe and effective (FDA, 2005; Musuamba et al., 2017). Developing novel therapies often involves early dose-ranging studies in clinical trials that first increase the dose (corrected for body weight) until dose-limiting toxicity occurs and then reduce the dose below that level for pivotal efficacy trials. The dosing regimen tested in these pivotal studies will be the regimen that is approved by FDA.

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5 A pivotal trial or pivotal study is a clinical trial or study that intends to provide the ultimate evidence and data that FDA uses to decide whether to approve a potential new medicine. A pivotal trial is usually a Phase III clinical trial, but in exceptional cases, a Phase II study can serve. They are sometimes also referred to as registration trials.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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That is, if a weight-based dosing regimen is used in these pivotal studies, then a weight-based dosing regimen will be approved. Seldom, if ever, do pivotal studies compare a weight-based dosing regimen and a fixed dose. Therefore, an adult dose for many injectable or infusible drugs is frequently weight based because of the early drug development process.

DRUG DOSING

The dosing regimen for a given drug can contribute to the discarding of drugs. One of the main difficulties facing physicians who are attempting to determine the most effective dose of a drug is that different individuals have highly variable abilities to metabolize and eliminate drugs, which means that individuals given comparable doses do not always receive comparable exposures. The use of height and, particularly, weight in determining dose is based on limited preclinical and clinical evidence combined with the general understanding that larger patients have a larger volume of distribution, leading to the presumption that they require a higher dosage to provide the same therapeutic effect. It has been observed, however, that even if doses are adjusted based on body weight, individuals differ in their capacity to metabolize and eliminate drugs due to a combination of physiologic variables, genetic characteristics, and environmental factors, such as food intake and drug–drug interactions (Ahmed et al., 2016; Belle and Singh, 2008; Brunton et al., 2017).

Such variation has received particular attention for anticancer drugs, which often have a steep dose–response relationship and narrow therapeutic index, potentially leading to severe dosing errors (Pai, 2012). To optimize the therapeutic effect, anticancer dosing has historically been guided in both preclinical and early clinical studies by the determination of the “maximum tolerated dose”—that is, the largest dose that a patient can be given before the onset of severe, life-threatening toxicity (Musuamba et al., 2017). This approach for traditional cytotoxic agents has been supported in both preclinical and clinical studies, which have demonstrated that the greater the dose intensity (dose per unit time), the greater the response.

In light of this, new approaches are being explored to determine the optimal therapeutic dose, including dosing based on therapeutic drug monitoring and genotyping of drug-metabolizing capacity or on the area under the plasma concentration curve. The goal is to ensure that sufficiently high local drug concentrations are achieved to maximize efficacy without unacceptable toxicity.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

Weight-Based Dosing

Most injectable or infused drugs, especially chemotherapy agents, are dosed according to a patient’s body size (e.g., weight, body surface area) because of perceived contribution of body size to individual variations in how drugs are absorbed, distributed, metabolized, and the excreted pharmacokinetic variability (Kaestner and Sewell, 2007; Pan et al., 2016). This practice, however, is uncommon for other medications with sufficiently high therapeutic index, such as antibiotics and allergy medications, for which the dose required for a patient to receive a therapeutic benefit is much lower than the dose necessary to reach the toxic threshold (Tamargo et al., 2015). Based on a 2012 systematic review of FDA-approved drugs, out of 240 systemic drugs, 175 had a weight-based dosing recommendation for adults (Pai, 2012). For some medications, such as hydrocortisone, vancomycin, linezolid, and aprotinin, weight-based dosing has been shown to be superior to other methods for adult patients (Pan et al., 2016). However, weight-based dosing has important limitations for certain populations. For example, because of the lack of specific guidance on limiting toxicity, clinicians may struggle to accurately administer medications to patients with extreme body sizes (Pan et al., 2016). Despite these limitations, the Joint Commission International Accreditation Standards for Hospitals requires that the hospital policy should require weight-based dosing in particular circumstances, such as in pediatric or older patients (Pan et al., 2016).6

Among the various dosing strategies that take weight and body composition into account, weight-based dosing is the least consistent across an entire population in terms of the effective dose that individuals receive. Determining a dose solely on the basis of body weight makes an implicit assumption that all individuals have approximately the same body composition, but that is not the case. To address such issues, early-phase clinical trials need, to the extent possible, to include bodies at the extremes of the weight continuum in order to provide the necessary data for determining the appropriate modifications to the strictly body-weight dosing or to dosing determined according to body surface area (BSA), which is a variant of weight-based dosing.

Improving the safety and efficacy of weight-based dosing will require hospitals and other relevant organizations to implement standard operating procedures for weighing patients and creating proper weight documentation, verifying pharmacies’ quality control for these dosing regimens, and ensuring the availability of appropriate resources and

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6 It should be noted that body weight increases faster with age in pediatrics, so other dosing methods may be more cost efficient if dosage is based on weight.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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functional equipment for necessary health care delivery (Pan et al., 2016). In one study, 46 percent of inpatients receiving a narrow therapeutic index antibiotic did not have their weight documented because of workflow interruptions and heavy workloads (Charani et al., 2015). In another example, a study analyzing administration errors made by physicians and nurses attempting to manually calculate weight-based dosing for an N-acetylcysteine regimen for acetaminophen overdose found that 26 percent of the observed calculations were wrong and led to dosing errors (Selvan et al., 2007). By contrast, there was 100 percent accuracy in dose calculations and an improvement in patient safety for those who used an approved weight-based dosing chart. Without proper procedures, inaccurate weight estimates and omitted weight documentation can contribute to dosing errors. A variant of weight-based dosing that takes a patient’s body composition into account is BSA-based dosing.

Fixed or Flat Dosing

Fixed dosing (also known as flat dosing) refers to strategies that include no correction for body weight or other pharmacological parameters (Mathijssen et al., 2007). Fixed dosing has long been common in nononcological treatments, but it has only recently gained increasing use in the oncology field (Hendrikx et al., 2017).

Fixed-dose prescribing has been used for newer targeted therapies covered under Medicare Part B that are highly selective for specific cellular pathways and molecular targets, that demonstrate different relationships between exposure and effect on the molecular target, and that display quite different dose-limiting toxicities than cytotoxic chemotherapy.7 Fixed dosing of these targeted agents has become standard despite wide interindividual variation in plasma concentrations following standard dose regimens and substantial interindividual variability in plasma concentration throughout the dosing interval. Such heterogeneity is thought to be due to the genetic heterogeneity of drug targets associated with tumor response and pharmacokinetics factors, including metabolism and oral absorption (bioavailability), environmental factors, and adherence to the regimen. Although oral dosing offers the convenience of self-administration, food intake and drug–drug interactions and adherence have been shown to be challenging, potentially compromising clinical outcomes.

Fixed-dosing approaches offer several advantages over weight-based dosing (Pan et al., 2016), such as greater convenience and safety, with fewer calculations, preparation, and administration errors (Mathijssen et

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7 See https://www.uptodate.com/contents/dosing-of-anticancer-agents-in-adults (accessed September 23, 2020).

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

al., 2007). Additionally, the ability to use a single vial per patient without the need to discard unused drug could also have a very favorable effect on the expenses associated with anticancer chemotherapy (Hall et al., 2020; Markman, 2005). Fixed dosing lowers stocking and distribution costs and associated complexities. Enhanced patient safety often accompanies fixed-dosing approaches as well.

Like dosing based on body size, fixed chemotherapy dosing is based on clinical trial data from an “average-sized patient.” This appears to result in a toxicity profile that is similar to the one obtained with dosing based on weight or BSA for selected cytotoxic agents (Markman, 2005). The optimal dosing of novel selective targeted therapies and immunotherapies remains unclear in many settings. Increasingly, fixed dosing is proving valuable for targeted agents (such as the tyrosine kinase and BRAF inhibitors) and some monoclonal antibodies8 that target the immune system. For example, in 2014, FDA approved pembrolizumab, a drug used to treat several forms of advanced cancers, to be dosed based on weight (FDA, 2014). Almost 2 years later, new approvals for pembrolizumab to treat different forms of cancer moved from weight-based to fixed dose. Currently, pembrolizumab is given with fixed dosing for all indications (FDA, 2020).

In brief, because of convenience, safety, and the potential cost savings in the manufacture, packaging, and storing of fixed doses, fixed dosing for all patients regardless of body size characteristics has become the standard for essentially all oral targeted therapies.

Other Dosing Practices

Variation in body size characteristics does not adequately explain most interindividual pharmacokinetic variability for anticancer agents, so researchers and clinicians have tried various other dosing practices in an effort to give patients the most effective doses for their individual situations (Brunton et al., 2017). Pharmacokinetics attempts to understand how the body handles drugs, including absorption (for oral drugs), distribution (to different organs/body compartment), metabolism (activation/inactivation by enzymes), and elimination (generally renal or hepatic) (Brunton et al., 2017). Because of interest in more personalized or precision dosing, pharmacogenetic- and pharmacokinetic-based dosing strategies have received considerable attention, although their use in clinical practice has remained limited up to this point.

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8 Monoclonal antibodies are laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance, or mimic the immune system’s attack on cancer cells. They are designed to bind to antigens that are generally more on the surface of cancer cells than healthy cells.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

Therapeutic drug monitoring involves measuring plasma drug concentrations to adjust dosages to achieve optimal drug concentrations. Although it is accepted as a way to guide dosing of some agents with large pharmacokinetic variation in the noncancer setting (including antibiotics, such as aminoglycosides and vancomycin, anticonvulsants, immunosuppressant drugs, and lithium), it has not been broadly used in oncology except to minimize toxicity with high-dose methotrexate. Additional clinical trials and implementation studies will be required before this approach can be integrated into clinical practice. Dosing based on therapeutic drug monitoring and genotyping of drug-metabolizing capacity are more sophisticated and potentially more individualized or personalized approaches but are rarely available or used.

VIAL SIZES

The need to choose vial sizes for weight-based drugs is unique to this type of drug; there is nothing analogous for fixed-dose drugs. A manufacturer will know what the recommended doses are in terms of milligrams of drug per kilogram of body weight or the equivalent for BSA and then must decide how much drug to package in each vial. If the vial is too large, a large percentage of it will likely be discarded for each single use. If it is too small, many patients will require more than one vial, and significant portions of the subsequent vials may be discarded. Manufacturers can choose to produce multiple vial sizes in an effort to minimize discarded drug, but that has its own disadvantages, as each size requires its own regulatory approval, manufacturing process and validation, inventory, shipping, and recordkeeping. An added complication is that even if a medication has been given regulatory approval for multiple vial sizes, there is no guarantee that drug manufacturers will produce or that drug distributors will carry all the approved sizes.

Finding the optimal balance between too many and too few vials has been a topic of debate for researchers and policy makers in recent years. FDA does not regulate vial sizes. Rather, it approves the sizes suggested by the new drug’s manufacturer, which are determined during the clinical development phase of drug development. Manufacturing, distribution, formulation, and safety are key considerations when selecting vial size (FDA, 2013).

Manufacturing and Distribution

A key issue in selecting vial sizes is whether the drug is intended to be used for an injection or infusion of a single dose of medication. Because single-dose vials contain one dose of a drug to be used one time

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

for a single patient, they have less excess volume. They usually do not include antimicrobial preservatives to reduce the risk of vial contamination from bacteria growth and, therefore, are discarded immediately after use. Multiple-dose vials are intended to contain more than one dose of a drug and therefore do contain antimicrobial preservatives. In the United States, FDA requires drug manufacturers to add preservatives to multiple-dose vials to prevent microbial growth (FDA, 2018c). However, some markets outside the United States have raised concerns about preserved multiple-dose drugs (Biophorum, 2020). Thus, the requirements from different markets could lead to complications in the supply chain.9 Additionally, manufacturers may consider a high fill volume to be necessary to cover all potential weight ranges of patients, but this could lead to leftover drug for lower-weight patients.

One way to reduce the amount of discarded drug for lower-weight patients is to offer multiple vial sizes for a drug. That leaves manufacturers and distributors with two big decisions: how many different sizes should be offered and what quantity of each to produce. With multiple sizes, each size must be developed, validated, and manufactured. This increases the effort and time required to bring a drug to market. In addition, managing multiple vial sizes of the same product may add complexity to manufacturing and distribution logistics, such as inventory and administrative costs. Each new vial size must be sent to regulatory agencies in multiple countries for validation and approval in order to manage a global supply chain or inventory. Furthermore, all sizes of the same product would typically have the same shelf life, but the demand may differ for different vial sizes and some vial sizes may be less likely to be used before the expiration date than others.

Formulation and Safety

The physical form in which a drug is manufactured or administered (e.g., powders or injectable or infusible solutions) is decided on in the early phases of its clinical trial. After drug development, different sectors of the biopharmaceutical supply chain come together to introduce the drug to market. The United States Pharmacopeia (USP) prepares a monograph for each drug, which is a detailed label that provides information regarding the identity, quality, purity, strength, packaging (e.g., multiple- or single-dose vials), and labeling requirements.

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9 To the committee’s knowledge, there is a dearth of available publications that suggests that drugs currently contained in single-dose vials would not work well or pose safety concerns when they are mixed with antimicrobials and packaged into multiple-dose vials.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

GUIDANCE FROM FEDERAL AND NONGOVERNMENTAL ORGANIZATIONS

FDA, the Centers for Medicare & Medicaid Services (CMS), and the Centers for Disease Control and Prevention (CDC) all develop regulations and guidelines that have implications for ensuring access to effective drugs, public safety, and managing federal health care spending. However, because these agencies’ guidelines are not harmonized and may even be in conflict with each other, systematic efforts to reduce discarded drugs can be a challenge. In addition to the federal guidance, recommendations from scientific nongovernmental organizations that set standards aimed at ensuring drug safety (such as the USP) have enormous downstream ramifications for public spending by Medicare and private health care payers.

FDA

FDA makes regulatory decisions on how drugs can be used safely and effectively (FDA, 2018a) which can influence the cost of medications. During its review of medical products, FDA approves package size, package type terms, and discard statements as part of product labeling (FDA, 2017). Currently, however, FDA does not regulate vial sizes as part of the drug approval process. FDA has limited influence over the vial sizes that an individual manufacturer markets or over the design of the foundational clinical trials that sponsors submit as a prerequisite to obtaining regulatory approval. This also includes the oversight of clinical trials undertaken by companies that seek to obtain new drug labels or modify existing drug labels, although there are evidently some aspects of FDA oversight that clearly influence what manufacturers do. In October 2018, FDA issued guidance on selecting appropriate language for labeling injectable medical products for human use, packaged in multiple-dose, single-dose, and single-patient use containers (FDA, 2018b). Specifically, the recommendations sought to provide clarity on drug labels to help address unsafe injection practices resulting from improper use of medication vials for more than one patient.

CMS

CMS has implemented various approaches to cost containment for its health insurance programs (namely Medicare and Medicaid), including managing coverage decisions for drugs. Although CMS encourages health care providers to use drugs in the most efficient way in order to contain drug costs, it also expects providers to use drugs in a clinically

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

appropriate manner, and this requirement leads to situations where the remainder of a single-dose vial must be discarded after administering the necessary amount of the drug to patient. In 2007, CMS introduced the JW modifier, a coding mechanism to separately report the amount of a drug used from a single-dose vial and the discarded amount when submitting claims for reimbursement. This policy was initially voluntary, but in 2017, CMS made it mandatory (CMS, 2016). A detailed discussion on reimbursement with the JW modifier is presented later in the chapter.

Currently, Medicare reimburses health care providers up to the amount of drug indicated on the vial or package label of a single-dose product, including what is discarded, and patients have cost-sharing responsibility for both the portion they receive and the portion that is discarded. Health care providers must use the smallest package size available from the manufacturer or the package size that is the closest to the patient’s prescribed dosage amount (CMS, 2016).

CDC

Although CDC does not have oversight of drug availability and spending, its policies have implications for health care expenditures and drug safety. Currently, CDC guidelines call for single-dose vials to be used for one patient only (CDC, 2019). The intention is to protect patients from infectious disease outbreaks that may occur if a vial is contaminated after its first puncture and then reused. If microorganisms or contaminants enter a vial and are able to grow before its next use, the second recipient could potentially develop an infection (CDC, 2019). However, no clear evidence exists that vial sharing is responsible for any clinically significant infections. Nevertheless, CDC guidance and concerns about liability stemming from the risk of infection serve as a restraint to vial sharing.

USP

The USP is an independent, scientific, nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines. These standards are based on public comments and expertise from relevant stakeholders, including patients, academics, regulatory authorities, the health care industry, and drug manufacturers (USP, 2020a). Medicines contained in single-dose vials are either given directly via injection or mixed with a solution or another drug, packaged, and labeled—a process known as compounding—to create a new formulation to be given to a patient as an infusion using a drug-delivery device (FDA, 2018d). As FDA does not approve compounded drugs (FDA, 2018d), the USP guidance (called “General Chapters”) for compounding establishes procedures,

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

methods, and practices that practitioners use to help ensure the quality of compounded preparations (USP, 2020b). USP General Chapter 797 specifies that after an initial puncture of a vial or once part of the contents of a vial have been extracted—generally by inserting a needle attached to a syringe—any remaining contents must be used within 1 hour unless the vial is kept in an International Organization for Standardization (ISO) 5 environment,10 which extends the time to 6 hours (USP, 2009). In addition, USP General Chapter 1151 on injections provides guidelines to drug manufacturers on designing their products to meet the label claim and acceptable overfill to avoid excesses and deficiencies that may arise from overfills and allow for correct dosing (USP, 2012).

Current Guidance on Repackaging Single-Dose Vials

FDA, CMS, and CDC each have established guidance on the repackaging of single-dose drugs—that is, dividing the content of a single-dose vial into multiple individual doses— with varying parameters (see Figure 2-2). According to FDA (2015b), “appropriately labeled, single-dose vials that contain significantly more drug than is required for a single dose may result in the misuse of the leftover drug product.” Similarly, it noted that “the need to combine several single-dose vials for a single patient dose may lead to medication errors and microbial contamination” (FDA, 2015b). FDA conveys caution but is silent on whether repackaging is allowed:

  • “Single-dose vials should not contain a significant volume beyond what would be considered a usual or maximum dose for the expected use of the drug product.
  • Consumers and/or health care providers should not be routinely required to use more than one vial to administer a typical single dose of the drug product.”

According to CMS (2012), “it is permissible for health care personnel to administer repackaged doses derived from a single-dose vial to multiple patients, provided that each repackaged dose is used for a

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10 An ISO 5 environment is a primary engineering control, such as a laminar airflow workbench or compounding aseptic isolator, that allows for no more than 100 particles per cubic foot of air, which acts to minimize the chances of a vial being contaminated by environmental microorganisms (USP, 2009). A variety of classification types govern cleanroom cleanliness, but the primary system in the United States is the International Organization for Standardization (ISO). The cleanroom class is the level of cleanliness the room complies with, according to the quantity and size of particles per volume of air. The minimum standard for pharmaceutical cleanrooms is generally ISO 5.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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FIGURE 2-2 Comparison of FDA, CMS, and CDC guidance on the use of single-dose vials.
NOTE: CDC = Centers for Disease Control and Prevention; CMS = Centers for Medicare & Medicaid Services; FDA = U.S. Food and Drug Administration.
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

single patient in accordance with applicable storage and handling requirements.” CMS allows repackaging under specified conditions, using qualified, trained personnel under ISO Class 5 conditions and a primary engineering control, which is used for preparing supplies for drug repackaging under a hood.

According to CDC, vials labeled as single-dose should only be used for one patient and should not be split into multiple single-use vehicles (e.g., syringes) (CDC, 2019).

Also, the USP allows for the contents of a single-dose vial to be prepared into multiple final dosage forms in either an infusion bag or syringe if all the conditions in USP General Chapter 797 are followed (USP, 2016). Some U.S. hospitals with ISO 5 facilities use vial sharing by scheduling multiple patients who are treated with the same drug to come in on the same day, a process known to some as batching (see Chapter 4). Because USP General Chapter 797 has an outsized influence on the extent of vial sharing, its policies have enormous downstream ramifications for public spending by Medicare and private spending by health care payers.

Repackaging single-dose vials into multiple doses creates a billing challenge for the health care system. The expectation is that a single patient is charged for the full vial, not for what was used. This could lead to the system seeking full reimbursement for one vial from each of multiple patients who shared a vial. That is, if two patients are dosed from a single-dose vial, reimbursement for its full cost could be sought from each patient or insurer—potentially at a profit for the system. There are at least two ways to avoid this incentive: produce vial sizes that are better calibrated to the average single dose or refine the reimbursement system to allow the health care system to charge partial amounts. The latter possibility is hindered by the lack of harmonization across agencies as to whether repackaging is appropriate.

CLINICIAN ACQUISITION OF AND PAYMENT FOR DRUGS

The final leg of the journey of single-dose drugs from manufacturer to patient is the administration by a physician and the associated payments for this service. Heath care providers have different arrangements with intermediaries such as distributors and pharmacy benefit managers (PBMs), and with health care payers for obtaining the drugs. The intermediaries typically handle most aspects of the drug-purchasing process on behalf of private payers, federal and state programs, employers, and other payer types.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

Distributors11 negotiate and purchase drugs directly from manufacturers at a discounted rate, and generally follow current good manufacturing practices (CGMPs) to ensure that the drugs are stored appropriately and safely.12 They then sell the drugs to clients at a wholesale acquisition cost plus some negotiated percentage. Distributors may choose not to stock all available sizes of the same product, as this would require additional storage space, suppliers, and transportation expenses and impose a risk that the products may exceed their allowable shelf life before leaving the distribution center. PBMs negotiate contracts and drug prices with drug manufacturers and wholesalers on behalf of payers and pharmacies (NASEM, 2018; Schulman and Richman, 2018). They are significant in the distribution of specialty drugs.13 PBMs manage drug formulary and use management strategies to define the lists of drugs that a physician can administer to a patient and receive reimbursement for based on the individual’s health insurance plan (Royce et al., 2020). PBMs receive payments for their administrative services plus a portion of negotiated rebates from manufacturers (NASEM, 2018; Sood et al., 2017). Some PBMs operate their own specialty pharmacies and offer patients mail services for drugs to be sent to the physician for administration in a practice setting. Currently, many of the largest health insurance companies in the United States have PBMs (Paavola, 2019).14

Clinician Acquisition of Weight-Based Drugs

Traditionally, most clinician-administered drugs have been acquired and distributed by a process known as “buy and bill” (Polite et al., 2014) (see Figure 2-3), under which the health care provider is responsible for managing drug inventory at the practice setting. These health care providers acquire the drugs by purchasing from manufacturers directly or

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11 Three distributors—AmerisourceBergen, Cardinal Health, and McKesson—cover almost 92 percent of the market. In 2017, specialty drugs, many of which are infusible, and injectable drugs that are dispensed in weight-based, single-dose vials, accounted for more than 30 percent of full-line distributors’ revenues (Deloitte, 2019).

12 CGMPs include procedures for storing drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity are not affected.

13Specialty drugs is a general label for medications that are highly expensive, are complex molecularly, have limited availability or a specialized distribution network, have unique storage or shipment requirements, and are used for treating rare and complex disease indications. The pharmacies that stock and distribute these specialty drugs are referred to as specialty pharmacies.

14 UnitedHealth owns both CatamaranRx and OptumRx as PBMs; Aetna now has access to CVS Caremark, the PBM of CVS Health; Anthem owns a PBM called IngenioRx; Cigna merged with Express Scripts; and Humana has an in-house PBM.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Image
FIGURE 2-3 Flow of payments and drugs with buy and bill.
NOTE: For drugs in single-dose vials, physicians are reimbursed for the drug administration fee plus an amount for the quantity of drug that is discarded.

from intermediaries, such as wholesalers or specialty pharmacies; they then store them in their practices, administer them as needed, and submit a claim to either Medicare or the patient’s health insurance. This means that the provider decides which vial sizes to buy and stock, often with no or little knowledge of the types of patients the physicians’ practices and hospital outpatient departments serve. Over the past decade, buy and bill has been criticized for creating incentives for physicians to choose the drug with the higher market-based price in situations where there are therapeutic alternatives (Berndt and Newhouse, 2012).

Currently, some payers have adopted arrangements to circumvent buy and bill for physician-administered drugs that involve contracting with third-party specialty pharmacies that handle drug acquisition instead of the providers directly purchasing the drug. These alternatives are known as white bagging (see Figure 2-4) and brown bagging (see Figure 2-5).

In white bagging, heath care providers purchase patient-specific medication from a pharmacy, typically a specialty pharmacy, and the patient pays the copayment or coinsurance to the pharmacy. The pharmacy delivers the medication directly to the physician’s office, hospital or clinic, and a clinician administers the drug. The payer reimburses the pharmacy. Some health care providers, particularly rural hospitals and smaller clinics, may find it advantageous to use white bagging to avoid concerns about stocking drugs that may not be used before their expiration date.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Image
FIGURE 2-4 Flow of payments and drugs under “white bagging.”
NOTES: For drugs in single-dose vials, physicians are reimbursed for the drug administration fee plus an amount for the quantity of drug that is discarded. The process reduces the opportunity for the physician office, hospital, or clinic to earn margin on the medication itself.
Image
FIGURE 2-5 Flow of payments and drugs under “brown bagging.”
NOTES: For drugs in single-dose vials, physicians are reimbursed for the drug administration fee plus an amount for the quantity of drug that is discarded. The process reduces the opportunity for the physician office, hospital, or clinic to earn margin on the medication itself.
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

Under brown bagging, the specialty pharmacy dispenses the drug directly to the patient, who transports the drug to the health care provider. Again, the physician neither buys nor bills for the drug but is paid a drug administration fee.

Both white bagging and brown bagging reduce a physician’s cost for purchasing and stocking expensive medications. The physician is paid only for the professional services associated with administering the drug. However, since a drug acquired through these means can only be given to the patient for whom it was ordered, any excess in the vial must be discarded even under conditions where vial sharing may be permitted. Also, both methods may increase medication errors, may lead to delays in care, and can negatively impact patient outcomes (ASCO, 2016).

Although some commercial payers are using alternative arrangements that remove providers from the drug acquisition process, buy and bill is still the traditional method of payment for provider-administered drugs (Drug Channels, 2016).

Current Payments for Clinician Administration of Infused or Injected Drugs

The likelihood of discarding drugs is also influenced by how clinicians are reimbursed by payers. Spending on clinician-administered drugs under Medicare Part B is highly concentrated in a relatively small number of drugs (ASPE, 2020). The top 20 drugs in terms of Medicare payment amount accounted for almost 60 percent of the total Part B spending on prescription drugs in 2017 (ASPE, 2020).

As mentioned in Chapter 1, the Medicare Modernization Act of 2003 established average sales price (ASP) as the basis for Medicare Part B drug reimbursement. The ASP payment model reimburses clinicians based on the ASP plus a percentage add-on for administering the drug.15 As a result, the ASP add-on for administration is higher for high-priced drugs than low-priced drugs. Administrative complexity is not necessarily proportional to the ASP, however. The ASP payment model was designed more than a decade ago to cover any added acquisition-related expenses for handling and storing the drugs. An unintended consequence of the current ASP payment model is that it has the potential to incentivize use of higher priced drugs because administration-related payment to clinicians increases with the price of the drug (Jacobson et al., 2010; OIG, 2012; Werble, 2017), many of which have been identified as those with the JW modifier used to indicate discarded drug from single-dose vials. (See Box 2-1 for a discussion on the JW modifier.)

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15 See https://www.congress.gov/bill/108th-congress/house-bill/1 (accessed September 23, 2020).

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

For drugs in single-dose vials, Medicare pays health care providers for the quantity of drug that is administered to the patient and the quantity that is discarded, in addition to the fee for administering the drug.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

Impact of Payment Policy on Patients

When patients are responsible for drug cost-sharing, their share is based on the full content of the single-dose vial even if they received just a portion of it. Traditional fee-for-service Medicare beneficiaries are responsible for up to 20 percent of the Medicare-approved amount for covered Part B prescription drugs (CMS, 2020c), and approximately 81 percent of these beneficiaries have supplemental insurance or drug coverage purchased separately, from Medicaid, or from prior employers to cover some or all of this cost (Cubanski et al., 2019). The other 19 percent of beneficiaries have no supplemental coverage and are required to pay the 20 percent coinsurance for Part B drugs out of pocket, with no cap on annual total out-of-pocket expenses. As a result, part of the cost of the discarded portion of a single-dose vial is passed along to patients, almost always without their knowledge. Although those patients with supplementary insurance are insulated from these costs, patients without it may find that their financial responsibility includes the discarded portion of the drug. Among Medicare beneficiaries with cancer, those without supplemental insurance incur substantially higher out-of-pocket costs than their counterparts with private or other supplemental coverage (Narang and Nicholas, 2017). Therefore, while the number of Medicare beneficiaries affected by this issue may be a small portion of the Medicare population, the people affected face undue burden of out-of-pocket costs.

Thus, in an era where Medicare Part B drug spending is growing faster than drug spending in other federal health care programs, the United States has a tremendous opportunity to realign incentives to encourage health care providers to make the most efficient choices for their patients and to decrease the amount of drugs discarded.

Realigning Incentives for Clinician Administration of Infused or Injected Drugs

In the past decade, proposals from the federal government—from both the U.S. Congress and the executive branch—on paying for clinician-administered drugs have focused on an array of provisions that seek to eliminate misaligned financial incentives and address the growing concerns about rising costs, quality of care, and inefficient spending. One proposal, for instance, has been to change the provider add-on percentage to a flat rate fee (MedPAC, 2015; NASEM, 2018). In other words, health care providers would no longer be reimbursed based on a percentage of the ASP of the drug dispensed. Other proposals have called for developing payment bundles for drugs and services (Werble, 2017) and for using private-sector vendors to procure, distribute, and bill Medicare for certain Medicare clinician–administered drugs (Sachs, 2018).

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

Under the current ASP payment model, prescribers largely determine which drugs are to be purchased, and patient cost-sharing is specified by health insurance plans. Medicare and private payers reimburse health care providers for the drugs they administer based on the drug’s average sales price plus a percentage add-on for administering the drug. Uncoupling the payments from the drug average sales price and focusing the payment for clinical administration on CMS’s assessment of the time and complexity of treatment administration and safety monitoring would minimize incentives for clinicians’ selection and administration of more expensive drugs when alternatives are available. These payments could be made to vary somewhat based on drug categories and classes.

The Center for Medicare & Medicaid Innovation (CMMI), which is managed by CMS, has designed, implemented, and tested new health care payment models to deliver better health outcomes to Medicare beneficiaries while reducing spending. For example, indication-based pricing sets specific prices based on particular drug indications that are paid to the manufacturer according to the expected efficacy of a drug in each of its indications (Chandra and Garthwaite, 2017; CMS, 2018). The oncology care model encourages participating health care providers to improve care and lower costs through episode-based payment approaches (CMS, 2020a). CMS defines an episode as “the set of services provided to treat a clinical condition or procedure” (CMS, 2020b). The episode-based payment approach combines all the payments for services during an episode of illness—from diagnoses, procedures, and drugs furnished to a beneficiary—into a single payment.

Reimbursement by treatment episode rather than by the volume or the vial cost is a form of the episode-based model. The model’s basic idea is to minimize the influence of drug-derived revenue on clinician-administered drugs, given the rapidly rising drug costs and expenditure in the Medicare Part B program. The underlying concern with discarded weight-based drugs is that payers believe that they are paying for discarded medication. One approach to addressing this issue would be to focus on efforts to reallocate unused drugs by sharing vials among multiple patients. As described later in this chapter, to the extent that these practices become widespread, drug manufacturers are likely to adjust prices of their drugs upward to reflect the fact that more patients are being treated by the same amount of a given drug. Raising drug prices combined with the costs associated with developing methods to allocate drugs to multiple patients from single-dose vials would likely not result in any actual financial savings to payers and patients. This would reflect true economic waste in the sense that those resources used to reallocate drugs would not have generated additional cost reductions to payers.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

PATIENT QUALITY OF CARE

The quality of a patient’s care is the most important consideration in every aspect of health care. Specifically, patients who are receiving weight-based drugs need to be able to trust that these drugs are effective and prepared under safe conditions and that medical errors in dosing will be avoided. This section examines patient safety and quality-of-care issues related to weight-based drugs, with a particular focus on the implications for small practices and rural hospitals.

Changing Roles of Health Care Providers

Peeling away all the layers of the drug manufacturing process, public policy, and health care financing, the clinician writes a prescription for a patient for whom a particular dosage of a weight-based drug is expected to treat that patient’s disease or condition. Health care is regulated by professional codes of ethics and guidelines, which are set by a wide variety of professional societies. For any health care professional, the best interest of the patient should be at the core of the practice. At least three ethical principles are at the heart of the provider–patient relationship: beneficence, nonmaleficence, and respect for autonomy. Adhering to beneficence and nonmaleficence, clinicians take actions that maximize their patients’ health and well-being and avoid actions that will unnecessarily harm their patients. When it comes to a drug in a single-dose vial, the goal is to maximize the likelihood that the correct dose is prescribed and the drug is delivered as directed. By its very nature, a single-dose vial is meant to minimize the risk of vial contamination. Repackaging a single-dose vial into smaller doses (dividing the contents of one vial into two or more) increases the risk of vial contamination. While the clinician may be aware that additional compound remains in the vial or enough is left behind to dose another patient, what happens to the vial and its contents is secondary to delivering the appropriate level of care to the patient being treated at that moment.

The ethical norms that ought to guide the practice of clinicians are set and monitored by oversight bodies in the form of licensing and accreditation requirements (IOM, 2000). Additional ethical norms come into play when there is an institutional stakeholder involved in purchasing, delivering, and overseeing medications.

Stewardship

Stewardship in the context of a health care system has at least two meanings. A health care system has a responsibility to care for both

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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its patient population and the overall system that delivers the care to its patients. In the latter sense, being a good steward involves responsibly managing financial and human resources. Stewardship for health care providers in the case of the appropriate use of single-dose vials means balancing the available resources with the best interest of the patient population. This balance likely creates an incentive for some systems to minimize the amount of drug they discard. One way to do this at a health care system level would be to consider drawing multiple doses from a single-dose vial. As discussed earlier, according to the USP, CMS, and FDA, it is possible to repackage the contents of a single-dose vial if all the conditions in USP General Chapter 797 are followed (USP, 2016). The risk of contamination can be minimized, especially when a licensed pharmacist conducts repackaging (dividing a single-dose vial into more than one sterile vial). This approach would make the most sense in a large outpatient setting where multiple patients needing the same medication could be scheduled on the same day for treatment.

Accountability

The health care system is accountable to a variety of stakeholders, including its patients and the purchasers of the health care it delivers. In reference to patients, a health care system should be as transparent as possible in care delivery, including with medications. One concern is that when a single-dose vial is prescribed for a patient, the patient may be unaware that the charge will be for the full vial and not just what was used. Generally speaking, patients do not realize that some of the medication is discarded or that the cost of the discarded portion is billed to their insurance carrier or to them as direct costs in the form of copayment or coinsurance (if they have no insurance). This lack of transparency can lead to economic harm to the patient and leaves the patient out of any public policy discussion about vial size (i.e., patients might demand action if they understood the expense). However, using the single-dose vials as prescribed also minimizes the risk of contamination. Some patients may consider the additional cost acceptable to avoid the additional risk. And, of course, their willingness and ability to pay will vary with the drug’s cost.

KEY FINDINGS

  1. When a dosing regimen based on body size (e.g., body surface area, weight) is used in pivotal studies as part of the drug development process, then that regimen will be approved by the U.S. Food and Drug Administration. Alternatives to weight-based dosing might be just as safe and effective, but comparison of weight-based dosing with alternative dosing is seldom done in pivotal trials.
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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  1. Fixed dosing can eliminate complexities in dosing and administration of drugs, such as the need to use only parts of vials or multiple vials.
  2. Administering medications from multiple different vial sizes may increase the risk of medication error and vial contamination.
  3. Currently, the regulation and guidance on repackaging of drugs contained in single-dose vials, from the U.S. Food and Drug Administration, the Centers for Medicare & Medicaid Services, and the Centers for Disease Control and Prevention, are in conflict.
  4. Medicare and other private payers reimburse health care providers for the drugs they administer based on the drug’s average sales price plus a percentage add-on for administering the drug. As a result, the dollar amount of the add-on is larger for drugs with higher prices.
  5. Health care providers receive reimbursement for the quantity of drug in single-dose vials, including that which is discarded, and patients have cost-sharing responsibility for both the portion they receive and the portion that is discarded.
  6. Regardless of health insurance provider, patients’ financial responsibility in the form of copayments and coinsurance is derived from the cost of the full vial, including any discarded portion of a vial used in their treatment. Medicare beneficiaries without supplemental private or public insurance coverage are responsible for up to a 20 percent coinsurance.

CONCLUSIONS

  1. Empirical evidence supporting the use of weight-based dosing instead of fixed dosing for injectable or infused drugs is limited.
  2. The use of trials considering different dosing strategies (e.g., weight based versus fixed dose) early in the drug development process could help to determine if dosing based on a patient’s body size (e.g., weight or body surface area) provides greater benefit than a fixed dose for a given therapeutic agent.
  3. Regulatory guidance governing vial sharing varies among the U.S. Food and Drug Administration, the Centers for Medicare & Medicaid Services, the Centers for Disease Control and Prevention, and the United States Pharmacopeia, and thus creates ambiguity and confusion for clinicians and health care administrators, although there is limited information about the safety of vial sharing.
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
  1. Under the current system in which drugs are produced, administered or paid for, health care providers do not have incentives that encourage the efficient use of infused or injectable drugs in single-dose vials. They receive payment for up to the amount of drug indicated on the label of a single-dose vial, including that which is discarded. This lack of incentives could discourage efforts to reduce the amount of discarded drugs.

RECOMMENDATIONS16

RECOMMENDATION 2-1: The U.S. Food and Drug Administration should require sponsors of pivotal trials for new or extended therapeutic indications to use fixed dosing for a given clinical indication unless safety and efficacy would be compromised. Manufacturers of products already in the market should consider conducting additional studies after approval so that these drugs can, when indicated, be converted to fixed dosing.

RECOMMENDATION 2-2: The Secretary of the U.S. Department of Health and Human Services should direct the Centers for Medicare & Medicaid Services, the U.S. Food and Drug Administration, and the Centers for Disease Control and Prevention to work with the United States Pharmacopeia and other nonfederal partners, pharmacists, and infectious disease experts to review and harmonize existing policies and guidelines on drug administration and repackaging. These policies and guidelines should be informed by the successful experiences from other industrialized countries in reducing the amounts of discarded drugs.

RECOMMENDATION 2-3: The Secretary of the U.S. Department of Health and Human Services should require the Centers for Medicare & Medicaid Services (CMS) to uncouple add-on payments to clinicians for infused or injected drugs under Medicare Part B from the drug average sales price, focusing the add-on payment instead on CMS’s assessment of the time and complexity of drug management and safety monitoring.17

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16 These recommendations will be discussed fully in Chapter 6.

17 The text in this recommendation was modified since the prepublication release of this report to improve technical accuracy of the language around payments to clinicians for infused or injected drugs under Medicare Part B.

Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×

RECOMMENDATION 2-4: The Secretary of the U.S. Department of Health and Human Services should require the Center for Medicare & Medicaid Innovation to design and evaluate new payment models that reimburse health care providers by treatment episode, rather than by the volume or cost of a drug vial. Findings from the demonstrations should be disseminated widely to other relevant federal agencies, private payers, purchasers, clinicians, and consumers.

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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Page 43
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Page 44
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Page 46
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Page 47
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Page 48
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 49
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 50
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 51
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 52
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 53
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 54
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 55
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 56
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 57
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 58
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
×
Page 59
Suggested Citation:"2 Single-Dose Vials of Weight-Based Drugs." National Academies of Sciences, Engineering, and Medicine. 2021. Medications in Single-Dose Vials: Implications of Discarded Drugs. Washington, DC: The National Academies Press. doi: 10.17226/25911.
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Page 60
Next: 3 Scope of Discarded Drugs from Single-Dose Vials »
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Every year, significant amounts of expensive drugs are discarded. This is due in part to the growing number of prescription drugs that are administered in variable doses (rather than fixed or flat doses) based on a patient's weight or body size. Strict regulations and guidance generally prohibit or severely restrict the acceptable time frame for sharing medication from single-dose vials among patients, and so the unused amount will typically be discarded. Due to the current system for producing, administering, and paying for drugs in the United States, significant - but indeterminate - amounts of expensive prescription drugs are discarded each year.

At the request of the Centers for Medicare & Medicaid Services, Medications in Single Dose Vials: Implications of Discarded Drugs explores the federal health care costs, safety, and quality concerns associated with discarded drugs that result from the weight-based dosing of medicines contained in single-dose vials.

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