In Selecting Closed-System Transfer Devices, Anticompetitive Bundling Practices Put Health Care Professionals at Risk

Closed-system transfer devices (CSTDs) mechanically prohibit the transfer of environmental contaminants into the system and prevent hazardous drug or vapor concentrations to escape outside the system, according to the National Institute for Occupational Safety and Health (NIOSH).

In the United States, the first CSTD was approved in 1998, and was followed by several other devices that were approved based on 510(k) submissions. These 510(k) submissions are meant to indicate substantial equivalence to the reference product. In some cases, 510(k) submissions are also accompanied by a special designation known as an ONB code, which indicates that additional data has been submitted demonstrating the efficacy of the medical device.

Currently, 6 CSTDs have been approved by the FDA: Equashield, PhaSeal, ChemoClave, ChemoLock, Vialshield, and Onguard/Tevadaptor.^1,2 Based on the definition of a CSTD, these products serve 2 important functions: reducing hazardous drug exposure in health care professionals compounding and administering these therapies, and preventing the transfer of environmental contaminants into parenteral medications.^1,2

The Occupational Safety and Health Administration (OSHA) has recognized the risks of compounding and administering hazardous drugs, including the potential for “splattering, spraying, and aerosolization” of these medications, which may result in accidental exposure of health care professionals. Health consequences of chronic, low-level exposure to these medications include the potential for genotoxic, teratogenic, and carcinogenic effects.³

In recognition of these risks, the United States Pharmacopeia has developed the USP <800> standard to help reduce the risk of exposure to hazardous medications in all health care professionals. In addition to requiring new processes for handling, storage, and compounding of hazardous drugs, these guidelines recommend the use of CSTDs in the pharmacy environment, and require use of CSTDs during administration of hazardous drugs to patients.

Because USP <800> is a legally enforceable standard, CSTDs will eventually be used in all health care facilities where hazardous drugs are prepared and administered.² Although all 6 CSTDs currently on the US market have been approved by the FDA, these approvals were not based on a single, standardized test. In some cases, evidence supporting CSTD protective efficacy is based on studies performed in laboratories under conditions that are not reflective of real-world conditions.

Considering the widespread use of CSTDs mandated by USP <800>, and the importance of protective efficacy, NIOSH developed a protocol for testing all available CSTDs under the same conditions. In this way, CSTDs may be compared directly, enabling health care professionals to make an informed decision when selecting a product to protect their health, and the health of their patients.³

The NIOSH Protocol

The NIOSH protocol was designed to establish which CSTDs are truly effective in preventing drug vapors or liquids from escaping into the environment. This performance protocol enables unbiased comparison of CSTDs, and provides some basis for choosing a product based on its comparative efficacy with other systems. According to NIOSH, this protocol is not applicable to CSTDs that use an air-cleansing system (also known as filter venting systems), as only products that are closed from the outside environment can be evaluated.^4,5

In the past, several attempts to assess CSTDs have included use of the inorganic tracer gas sulfur hexafluoride, lactose powder, and fluorescent compounds. However, for this protocol, NIOSH settled upon 70% isopropyl alcohol (IPA) as a tracer compound, due to its propensity to generate vapor at room temperature, its ubiquity, and the availability of equipment to reliably measure concentrations of IPA within a test environment using a gas analyzer (the Miran SapphIRe detector, which reports IPA concentrations in parts per million once per second).^4,5

Per the NIOSH protocol, the detector continuously measures IPA concentrations in a sealed environmental test chamber (Secador Techni-dome 360 Large Vacuum Desiccator) where CSTD manipulations occur. Furthermore, the CSTD test protocol specifies testing for several types of connections made with CSTDs, including connection of the CSTD with several types of adaptors. These may include adaptors that connect with vials, ports, Y-sites, and intravenous bags.4 IPA detectors have an important limitation: they cannot establish that zero IPA has escaped from a CSTD.

However, they can establish that IPA is not present at concentrations above a lower limit of detection, below which the detector cannot reliably establish IPA levels. For the Miran SapphIRe detector, this limit of quantification is 1 part per million—an astonishingly low concentration that is equivalent to 1 teaspoon of water in a 5000-liter tank. According to NIOSH, this setup offers assurance that, “CSTD performance was as good as could possibly be measured using the particular instrument within the evaluation protocol.”⁴

Results of Independent Tests With CSTD Systems

CSTDs fall into 2 general categories: mechanically closed systems, and systems that rely on a carbon filter, which are also known as filter-vent systems, or “air-cleansing” systems. Filter-vent systems include Texium/SmartSite, Onguard/Tevadaptor, and ChemoClave. Importantly, all but 1 of these CSTD manufacturers have an available mechanically closed system, with the exception of 1 maker: B. Braun/Teva, the manufacturer of OnGuard/Tevadaptor (Table 1).⁶

NIOSH states that filter-vent systems cannot be evaluated using the NIOSH protocol. To identify the reasons for exclusion of filter-vent systems from the NIOSH protocol, and evaluate available systems, Fred Massoomi, PharmD, FASHP, pharmacy operations coordinator for Nebraska Methodist Hospital Pharmacy, performed a series of exploratory tests subjecting each of the 6 available CSTDs to the protocol procedures.³

These independent tests simulated manipulations that typically occur in the preparation and administration of intravenous medications. In the first test, researchers simulated 1) preparation of an intravenous bag, and 2) the transfer of medication from a vial into the Y-site of an intravenous bag at bedside. In the course of these tests, a total of 8 manipulations were performed for each of 6 systems, with manipulations defined as transfer of IPA 70% from vials to intravenous bags/tubing within the sealed environmental test chamber. The number of manipulations resulting in IPA readings above 1 part per million for each system.³

Using the Equashield and Phaseal systems, none of the 8 manipulations resulted in IPA readings above 1 part per million, whereas ChemoLock registered higher levels in 2 cases, and ChemoClave, VialShield and OnGuard/Tevadaptor failed on the test for all 8 manipulations. Moreover, only the Equashield and Phaseal systems maintained IPA levels below the lower limit of detection across all manipulations performed (Table 2).³

In a second independent test, Massoomi and colleagues tested each CSTD system using litmus paper applied to the membranes of components that are connected during transfer of 5-fluorouracil from a vial to a CSTD. Because 5-fluorouracil is a very basic drug, with a pH of approximately 9.2, any color change indicates potential leakage of medication. Each litmus test was performed a total of 20 times for each product, with tests judged as a success or failure based on the presence or absence of a color change.³

Only one device, Equashield, did not show any leakage on this test (a 0% failure rate). The next-best performing systems were Phaseal, which had a failure rate of 30%, and ChemoLock, which had a failure rate of 85%. Three systems—ChemoClave, VialShield, and On/Guard Tevadaptor&mdash;failed all 20 tests, with major leaks detected on all samples (Table 3).³

Pharmacy Choice in CSTDs

Although the FDA has approved CSTDs as a monolithic category, the studies used to approve them have not followed a single protocol. Under the NIOSH protocol, all systems were tested using a single method, enabling health care professionals to make a decision as to which systems will provide optimal protective efficacy for them, and their patients. As discussed, results of testing using the NIOSH protocol are inconsistent with the FDA’s categorization of products that are considered CSTDs as “substantially equivalent.”³

Rather than recognizing an evolving scientific understanding of CSTD efficacy, policy makers have entered into the debate, criticizing the NIOSH protocol, and attempting to suppress the lability of health care professionals to act on a new scientific understanding of CSTDs. This political action to limit CSTD choice includes a letter to NIOSH from US Rep Charles W. Dent (R-PA) and US Rep Rosa DeLauro (D-CT) encouraging NIOSH head John Howard, MD, to reexamine the protocol, to consider a communication from Teva/B. Braun delivered through diplomatic channels.

This communication led NIOSH to delay review of the protocol by 120 days, and successfully forced modifications to the protocol pursuant to comments from the private pharmaceutical firm.^7,8 To justify this position, detractors of the NIOSH protocol cite concerns with creating an unfair advantage for one manufacturer over another. However, considering that suppression of the NIOSH protocol creates a competitive advantage for Teva/B. Braun, in some quarters, suppressing the NIOSH protocol may be considered anticompetitive.^7,8

Analogous situations have occurred in the area of drug development with no concerns or outside interference from policy makers. For instance, in 2010, the FDA mandated cardiovascular safety studies for all antidiabetic drugs. When 2 studies showed a cardiovascular benefit (with empagliflozin and liraglutide), policy makers did not intervene on the basis of creating an unfair competitive advantage for these products.

It would be unusual for policy makers to involve themselves in the design of a trial evaluating pharmaceutical products, and in the same way, it is unusual for policy makers to prevent standardized testing of medical devices.^9-11

Financial Pressure on Hospitals

In addition to exerting political pressure, Teva/B. Braun uses financial pressure to force hospitals and health care systems to use OnGuard/Tevadaptor, overruling the concerns of health care professionals who use their products. Teva/B. Braun is able to exert this pressure because the company manufactures a range of medical devices, many of which are already purchased by hospitals on a regular basis as part of long-term contracts.

Through these contracts, representatives of Teva/B. Braun can increase or decrease the price of these other supplies, at will. Hospitals that agree to use OnGuard/Tevadaptor receive a price advantage, and hospitals that use another product to improve safety are penalized through increased prices on other medical equipment.^12-14

Exerting financial pressure through existing contracts, known as “bundling,” can prevent health care professionals from obtaining protective equipment to safeguard their health. Many health care professionals have publicly expressed outrage at this practice.

Some examples are listed below:

• Tim Bassett, RPh, director of pharmacy of Spooner Health System, Inc, in Spooner, Wisconsin, wrote: “I’m writing to defend my right as a health care professional to choose a CSTD based on published studies AND my professional opinion to protect my employees and patients. B. Braun’s ‘filtering’ device utilizing activated charcoal is NOT a ‘closed system,’ and should not be considered such. B. Braun’s massive ad campaign touting their product as compliant is simply not true. Furthermore, hospitals and health care facilities that are contracted with B. Braun to use their IV solutions, pumps, and IV administration sets are being REQUIRED to buy their ‘supposed’ CSTD. This is bundling, and not legal in our opinion, besides the fact that we are being forced to buy a product (of forfeit our contract) that we believe to not be as safe as others on the market. This is a safety matter, not a marketing one; and patient/worker safety should NEVER be ‘bundled’.”¹²

• Travis Dash, PharmD, a clinical pharmacist specializing in hematology/oncology at Agnesian HealthCare, commented: “At my organization, I was blindsided by B. Braun when I was pressured to implement the OnGuard system due to contractual obligations. The decision on using a CSTD should not be based on product bundles of medication shortages, but instead on sound scientific evidence. During my uphill battle with B. Braun, I performed a thorough assessment of the OnGuard system, and found the following: 1) ‘Filter-based system’ does not meet the definition of NIOSH, nor does it meet the definition of ISOPP for what should be considered a closed system. 2) B. Braun OnGuard does not have any peer-reviewed evidence on contamination prevention. A hospital/clinic will not use a medication based on white paper evidence, and I feel that CSTDs should be no exception. 3) The OnGuard system has been on the market for 8 years, and no facility has published a peer-reviewed study on its ability to reduce exposure, only company-generated white papers. 4) OnGuard is not compatible with docetaxel, DMA, paclitaxel, Treanda (aqueous), and other cytotoxic agents. At our facility, we want to be protected against all medications, not just some. 5) The OnGuard system is not considered to be a CSTD in its home country of manufacture in Israel, (2006), and was banned for sale in Sweden (2008), under a court ruling.”¹³

• James Jorgenson, RPh, MS, FASHP, chief executive officer & chairman of the board, Visante, Inc. & Visante Limited, wrote, “Organizations such as the American Society of Hospital Pharmacists have stated that they do not consider filtration-based systems closed. The International Society of Oncology Pharmacy Practitioners has stated that a CSTD must be ‘airtight and leak-proof.’ Clearly, an air cleaning or filtration system is not airtight. These types of products should not even be included in the category of CSTDs.”¹⁴

Health care professionals are not the only stakeholders expressing concern. ICU Medical published a white paper on bundling, entitled “breaking the bundle” noting that: 1) bundling creates financial disadvantages for smaller vendors with clinically preferred products, 2) bundling may force hospitals to pay a higher price for inferior technology, and 3) in some cases, large vendors may attempt to rush hospitals into a bundled contract without considering alternatives.

In an important lesson presented in the white paper, ICU noted a case study in which the vendor of a clinically preferred product arranged a discount to outcompete a bundled contract.¹⁵ Another manufacturer, Equashield, is running an advertising campaign analogizing the situation with CSTDs to sales of scuba gear. In the advertisement, a sign next to a leaky scuba tank reads, “add this tank to the bundle and save and additional 20% off everything,” drawing attention to the absurdity of the practice.

Medications are chosen based on peer-reviewed evidence. A hospital would never bundle an inferior product made by one pharmaceutical company to save money on another product. The same standard should be applied to medical devices.

Conclusions

CSTDs help reduce exposure to medications that, even with low-level exposure, can cause serious long-term health consequences in health care professionals. As shown by tests on all commercially available systems using the NIOSH protocol, CSTDs are not a monolithic group of products. Health care professionals should decide which products are best for their institution.

Through the anticompetitive practice of bundling, unscrupulous manufacturers are forcing health care professionals to use clinically inferior products. Pharmacists must be aware of the available evidence, and should make evidence-based decisions based on their clinical judgement without interference.

References

• Centers for Disease Control and Prevention. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. http://www.cdc.gov/niosh/docs/2004-165/pdfs/2004-165.pdf. Accessed July 2016.
• Page MR. USP <800>: New Regulations to Protect Health Care Workers from Hazardous Drugs. http://www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2015/april-2015/usp-800-new-regulations-to-protect-health-care-workers-from-hazardous-drugs. Accessed September 2016.
• Page MR. Independent Tests Show Key Differences in Protective Efficacy of CSTDs, with Important Implications for Pharmacists. http://www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2016/july-2016/independent-tests-show-key-differences-in-protective-efficacy-of-cstds-with-important-implications-for-pharmacists/. Accessed September 2016.
• NIOSH. A Vapor Containment Performance Protocol for Closed System Transfer Devices Used During Pharmacy Compounding and Administration of Hazardous Drugs. http://www.cdc.gov/niosh/docket/review/docket288/default.html. Accessed September 2016.
• Massoomi F. Assessing Vial Transfer Devices for Handling Hazardous Drugs. http://www.pppmag.com/article_print.php?articleid=515. Accessed September 2016.
• Page MR. Closed-System Transfer Devices: Design Characteristics and Evolving Performance Standards. http://www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2015/december-2015/closed-system-transfer-devices-design-characteristics-and-evolving-performance-standards. Accessed September 2016.
• Regulations.gov. Comments received from Congressmen Dent and DeLauro and response from Dr. John Howard (NIOSH). https://www.regulations.gov/document?D=CDC-2015-0075-0021. Accessed September 2016.
• Regulations.gov. NIOSH response to incoming comments received from Anat Katz (Embassy of Israel) and follow-up responses. https://www.regulations.gov/document?D=CDC-2015-0075-0016. Accessed September 2016.
• Hirshberg B, Raz I. Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. Diabetes Care. 2011;34(suppl 2):S101-S106.
• Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827.
• Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.
• Regulations.gov. Comment from Tim Bassett. https://www.regulations.gov/document?D=CDC-2015-0075-0011. Accessed September 2016.
• Regulations.gov. Comment from Travis Dash. https://www.regulations.gov/document?D=CDC-2015-0075-0026. Accessed September 2016.
• Regulations.gov. Comment from James Jorgenson. https://www.regulations.gov/document?D=CDC-2015-0075-0014. Accessed September 2016.
• ICU Medical. Maximizing Savings on Clinically Preferred Infusion and Oncology Consumables by Avoiding Bundled Contracts that Jeopardize the Bottom Line. Accessed September 2016.