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Evidence of CSTD Benefits: A Rebuttal
October 2018 : Cleanrooms & Compounding - Vol. 15 No. 10

NIOSH estimates that approximately 9 million US health care workers may be exposed to hazardous drugs (HDs) based on their work descriptions.1 Recognizing the danger posed to workers by HD exposure, many organizations in the US have implemented guidance documents on safe HD handling practices (see TABLE 1). Similarly, organizations in countries around the world have established guidance documents, in addition to the International Society of Oncology Pharmacy Practitioners (ISOPP), which published international guidance for handling HDs.2,3 In 2016, USP published Chapter <800> Hazardous Drugs—Handling in Healthcare Settings. Chapter <800> is an enforceable standard, containing both best practice recommendations and mandates for reducing the occupational exposure of health care workers who handle nonsterile and sterile HDs.4 USP <800> will become effective December 1, 2019.4

Both USP and ISOPP recommend the use of closed system drug-transfer devices (CSTDs) to reduce worker exposure to HDs. It is important to note that USP <800> recommends CSTDs for the preparation of HDs and requires their use for the administration of HDs. This differentiation is based on the fact that nursing personnel, unlike pharmacy staff, have only personal protective equipment (PPE) to prevent exposure to these drugs, and according to the Hierarchy of Industrial Controls, PPE is the least effective means of protecting workers.5 Conversely, when manipulating HDs, pharmacy staff utilizes engineering controls, which are one of the most effective measures to protect workers; CSTDs are considered a supplement to engineering controls.

As of 2018, there are approximately 10 products on the market that appear to meet the NIOSH description of a CSTD: “A drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system.”6

CSTD Effectiveness

The recently published Cochrane Review, Closed-System Drug-Transfer Devices in Addition to Safe Handling of Hazardous Drugs Versus Safe Handling Alone for Reducing Healthcare Staff Exposure to Infusional Hazardous Drugs, concluded that “There is currently no evidence to suggest that closed-system drug transfer devices in addition to safe handling of infusional HDs offers any health or financial benefits compared to safe handling alone (very low quality evidence).”7

Given that this review article contradicts the guidance established by a wide variety of venerable organizations that endeavor to ensure health care workers are protected from unnecessary exposure to HDs, the review warrants a close examination of both its methodology and conclusions.

Study Inclusion Challenges

There are some significant flaws in the design of the review. Although the review article states that there currently is no evidence to suggest that CSTDs in addition to safe handling practices offer any health or financial benefits compared to safe handling practices alone, the studies reviewed by Gurusamy et al7 were not designed to evaluate health benefits and only five examined financial benefits.

Twenty-three studies were included in the final review out of the 83 that were deemed eligible. Few of the studies that were included in the review were designed to evaluate the efficacy of CSTDs via pre- and post-implementation studies following implementation of one or more of the several types of CSTDs currently on the market. At the same time, other studies were included as part of the review on the basis that some of the institutions conducted surveys of surface contamination and used CSTDs at the time of the surveys. Therefore, surface contamination studies were reviewed alongside studies that were designed to evaluate CSTDs. These studies primarily measured surface contamination for specific drugs, and only 4 of the 23 studies measured the presence of drugs in the urine of health care workers. Studies that are specifically designed to evaluate the efficacy of a CSTD in reducing surface contamination with HDs can control a number of variables, such as time interval between pre- and post-intervention, locations sampled, methodology employed for sampling and analysis, and limiting the number of personnel who do the sampling. On the other hand, when a CSTD is used in a facility where routine sampling is done, there is little to no control over these variables.

In addition, the review authors discounted several simulation studies stating that they were not relevant to the health care setting. While simulation studies may not be appropriate for studies of the effectiveness of drug treatment and other epidemiological studies measuring health effects as the outcome, simulation studies are appropriate for the testing of safety equipment such as gloves, respirators, and engineering controls,5,8 as well as some medical devices, and CSTDs are classified as such by the FDA.9 In fact, simulation studies can be carried out under well-controlled conditions, something that is not possible in health care environments.

Flaws in the Study Evaluation

Each published article included in the review contained the term CSTD either in the title or abstract even though some of the devices in the original studies would likely not meet the current NIOSH definition of a CSTD. Furthermore, some CSTDs may perform better than others; nonetheless, all results were included without any acknowledgement or caveats as to the effectiveness of a given device at controlling contamination. By combining the results of studies that used various brands of CSTDs, the results for studies that showed a reduction in contamination could be diluted by those that did not. There could be many reasons why contamination was not reduced, including less effective CSTDs.

Based on the nature of the original studies, it was not possible to blind the workers as to what was being tested. However, surface wipe samples are typically sent to an analytical laboratory as blinded samples; thus, the chemist would not know the nature of the sample. Nonetheless, all the reviewed studies were reported to have high-risk for bias in measurement of outcomes based at least in part on the non-blinded study design. Applying strict criteria for bias may make sense in other types of studies, such as those evaluating the efficacy of a drug treatment; however, it is not as applicable to these studies, as randomized, controlled studies are not an option. It can be argued that the reviewers’ criteria is overly strict, making it inappropriate to rate the quality of the evidence “very low” for all the studies.

Studies in the review article also received a failing mark for not evaluating health effects, even though the studies were designed only to evaluate surface contamination and/or the presence of one or more HDs in the urine of health care workers. The presence of HDs in urine may be considered a health effect, but this has never been documented by epidemiological studies. None of the original studies reported that they tried to link health effects to the use of CSTDs. Therefore, it was inappropriate for the review article authors to include this parameter in their evaluation.

Glaring Omissions

In one glaring omission, the review article authors disregarded positive findings with cyclophosphamide in their summary even though surface contamination with cyclophosphamide was significantly reduced in several studies, including two US studies by Sessink et al,10,11 and the review article authors themselves reported that the mean overall cyclophosphamide level was reduced by more than one-third. This is a critical oversight because cyclophosphamide, a known human carcinogen, historically has been the drug most commonly sampled in surface contamination studies of antineoplastic dugs and was common to all of the 18 reviewed studies that evaluated surface contamination. Furthermore, it appears that most, if not all, of the 18 studies included data on cyclophosphamide contamination in the pharmacy. And yet, the review authors only included data on cyclophosphamide contamination in the pharmacy from eight of the 18 studies. This oversight resulted in the authors drawing inaccurate conclusions regarding reductions in surface contamination.

Similarly concerning is the fact that the review authors stated that they considered the various study populations to be similar, even though the workers who handled the drugs in the 23 studies varied considerably. The authors grouped oncology nurses, pharmacy technicians, and/or pharmacists who handled the drugs as a single homogenous population. This disregards the fact that handling activities vary considerably for each of these categories of health care workers, and thus exposure opportunities may also vary accordingly.

In Conclusion

It is troubling that the conclusions presented by the review article authors do not represent the intent of the original studies, nor the findings of the original study authors. While CSTDs cannot completely eliminate surface contamination during drug preparation and administration, several studies have shown a reduction in surface contamination after the implementation of a CSTD.10-12 A recent, well-designed study that evaluated a CSTD in 13 US hospitals, which was not available to the Cochrane authors, demonstrated a significant reduction in surface contamination with two drugs.13 It is unfortunate that this review article has the potential to adversely affect the health and safety of so many health care workers who may be exposed to antineoplastic and other HDs over the course of their working lifetime. Certainly, there are a number of factors that can contribute to surface contamination with HDs, including contamination on the vials, workload, technical skill, accidents, etc. Nonetheless, a CSTD is an additional tool available to health care workers to help lower surface contamination and reduce potential exposures to these drugs.

Were we to follow the incorrect logic of the review article authors, we would also need to ask: Do we have definitive studies that demonstrate reduction or elimination of contamination/exposure for chemotherapy gloves, protective gowns, or biological safety cabinets? Were health care facilities to embrace the flawed logic of the review article authors and eliminate CSTDs to reduce costs, they could make a similar argument to save millions of dollars by eliminating other types of safety equipment for which we also do not have data quantifying health benefits.

A robust strategy to protect the health and safety of workers who handle HDs must include training, utilizing engineering and administrative controls, ensuring proper PPE use, and implementing a CSTD. While CSTDs are only one aspect of a comprehensive approach, they are a critical tool in providing a safe working environment for health care workers.

Thomas H. Connor, PhD, received his BS and MS in microbiology from the University of Rhode Island, and his PhD in environmental toxicology from The University of Texas Medical Branch, Galveston. He joined NIOSH in 2001 as a research biologist focusing on occupational exposure to HDs. Tom was the lead author on the NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs, updates to the NIOSH list of hazardous drugs, along with other related NIOSH documents. He recently retired from NIOSH.

Disclaimer

Thomas H. Connor, PhD was a member of the Carmel Pharma Board of Directors when they were the manufacturers and distributors of the PhaSeal CSTD. He was a reviewer for the protocol and final Cochrane Review on CSTDs discussed in this article.7


Table 1

Organizations Providing Safe Handling Guidance

With the clear need for personnel protection from HDs, a wide variety of US and international organizations have implemented guidance documents to ensure that health care workers utilize safe handling practices for HDs:

Table References

  1. Power LA, Coyne JW. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/handling-hazardous-drugs.ashx. Accessed September 6, 2018.
  2. International Society of Oncology Pharmacy Practitioners. Standards of practice: Safe handling of cytotoxics. J Oncol Pharm Pract. 2007;13:1-81.
  3. National Institute for Occupational Safety and Health (NIOSH). Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. www.cdc.gov/niosh/docs/2004-165. Accessed September 6, 2018.
  4. United States Department of Labor. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. www.osha.gov/SLTC/hazardousdrugs/controlling_occex_hazardousdrugs.html. Accessed September 6, 2018.
  5. Polovich M, Olsen M, LeFebvre, K. Chemotherapy and biotherapy guidelines and recommendations for practice (4th ed). Pittsburgh, PA: Oncology Nursing Society; 2014.
  6. Polovich M, Olsen M. Safe handling of hazardous drugs (3rd ed). Pittsburgh, PA: Oncology Nursing Society; 2017.
  7. United States Pharmacopeial Convention. USP general chapter <800> hazardous drugs—handling in healthcare settings. www.usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare. Accessed September 6, 2018.

References

  1. United States Department of Labor. Bureau of Labor Statistics. Employment projections: Industry-occupation matrix data, by occupation. www.bls.gov/emp/tables/industry-occupation-matrix-industry.htm. Accessed September 6, 2018.
  2. International Society of Oncology Pharmacy Practitioners. Standards of practice: safe handling of cytotoxics. J Oncol Pharm Pract. 2007;13:1-81.
  3. Mathias PI, MacKenzie BA, Toennis CA, et al. Survey of guidelines and current practices for safe handling of antineoplastic and hazardous drugs used in 24 countries. J Oncol Pharm Pract. 2017; Jan:1078155217726160. doi: 10.1177/1078155217726160. [Epub ahead of print]
  4. United States Pharmacopeial Convention. USP general chapter <800> hazardous drugs—handling in healthcare settings. www.usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare. Accessed September 6, 2018.
  5. National Institute for Occupational Safety and Health (NIOSH). Hierarchy of controls. www.cdc.gov/niosh/topics/hierarchy/default.html. Accessed September 6, 2018.
  6. National Institute for Occupational Safety and Health (NIOSH). A vapor containment performance protocol for closed system transfer devices used during pharmacy compounding and administration of hazardous drugs. www.cdc.gov/niosh/docket/review/docket288/default.html. Accessed September 6, 2018.
  7. Gurusamy KS, Best LM, Tanguay C, et al. Closed-system drug-transfer devices in addition to safe handling of hazardous drugs versus safe handling alone for reducing exposure to infusional hazardous drugs in healthcare staff. Cochrane Database Syst Rev. 2018;Mar(3):CD012860.
  8. Controlled Environment Testing Association [CETA]. CETA compounding isolator testing guide: CAG-002-2006. www.escoglobal.com/resources/pdf/CETA_Compounding_Isolator_Testing_Guide_2006.pdf. Accessed September 6, 2018.
  9. US Food and Drug Administration (FDA). Premarket notification (510k). www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/
    premarketsubmissions/premarketnotification510k/default.htm. Accessed September 6, 2018.
  10. Sessink PJ, Connor TH, Jorgenson JA, et al. Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device. J Oncol Pharm Pract. 2011;17(1):39-48.
  11. Sessink PJ, Trahan J, Coyne JW. Reduction in surface contamination with cyclophosphamide in 30 US hospital pharmacies following implementation of a closed-system drug transfer device. Hosp Pharm. 2013;48(3):204-212.
  12. Clark BA, Sessink PJ. Use of a closed system drug-transfer device eliminates surface contamination with antineoplastic agents. J Oncol Pharm Pract. 2013;19(2):99-104.
  13. Bartel SB, Tyler TG, Power LA. Multicenter evaluation of a new closed-system drug-transfer device in reducing surface contamination by antineoplastic hazardous drugs. Am J Health-Syst Pharm. 2018;75(4):199-211.

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