. A new peer review was not conducted. In very few cases, if any, would sufficient studies be available to conduct a formal meta-analysis relating to a specific drug. NIOSH response: The daily therapeutic dose at which serious organ toxicity, developmental toxicity, or reproductive toxicity occurs (10 mg/day in human adults and 1 mg/kg per day in laboratory animals) has long been used by the pharmaceutical industry to develop occupational exposure limits (OELs) of less than 10 μg/m after applying appropriate uncertainty factors. Although rare, NIOSH notes any labeling changes that could affect the status of a drug that has been previously classified as hazardous. of the issuing agency. All relevant comments received will be posted without change to www.regulations.gov, including any personal information provided. When studies are available for review of a drug being considered for placement on the List or for the reevaluation of a drug already on the List, quality may be evaluated by NIOSH scientists and independent peer reviewers on a case-by-case basis. The draft Policy and Procedures used to develop the drugs proposed for placement on the List in the February 2018 FRN described the methodology used by NIOSH since 2010. Commenters included pharmacists, professional organizations and associations, pharmaceutical manufacturers, medical centers and/or health systems, individuals who provided their names but not their affiliations, a company that provides risk assessments, a drug database, an insurance company, a medical school professor, a neurologist, and an anonymous commenter. Federal Register provide legal notice to the public and judicial notice The specific backgrounds of the professional staff engaged in the evaluation process may change over time, but NIOSH is committed to a high-quality process conducted by a team of professionals with the needed knowledge and experience. Comment: NIOSH should identify those drugs that pose a realistic risk to healthcare workers by considering such occupation exposure factors as drug type (e.g., small molecule, biologic), stability, dosage form, and route of exposure, and then evaluating them against the toxicity criteria. Two very similar drugs may have substantially different toxicities and at different doses. NIOSH response: NIOSH has not conducted a formal meta-analysis or systematic review for any drug currently on the List. Is the reconsideration process for addition or deletion of a drug to/from the hazardous drug list adequately described? What changes could be made to improve the utility of the information? .”. offers a preview of documents scheduled to appear in the next day's The draft Managing Hazardous Drug Exposures: Information for Healthcare Settings, which is in the docket for this activity, is intended to assist employers in establishing their own hazardous drugs management procedures specific to their workplace. “'When available, published, peer-reviewed scientific literature about the hazard potential of a particular drug, including any studies cited in the package insert that are relevant to workers in a health care setting.' USP added clarification about the application of chapter <800> to hazardous drugs, which can be found on its FAQ page.. If the latter is the case, could a sentence be added to clarify that?”. NIOSH consulted four independent peer reviewers, who were asked to consider the following questions: Overall, the independent peer reviewers found the draft Policy and Procedures to be clearly written and supported by the available science and the reconsideration process (now referred to as “reevaluation”) to be adequate. Public comments on the drugs and drug class proposed for placement on the List in 2018 are summarized and answered below. Saving Lives, Protecting People, The National Institute for Occupational Safety and Health (NIOSH), NIOSH Procedures for Developing the NIOSH List of Hazardous Drugs in Healthcare Settings, Draft NIOSH List of Hazardous Drugs in Healthcare Settings, 2020, Managing Hazardous Drug Exposures: Information for Healthcare Settings, National Institute for Occupational Safety and Health, U.S. Department of Health & Human Services. NIOSH should consider whether reliance on the AHFS Class 10:00 (antineoplastic agents) alone “is enough to necessitate Table 1 Start Printed Page 25449inclusion even if a drug does need to be on the NIOSH list.”. Comment: The List seems to be heavily weighted toward older drugs.Start Printed Page 25444. For example, NIOSH found that ibrutinib had developmental effects in animals but only at doses twice the maximum recommended human dose of 560 mg/day. The rationale for placing interferon beta-1b on the List is that information from the package insert indicated reproductive toxicity: spontaneous abortion in human clinical trials. 2. . on NARA's archives.gov. Accordingly, NIOSH continues to propose placing ivabradine on the List. The value for “low dose” should be drug-specific and a function of several factors such as normal therapeutic doses, body weight, and length of exposure. documents in the last year, 34 Centers for Disease Control and Prevention. The most important criteria for the review of human studies are strength of association, temporality, plausibility, and biological gradient. The new drafts, entitled the Procedures for Developing the NIOSH List of Hazardous Drugs in Healthcare Settings (Procedures) and the NIOSH List of Hazardous Drugs in Healthcare Settings, 2020 (List) are found in the Supplemental Materials tab of the docket and are available for public comment, as discussed above. NIOSH has determined that grouping all antineoplastic drugs together in one table is no longer the most useful or informative for users. NIOSH response: Although NIOSH typically reviews the FDA database on a monthly basis, the draft Procedures no longer specifies or indicates a frequency of database review to allow for flexibility in the event of unforeseen circumstances. In my opinion, a review of any animal studies should be conducted as they may offer insight regarding the potential risk posed by a drug. Darbepoetin alfa should not be placed on the List. Public Comment Summaries and NIOSH Responses, B. What improvements could be made to this risk management information to make it more useful to employers and healthcare workers? NIOSH list of hazardous drugs in healthcare settings 2020. documents in the last year, 929 It is not an official legal edition of the Federal . In rats, exenatide administered during the period of organogenesis reduced fetal growth and produced skeletal ossification deficits at doses that approximate the maximum recommended human dose. As such, the use of animal studies to evaluate the hazardous nature of a drug should be explicitly stated.”. Nine commenters expressed the sentiment that the List would be more useful if it identified drugs that pose a realistic risk to healthcare workers. Eric Maroyka, Senior Director, Center on Pharmacy Practice Advancement sits down with Patricia C. Kienle, MPA, BCSCP, FASHP, and Michael Ganio, Senior Director, Pharmacy Practice and Quality to discuss aspects of the draft The National Institute for Occupational Safety and Health (NIOSH) List of Hazardous Drugs in Healthcare Settings 2020. In light of these changes, NIOSH proposes a new List structure, described in the preamble to the draft List, which is available for review in the docket for this activity. 6. Therefore, in accordance with the draft Procedures some monoclonal antibodies may not meet the NIOSH definition of the term “hazardous drug.” Because the list of drugs proposed for placement on the List has been updated based on the draft Procedures, the monoclonal antibodies bevacizumab and trastuzumab are no longer proposed for placement on the List. In embryo-fetal development studies of dihydroergotamine mesylate nasal spray, intranasal administration to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weights and/or skeletal ossification at doses approximately 0.4-1.2 times the exposures in humans receiving the maximum recommended daily dose of 4 mg or greater. Persons with disabilities experiencing problems accessing this page should contact CDC-INFO at CDC-INFO email form: http://www.cdc.gov/info/, 800-232-4636 or the TTY number at (888) 232-6348 and ask for a 508 Accommodation PR#9342. Are the screening and evaluation categorization processes described by the draft policy and procedures scientifically sound? The other 273 were screened and the information available for 44 drugs suggested one or more toxic effects; those drugs were evaluated by NIOSH and shared with peer reviewers and stakeholders. Manufacturer recommendation: that females of reproduction potential use effective contraception during and for four months after completing therapy. The individuals and organizations who commented on this issue felt that USP's use of the NIOSH List raises the List to the level of a regulatory action, and should include only antineoplastic drugs on Table 1. The OFR/GPO partnership is committed to presenting accurate and reliable The President of the United States issues other types of documents, including but not limited to; memoranda, notices, determinations, letters, messages, and orders. This criterion is typically only used when toxicity information specific to the drug under evaluation is insufficient or unavailable but is available for the chemical analog. However, because NIOSH has reaffirmed in the draft Procedures that only those drugs approved by the FDA Center for Drug Evaluation and Research are included in the List, BCG is no longer included in the List. NIOSH response: NIOSH relies on a range of knowledge, experience, and skills to evaluate drugs for placement on the List, including but not limited to pharmacology, toxicology, medicine, and risk evaluation. NIOSH response: NIOSH concurs with commenters that the evidence of carcinogenicity for darbepoetin alfa in patients who did not already have cancer was insufficient to support a NIOSH finding of carcinogenicity. The draft Procedures considers the toxicity criteria in the definition of a hazardous drug to identify the hazard and some intrinsic molecular properties to characterize the hazard  Relevant information about this document from Regulations.gov provides additional context. It is unclear why animal studies were not included as a source of evaluating potentially hazardous drugs. As stated in the OMB Final Information Quality Bulletin for Peer Review (Bulletin), “[p]eer reviewers shall be charged with reviewing scientific and technical matters. NIOSH response: NIOSH's rationale for proposing the placement of triazolam on the List was that it mimics the benzodiazepines which are included on the List because they are teratogenic or cause other developmental effects. Fluconazole is included in the List on Table 3, but for two newer azole antifungals, the available information showed a toxic effect that does not meet the NIOSH definition of a hazardous drug (ketoconazole) and information does not demonstrate or support that the drug meets the NIOSH definition (itraconazole) in the FRN. NIOSH response: Drugs still under investigation are not included on the List because no scientific information, including information normally provided in package inserts, is available for NIOSH review. Changes to the List structure would place all drugs that meet the NIOSH definition of a hazardous drug and contain MSHI in the package insert and/or are classified by the National Toxicology Program (NTP) as “known to be a human carcinogen,” or classified by the International Agency for Research on Cancer (IARC) as “carcinogenic” or “probably carcinogenic” on Table 1. Comment: Peer reviews should be conducted before the close of the public comment period to allow public commenters time to review them. According to the reviewer, “[t]his approach may not be appropriate if indeed the purpose of the screening is to protect the health and well-being of workers who may be exposed to hazardous drugs. The new iteration is now referred to as “draft Procedures” throughout this notice. Does the draft policy and procedures clearly describe the process used by NIOSH to screen and evaluate drugs? 12/02/2020, 40 Comment: The language in the section titled “Application” indicates that the draft Policy and Procedures do not apply to healthcare workers who handle recombinant therapeutic proteins. I wonder whether the current regulatory climate permits NIOSH any level of control over the handling of drugs in this category.”. Is the information threshold scientifically sound? NIOSH response: Only a few of the drugs on the List are known to have an appreciable vapor pressure; reliable information concerning the vapor pressure of most drugs can be difficult to identify. The National Institute for Occupational Safety and Health (NIOSH) of the Centers for Disease Control and Prevention (CDC), in the Department of Health and Human Services announces that the following draft documents are available for public comment: (1) NIOSH Procedures for Developing the NIOSH List of Hazardous Drugs in Healthcare Settings (Procedures); (2) NIOSH List of Hazardous Drugs in Healthcare Settings, 2020 (List), including those drugs proposed for placement on the 2020 List, and (3) Managing Hazardous Drug Exposures: Information for Healthcare Settings. The inclusion of MSHI makes such drugs automatically hazardous under the NIOSH definition and thus, the extensive review process is not required. Reproductive toxicity/teratogenicity: The FDA classifies lapatinib as pregnancy category D indicating positive evidence of human fetal risk. Comment: NIOSH should include the professional qualifications of the NIOSH staff who perform these evaluations. On October 15, 2020, the FDA reissued the Emergency Use Authorization (EUA) for Non-NIOSH-Approved Disposable Filtering Facepiece Respirators Manufactured in China to … Because dosage forms can change and new dosage forms may be approved, dosage form is not considered in making List placement determinations. NIOSH response: In 2004, NIOSH used lists from several organizations as examples of hazardous drugs. Peer review comment: NIOSH should add “administrative controls” when discussing engineering controls, personal protective equipment, and other steps to manage the risk of exposure, because of their significance “in the well-accepted hierarchy of controls for minimizing exposure to workplace hazards.”. Ibrutinib was identified as a drug for which the available information shows a toxic effect that does not meet the NIOSH definition of a hazardous drug; blinatumomab was proposed for placement on the List on the basis of evidence which shows the drug is a neurotoxin at low doses. The large molecular size limits dermal absorption and aerosolization. Sargent EV and Kirk GD , Establishing Airborne Exposure Control Limits in the Pharmaceutical Industry, Am Ind Hyg Assoc J 49(6):309-13; Naumann BD and Sargent EV , Setting Occupational Exposure Limits for Pharmaceuticals, Occup Med 12(1):67-80; Sargent EV, Naumann BD, Dolan DG, Faria EC, Schulman L , The Importance of Human Data in the Establishment of Occupational Exposure Limits, Hum Ecol Risk Assess 8(4):805-822. All are open for a 60 day comment period. NIOSH response: The NIOSH List creates no legal obligation for its users; it is informational, not regulatory, in content. For some of these drugs, no drug-specific data were available in the package inserts to support warnings in the inserts regarding developmental or reproductive effects; for other drugs, the toxic effects occurred at doses higher than human recommended doses. Significant peer review and public comments on the draft Policy and Procedures are summarized and answered below in Section II; public comments on specific drugs are summarized and answered below in Section III. Because dosage forms can change and new dosage forms may be approved, dosage form is not considered in making List placement determinations. These drugs should be placed on the List because of their teratogenic and/or reproductive effects or the rationale for not proposing their placement on the List should be further explained. . Because the way cancer is treated therapeutically has changed, and the types of drugs used to fight cancer have changed, antineoplastic drugs are no longer all cytotoxic, genotoxic, and highly hazardous chemicals. establishing the XML-based Federal Register as an ACFR-sanctioned Comment: Exenatide should not be placed on the List. The NIOSH List of Hazardous Drugs in Healthcare Settings, 2020, A. The Federal Register Notice for the Draft of the 2020 NIOSH List of Hazardous Drugs is now available. May 2020.  It is unclear if NIOSH will conduct meta-analyses to test for consistency of results; how NIOSH will interpret evidence for, or absence of, concordance across species or between structural analogs of the drug; whether NIOSH will conduct categorical regression analyses to evaluate dose-response data; and how NIOSH evaluates routes of exposures. are not part of the published document itself. Draft NIOSH List of Hazardous Drugs in Healthcare Settings, 2020: Summary of Changes, C. NIOSH List of Hazardous Drugs in Healthcare Settings, 2020—Title, Reorganization, and Removals, IV. For example, three drugs were added to the 2016 List after it was initially published; they are identified on the NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016 web page, https://www.cdc.gov/niosh/docs/2016-161/default.html. In addition, there are no reports of teratogenicity, developmental toxicity, embryo-fetal toxicity, lethality, or reduced growth in clinical trials conducted in humans, or in real world use since FDA approval in 2015. Similarly, small-molecule kinase inhibitors, such as afatinib, crizotinib, dabrafenib, and imatinib, act through a targeted mechanism of action and are not directly cytotoxic; they primarily pose a reproductive and teratogenic risk. regulatory information on FederalRegister.gov with the objective of This drug was reviewed by NIOSH for a previous update to the, This drug was reviewed by NIOSH and presented in the 2018 FRN; it did not meet the criteria for a hazardous drug. Peer review comment: NIOSH should clarify whether a drug may be removed from the List based on changes to the package insert, “or if written requests from interested parties to the NIOSH Director are the only mechanism for consideration of a drug for deletion from the List (the reconsideration process as described). Comments are invited on any topic related to the procedures and drugs identified in this notice, including three draft documents: (1) NIOSH Procedures for Developing the NIOSH List of Hazardous Drugs in Healthcare Settings (Procedures); (2) NIOSH List of Hazardous Drugs in Healthcare Settings, 2020 (List), including those drugs identified in this notice as being proposed for placement on the List; and (3) Managing Hazardous Drug Exposures: Information for Healthcare Settings. when determining the potential for adverse health effects of hazardous drugs in healthcare workers. Accordingly, drugs that sublime should be handled using risk management strategies relevant to the conditions of use. NIOSH is seeking input from the public on the draft risk management strategies document and table to ensure that they contain accurate and helpful information. documents in the last year, 73 Document page views are updated periodically throughout the day and are cumulative counts for this document. Docket ID: CDC-2020-0046. The draft Procedures document is now focused on NIOSH's procedure for identifying hazardous drugs and no longer discusses managing the risk of exposure. documents in the last year, 769 documents in the last year, by the State Department informational resource until the Administrative Committee of the Federal Carcinogenicity/teratogenicity: Cited studies demonstrated an increased incidence of hepatocellular adenomas in mice. NIOSH's definition of a hazardous drug only covers drugs approved by FDA's Center for Drug Evaluation and Research and is not considered for inclusion on the, Dihydroergotamine AHFS Class: 5-hydroxytryptamine (HT) receptor binder, Ivabradine AHFS Class: Hyperpolarization-activated cyclic nucleotide-gated (HCN) blocker. In this Issue, Documents Seven commenters asked questions and offered suggestions about the procedures themselves. This prototype edition of the Comment: Triazolam should not be placed on the List. NIOSH determined that grouping all antineoplastic drugs together in one table is no longer the most useful or informative for the user. NIOSH response: NIOSH has determined that teratogenicity or other developmental toxicity after exposure to osimertinib were observed at doses higher than the maximum recommended human dose and reproductive effects at doses lower than the maximum recommended human doses were equivocal. NIOSH created and periodically updates the List to assist employers in providing safe and healthful workplaces by offering a list of drugs that meet the NIOSH definition of a hazardous drug. for better understanding how a document is structured but If available, NIOSH would give preference to them over animal and in vitro studies. NIOSH response: Compilation of the List is a hazard identification and hazard characterization process, as described in the draft Procedures. Please provide any additional studies or scientific information that evaluate or validate engineering, work practice or administrative controls to reduce exposures to hazardous drugs in healthcare settings. A Notice by the Centers for Disease Control and Prevention on 05/01/2020. Because the way cancer is treated therapeutically has changed, and the classes of drugs used to fight cancer have changed, antineoplastic drugs are no longer all cytotoxic or genotoxic. Accordingly, NIOSH proposes to place exenatide on the List. Counts are subject to sampling, reprocessing and revision (up or down) throughout the day. NIOSH does not review drugs that are not yet approved for use in humans. Reproductive toxicity: Cited studies in the package insert demonstrated reproductive toxicity in male and female rates. Peer review comment: NIOSH should provide “a more robust description of the evaluation criteria to include that these are shared across a number of other professional organizations and panels which also endorsed these same criteria.”. NIOSH response: NIOSH has determined that reproductive effects were observed in pregnant rats at doses near the equivalent maximum recommended human dose. Peer review comment: NIOSH should consider a more detailed process when evaluating study quality because “[t]he issue related to the quality of a study and, in turn, the strength of data i.e. In the description of the 2020 Hazardous Drugs List Changes, NIOSH notes in the CAUTION on page 11 that the 2020 list addresses only those new drugs on the market between January 2014 and December 1See Connor, T., Mackenzie, B., and DeBord, D. … B. Fluconazole meets the NIOSH criteria for a hazardous drug while the other two, ketoconazol and itraconazole, do not. NIOSH response: While some drugs may have low bioavailability by relevant routes of exposure due to molecular weight, other factors in the characterization of the hazard are considered as well. However, NIOSH did not independently evaluate triazolam. Comment: NIOSH indicated that 10 drugs—cetuximab, ibrutinib, ipilmumab, necitumumab, nintedanib, nivolumab, palbociclib, panitumumab, ramucirumab, and ruxolitinib—demonstrated available information that shows a toxic effect that does not meet the NIOSH definition of a hazardous drug. NIOSH does not review biologics reviewed by the FDA Center for Biologics Evaluation and Research. edition of the Federal Register. NIOSH should collaborate with healthcare to better understand the implications of identifying certain drugs as hazardous and the cost to implement USP <800>. Please explain. Document Drafting Handbook developer tools pages. the document speaks to the need for individual healthcare workplaces to create their own lists of hazardous drugs, but this places the burden of regulation on these institutions themselves, or more likely individuals within these institutions. Antineoplastic drugs are no longer all cytotoxic, genotoxic, and highly hazardous chemicals. The last paragraph of this section is particularly confusing to the reader. better and aid in comparing the online edition to the print edition. Peer review comment: NIOSH's discussion of an employer-performed site-based risk assessment to control the risk of exposure is confusing when placed in a document describing NIOSH's hazard identification procedures. NIOSH has formalized the methodology NIOSH uses to guide the addition of drugs to or removal of drugs from the List, in a document entitled Procedures for Developing the NIOSH List of Hazardous Drugs in Healthcare Settings (Procedures).1 As stated in the Procedures, NIOSH defines a hazardous drug as a drug that is: 1 NIOSH . 1. on Centers for Disease Control and Prevention, HHS. Agencies review all submissions and may choose to redact, or withhold, certain submissions (or portions thereof). Seven commenters opposed the inclusion of biological drug products (monoclonal antibodies) on the List. NIOSH response: A drug may be considered a hazardous drug but not a chemical carcinogen if, for example, a drug manufacturer includes a carcinogenicity warning in the drug's package insert but the evidence for carcinogenicity has not been reviewed by the International Agency for Research on Cancer (IARC); the National Toxicology Program (NTP), within the U.S. Department of Health and Human Services; the U.S. Environmental Protection Agency (EPA); or independently by NIOSH. relative risk, odds ratios, etc. NIOSH response: NIOSH reviews the relevant data on a drug when a label change is made, not just the data relating to the label change. NIOSH response: A drug may be removed from the List based on either a written request from an interested party or a change to the package insert. 4. These can be useful Accordingly, NIOSH proposes to place dihydroergotamine on the List. Therefore, at this time NIOSH is no longer proposing to place the class of botulinum toxins on the 2020 List. Drawing conclusions from a methodologically flawed paper can lead to misclassification of a drug. Peer review comment: The frequency of review of the FDA database should be specified earlier in the draft. Learn more here. . NIOSH also invites comments specifically on the following questions related to this activity: 1. Accordingly, NIOSH is not proposing to place these two drugs on the List. Accessed July 16, 2020. Specifically, whether NIOSH conducts categorical regression analyses to evaluate dose-response data for severity. documents in the last year, 746 The List now comprises only two tables: Table 1: Drugs that contain MSHI in the package insert and/or meet the NIOSH definition of a hazardous drug and are classified by NTP as “known to be a human carcinogen,” or classified by IARC as “carcinogenic” or “probably carcinogenic.”, Table 2: Drugs that meet the NIOSH definition of a hazardous drug, but do not have MSHI and are not classified by NTP as “known to be a human carcinogen,” or classified by IARC as “carcinogenic” or “probably carcinogenic.”. The fact that FDA has requirements for reporting of relevant safety related data supports the NIOSH presumption that a lack of information on an endpoint indicates a lack of concern for a specific type of hazard. The Centers for Disease Control and Prevention (CDC) cannot attest to the accuracy of a non-federal website. Moreover, caution should be taken when making determinations about potentially hazardous drugs because causality is not necessarily demonstrated by a strong association just as absence of causality is not necessarily demonstrated by weak associations; associations that demonstrate a monotonic trend in health outcome frequency (steadily increasing or decreasing without ever changing direction) are not necessarily causal if a confounding factor demonstrates a dose-response relationship with the health outcome; and prior beliefs should not be allowed to cloud judgment with regard to plausibility. Register (ACFR) issues a regulation granting it official legal status. Docket Folder Summary View all documents and comments in this Docket . were derived. Both drugs should be placed on the List because information available in the respective package inserts indicates that both drugs may cause teratogenic effects.
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