[Federal Register Volume 85, Number 85 (Friday, May 1, 2020)]
[Notices]
[Pages 25439-25451]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-09332]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

[CDC-2020-0046; NIOSH-233-C]


Hazardous Drugs: Draft NIOSH List of Hazardous Drugs in 
Healthcare Settings, 2020; Procedures; and Risk Management Information

AGENCY: Centers for Disease Control and Prevention, HHS.

ACTION: Notice and request for comment.

-----------------------------------------------------------------------

SUMMARY: 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.

DATES: Comments must be received by June 30, 2020.

ADDRESSES: Comments may be submitted, identified by docket numbers CDC-
2020-0046 and NIOSH-233-C, by either of the following two methods:
     Federal eRulemaking Portal: www.regulations.gov Follow the 
instructions for submitting comments.
     Mail: NIOSH Docket Office, Robert A. Taft Laboratories, 
MS-C34, 1090 Tusculum Avenue, Cincinnati, OH 45226-1998.
    Instructions: All information received in response to this notice 
must include the agency name and the docket numbers (CDC-2020-0046; 
NIOSH-233-C). All relevant comments received will be posted without 
change to www.regulations.gov, including any personal information 
provided.

FOR FURTHER INFORMATION CONTACT: Barbara MacKenzie, NIOSH, Robert A. 
Taft Laboratories, 1090 Tusculum Avenue, MS-C26, Cincinnati, OH 45226, 
telephone (513) 533-8132 (not a toll free number), 
email:[email protected].

SUPPLEMENTARY INFORMATION:

I. Public Participation

A. Request for Comments

    Interested parties are invited to participate in this activity by 
submitting

[[Page 25440]]

written views, opinions, recommendations, and/or data. 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. All three draft 
documents are available in the docket for this activity. NIOSH also 
invites comments specifically on the following questions related to 
this activity:
    1. Which unique ingredient identifier is the most useful for users 
of the List?
    2. Because there is conflicting evidence about the hazard posed by 
botulinum toxins to the workers who handle these drugs, NIOSH is not 
proposing the placement of botulinum toxins on the List at this time 
and invites additional studies, data, and expert opinions pertinent to 
this issue in order to evaluate the botulinum toxins more fully.

B. February 2018 Federal Register Notice

    In a Federal Register notice (FRN) published on February 14, 2018 
(83 FR 6563), NIOSH invited the public to participate in the 
development of the List and the procedures used to develop the List by 
submitting written views, opinions, recommendations, and/or data. 
Comments were invited on any topic related to the drugs reviewed by 
NIOSH for possible placement on the planned 2018 version of the List. 
NIOSH also sought comment on a draft Policy and Procedures for 
Developing the NIOSH List of Antineoplastic and Other Hazardous Drugs 
in Healthcare Settings (Policy and Procedures).\1\
---------------------------------------------------------------------------

    \1\ As discussed later in this notice, NIOSH has revised the 
draft Policy and Procedures based on peer reviews and public 
comments. The new iteration is now referred to as ``draft 
Procedures'' throughout this notice.
---------------------------------------------------------------------------

    Fifty-seven submissions were received in docket CDC-2018-0004 
(NIOSH-233-B) from 55 commenters (one commenter sent three separate 
submissions to the docket). 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. 
NIOSH also conducted a peer review, with four independent reviewers, of 
the draft Policy and Procedures.\2\
---------------------------------------------------------------------------

    \2\ See https://www.cdc.gov/niosh/topics/hazdrug/peer-review-plan.html for the peer review plan for the draft Policy and 
Procedures.
---------------------------------------------------------------------------

    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.
    NIOSH carefully considered all of the peer reviews and public 
comments and determined that significant, substantial changes should be 
made to the draft Policy and Procedures, the list of drugs proposed for 
placement on the List, and also to the organization of the List itself. 
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.
    Public comments on the draft Policy and Procedures and the drugs 
proposed for placement on the List and peer review summaries on 
specific drugs proposed for placement on the List are available in 
dockets CDC-2018-0004 and NIOSH-233-B.

II. Procedures for Developing the NIOSH List of Hazardous Drugs in 
Healthcare Settings

    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. In the February 
2018 Request for Comment, NIOSH requested comment on a draft Policy and 
Procedures for developing the List. The draft Policy and Procedures 
document was developed to formalize the methodology NIOSH uses to guide 
the addition of hazardous drugs to the List and create a process for 
requesting the removal from or placement of drugs on the List. Four 
independent peer reviewers and 55 public commenters offered input on 
the draft Policy and Procedures; their substantive comments are 
summarized below, followed by NIOSH responses.

A. Peer Review Summaries and NIOSH Responses

    NIOSH consulted four independent peer reviewers, who were asked to 
consider the following questions:
     Does the draft policy and procedures clearly describe the 
process used by NIOSH to screen and evaluate drugs?
     Are the screening and evaluation categorization processes 
described by the draft policy and procedures scientifically sound?
     Is the set of information sources used for classifying 
drugs sufficient to identify relevant hazards? Are there other 
information sources that should be included?
     Is the threshold of information required to move from the 
screening process to the full evaluation process clearly described? Is 
the information threshold scientifically sound?
     Is the reconsideration process for addition or deletion of 
a drug to/from the hazardous drug list adequately described?
     Are there any issues not considered by the charge 
questions that should be addressed?
    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. Two reviewers had questions about the information 
thresholds required to evaluate drugs, and all reviewers had editorial 
suggestions for improving the clarity of the draft. Peer reviews on the 
draft Policy and Procedures, as well as NIOSH's responses, are 
discussed below.
Scientific Approach
    Peer review comment: Some paragraphs in the section entitled, 
``Evidence of Health Effects in Workers from Handling Hazardous Drugs'' 
do not belong in the scientific approach section and should be moved to 
be part of section B ``Systematic and Sequential Methodology'' section.
    Peer review comment: The frequency of review of the FDA database 
should be specified earlier in the draft.
    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.
    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. The Procedures should state ``that this list is [a] hazard 
identification and not a risk assessment exercise. The subsequent 
description of a site risk

[[Page 25441]]

assessment does not seem appropriate here. The last paragraph of this 
section is particularly confusing to the reader. . .''
    NIOSH response: NIOSH is reorganizing and streamlining the document 
to make it more easily understood and to move information on site risk 
assessment to a separate draft document, Managing Hazardous Drug 
Exposures: Information for Healthcare Settings. The draft Procedures 
document is now focused on NIOSH's procedure for identifying hazardous 
drugs and no longer discusses managing the risk of exposure.
    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.''
    Peer review comment: NIOSH should list further tools to aid 
employers to protect workers.
    NIOSH response: In streamlining the document to make it more 
focused on NIOSH's procedures for identifying hazardous drugs, 
information on controlling the risk of hazardous drug exposure in the 
workplace was moved to the draft NIOSH document Managing Hazardous Drug 
Exposures: Information for Healthcare Settings.
Application
    Peer review comment: NIOSH should mention ``some other common 
healthcare job categories that are likely to be exposed . . . From my 
perspective, as a minimum, this should include porters, ward aides and 
unit clerks.''
    NIOSH response: Because the draft Procedures document only 
addresses NIOSH's procedure for identifying hazardous drugs, the 
``Application'' section is removed. Information about the application 
of the List can be found in the introduction of the draft Managing 
Hazardous Drug Exposures: Information for Healthcare Settings. However, 
rather than identifying job-specific titles, the document focuses on 
workplace activities.
Definitions
    Peer review comment: NIOSH did not include a mechanism to place 
investigational drugs on the List. There seems to be no ``mechanism in 
place for labeling investigational (i.e., non-FDA approved drugs used 
in preclinical and clinical research prior to submission of an NDA [new 
drug approval]) drugs as potential human health hazards. Although such 
drugs are not in widespread clinical use, personnel in academic and 
research-oriented facilities are potentially at risk from exposure to 
these drugs. . . . 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. I wonder whether 
the current regulatory climate permits NIOSH any level of control over 
the handling of drugs in this category.''
    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. 
Accordingly, the List is derived only from drugs approved by FDA's 
Center for Drug Evaluation and Research. For this reason, NIOSH 
encourages individual healthcare settings to develop their own 
formulary-specific lists of hazardous drugs, which could include 
investigational drugs that have not yet been approved by FDA.
Identifying, Screening, Evaluating, and Reviewing a Drug for Placement 
on the List: Screening Potentially Hazardous Drugs
    Peer review comment: It may be inappropriate for NIOSH not to place 
drugs on the List when NIOSH has determined there is insufficient 
information to support the placement. 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. From an occupational hygiene perspective, 
if there is no existing occupational exposure limit or threshold limit 
value for a chemical hazard, the best practice is to ensure that worker 
exposure to the chemical remains As Low As Reasonably Achievable 
(ALARA). This is because there is insufficient information to establish 
an exposure limit and, therefore, one should err on the side of caution 
and apply the ALARA principle. Employing this same train of thought to 
the draft policy and procedures, it would, in my opinion, be a best 
practice to add the drug that has insufficient information to the List 
until suitable scientific evidence demonstrates that it should not be 
included.''
    NIOSH response: FDA-approved drugs generally have a reasonable body 
of toxicity information because the manufacturers are required by FDA 
to provide this information to ensure patient safety when seeking 
approval for their drugs. The FDA requirements for tested and reported 
endpoints generally overlap with the NIOSH definition of a hazardous 
drug. 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.
    Peer review comment: A statement about the evaluation procedures in 
the draft Policy and Procedures indicates that NIOSH would only 
consider human studies. ``'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.' This clearly infers human studies 
only. However, the remaining parts of the draft policy and procedures 
mentions that animal studies should be reviewed . . . . It is unclear 
why animal studies were not included as a source of evaluating 
potentially hazardous drugs. 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. As such, the use of animal studies to 
evaluate the hazardous nature of a drug should be explicitly stated.''
    NIOSH response: The reviewer has interpreted the NIOSH statement 
differently than what the agency intended. Animal studies, where 
available, are also used in our evaluations. The draft Procedures 
document is being reorganized to clarify the information NIOSH 
considers in its evaluations, including relevant animal studies.
    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. relative 
risk, odds ratios, etc. is not clearly outlined with respect to the 
evaluation process. Drawing conclusions from a methodologically flawed 
paper can lead to misclassification of a drug. In addition, having an 
algorithm to determine the strength of a paper will also aid in 
minimizing any potential inter- and intra-reviewer differences. 
Although there is currently some guidance in the footnotes, it may be 
worthwhile to consider a more detailed evaluation process of relevant 
studies and place it in a more prominent location in the document or 
possibly as an Appendix.''
    NIOSH response: The majority of drug evaluations are based on 
information provided in the drug package insert; NIOSH relies on the 
quality of science

[[Page 25442]]

generated by a drug manufacturer, subsequently reviewed by FDA during 
the drug approval process, and then published in the drug package 
insert. Peer-reviewed, published studies are usually not available and 
therefore evaluating the quality of studies is not typically possible. 
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. In the case of a drug being 
reevaluated, conclusions about study quality would be discussed in a 
notice published in the Federal Register.
    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: The NIOSH List is adopted, endorsed, and/or 
referenced by a number of non-governmental organizations, including the 
American Society of Health-System Pharmacists (ASHP), The Joint 
Commission, and the Oncology Nursing Society.
    Because the organizations that may endorse the evaluation criteria 
may change, NIOSH declines to identify them in the Procedures document.
    Peer review comment: NIOSH should offer an example of why a drug 
identified as a hazardous drug because it poses as carcinogenic hazard 
might not be a classified as a carcinogen pursuant to the NIOSH 
Chemical Carcinogen Policy.
    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. In 
that case, NIOSH may consider it to be appropriately grouped with 
carcinogenic drugs, although it would not necessarily meet the criteria 
for an occupational carcinogen according to the NIOSH Chemical 
Carcinogen Policy.
    Peer review comment: NIOSH should clarify ``how the threshold 
dosages (10 mg/day or 1 mg/kg/day) for defining organ toxicity at 'low 
doses' . . . were derived. . . . Are these standard or commonly 
accepted definitions of 'low dose' exposure? Is there a scientific 
justification for them? If so, perhaps this could be referenced with a 
footnote.''
    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 [mu]g/m\3\ after applying 
appropriate uncertainty factors.\3\ OELs in this range are typically 
established for potent or toxic drugs in the pharmaceutical industry. 
NIOSH is adding text in footnote 16 of the draft Procedures to clarify 
and emphasize the derivation.
---------------------------------------------------------------------------

    \3\ Sargent EV and Kirk GD [1988], Establishing Airborne 
Exposure Control Limits in the Pharmaceutical Industry, Am Ind Hyg 
Assoc J 49(6):309-13; Naumann BD and Sargent EV [1997], Setting 
Occupational Exposure Limits for Pharmaceuticals, Occup Med 
12(1):67-80; Sargent EV, Naumann BD, Dolan DG, Faria EC, Schulman L 
[2002], The Importance of Human Data in the Establishment of 
Occupational Exposure Limits, Hum Ecol Risk Assess 8(4):805-822.
---------------------------------------------------------------------------

    Peer review comment: NIOSH should clarify a sentence concerning 
NIOSH's preference for human genotoxicity data which states: ``If 
available, NIOSH gives preference to those studies. . .''
    NIOSH response: This refers to human genotoxicity studies, which 
are rarely available. If available, NIOSH would give preference to them 
over animal and in vitro studies. NIOSH is adding text to clarify the 
agency's intent.
    Peer review comment: ``Following the 60-day period to allow for 
public and stakeholder consultations, it is unclear if NIOSH will be 
responding to any parties that have provided comments. On the contrary, 
if a party submits a written request for reconsideration, NIOSH will be 
responding in these instances. One would assume that, in both 
instances, a great deal of time and thought is expected to provide 
feedback to NIOSH. It would presumably be courteous to respond to any 
party that has provided comments for consideration.''
    NIOSH response: It is NIOSH practice to respond to all stakeholder 
and public comments and peer reviews in a Federal Register notice or in 
a document posted in the relevant NIOSH docket, to maintain a 
transparent and thorough administrative record.
Reconsideration (Reevaluation) of NIOSH Decisions to Place and Remove 
Drugs
    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). If the latter is the case, 
could a sentence be added to clarify that?''
    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. Although rare, NIOSH notes any labeling changes that could 
affect the status of a drug that has been previously classified as 
hazardous. No labeling change has ever resulted in the removal of a 
drug from the List, but labeling changes that demonstrate a lack of 
evidence of toxicity would be dealt with in the regular List updates.
    Only when a labeling change results in the addition of MSHI to a 
package insert will NIOSH automatically consider the drug to be a 
hazardous drug and add it to the List.

B. Public Comment Summaries and NIOSH Responses

    The public comments have been organized into the following topic 
areas: organization of the List and impact of United States 
Pharmacopeia (USP) Compounding Compendium chapter <800> Hazardous 
Drugs--Handling in Healthcare Settings; the nature of the List--
exposure/hazard characterization; monoclonal antibodies; periodicity; 
methodology/process; criteria clarification; and editorial suggestions.
Organization of the List and Impact of USP <800> Hazardous Drugs--
Handling in Healthcare Settings
    Seven commenters expressed concern about the impact of USP <800> on 
the NIOSH List, and, in turn, the effect on small pharmacies that 
compound pharmaceutical drugs. USP <800> incorporates by reference the 
NIOSH List and imposes certain requirements on its users when handling 
certain drugs on the List. 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.
    Comment: Prior to USP <800>, the NIOSH List was considered a 
``precautionary recommendation.'' But the USP <800> standards are too 
restrictive and overreaching, and the chapter's incorporation into 
state law places facilities at legal risk if they fail to comply. The 
ordering of the tables in the List implies risk stratification; USP 
<800> supports this impression by requiring heightened handling 
requirements for Table 1 drugs. Because

[[Page 25443]]

Table 1 includes drugs identified as antineoplastic, NIOSH should 
clarify the rationale and intent of Table 1, since drugs used as 
antineoplastics, but which are not cytotoxic or genotoxic, as 
traditional antineoplastics are, have been included. Moreover, USP 
<800> requires the use of personal protective equipment for Table 1 
drugs, which may delay care or undermine patient safety. NIOSH should 
collaborate with healthcare to better understand the implications of 
identifying certain drugs as hazardous and the cost to implement USP 
<800>.
    NIOSH response: The NIOSH List creates no legal obligation for its 
users; it is informational, not regulatory, in content. USP added 
clarification about the application of chapter <800> to hazardous 
drugs, which can be found on its FAQ page.\4\
---------------------------------------------------------------------------

    \4\ See USP, FAQs: <800 Hazardous Drugs--Handling in 
Healthcare Settings, https://www.usp.org/frequently-asked-questions/hazardous-drugs-handling-healthcare-settings.
---------------------------------------------------------------------------

    In response to peer reviews and public comments, NIOSH proposes a 
reorganization of the tables in the draft 2020 List in a manner that 
may address at least some of the concerns expressed. 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. Furthermore, some drugs carry multiple 
American Hospital Formulary Service (AHFS) code classifications and are 
not solely used as antineoplastic drugs. Therefore, when antineoplastic 
drugs are grouped as they were in earlier versions of Table 1 of the 
List, an appearance that these drugs pose the same hazard was 
inadvertently created (i.e., non-cytotoxic drugs with cytotoxic drugs). 
NIOSH determined that grouping all antineoplastic drugs together in one 
table is no longer the most useful or informative for the user. 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. 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. Table 2 would 
now contain drugs that meet one or more of the NIOSH hazardous drug 
criteria and may be developmental and/or reproductive developmental 
toxins but are not drugs which have MSHI or are classified as 
carcinogens or probable carcinogens by NTP or IARC. Table 3 would be 
removed and the drugs formerly placed in that table placed into Table 1 
or 2, accordingly.
Realistic Risk of Occupational Exposure
    Nine commenters expressed the sentiment that the List would be more 
useful if it identified drugs that pose a realistic risk to healthcare 
workers.
    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. Not refining the List to identify real risks of 
occupational exposure could lead to ``overwarning'' for drugs that 
present little or no workplace risk.
    NIOSH response: Compilation of the List is a hazard identification 
and hazard characterization process, as described in the draft 
Procedures. 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 \5\ when 
determining the potential for adverse health effects of hazardous drugs 
in healthcare workers. Risks associated with how and how often a 
hazardous drug is used in a particular setting, and evaluation of 
exposure factors for all occupational exposures is beyond the scope of 
the List. 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.
---------------------------------------------------------------------------

    \5\ See draft Procedures footnote 18, ``Properties of a drug 
molecule that may limit adverse effects in healthcare workers are 
typically chemical, physical and structural properties that affect 
its absorption (ability to enter the cells of the body), 
distribution, metabolism, and/or elimination e.g., chemical 
structure, molecular weight or mass.''
---------------------------------------------------------------------------

Monoclonal Antibodies
    Seven commenters opposed the inclusion of biological drug products 
(monoclonal antibodies) on the List.
    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. 
Therefore, all recombinant therapeutic proteins should be excluded from 
the List unless ``science-based or product-specific circumstances 
dictate otherwise.''
    Comment: Monoclonal antibodies (i.e., therapeutic proteins) are of 
such a large molecular weight that they do not pose a realistic risk to 
healthcare workers. For example, monoclonal antibodies ``are too large 
to be absorbed through skin contact, and if ingested, they would be 
destroyed by digestion; if inhaled, the pulmonary system would prevent 
absorption. Consequently, these drugs are all administered by 
injection. The only potential risk to healthcare workers is of an 
accidental needle stick, which would not inject a pharmacologically 
active dose.'' Accordingly, the monoclonal antibodies bevacizumab, 
blintumomab, and trastuzumab should not be placed on the List, and 
pertuzumab should be removed from Table 1.
    Comment: The draft Policy and Procedures should include a 
methodology describing how NIOSH evaluates monoclonal antibodies.
    NIOSH response: NIOSH applies the same methodology for evaluating 
each drug approved by the FDA Center for Drug Evaluation and Research, 
regardless of class. The definition of a hazardous drug in the draft 
Procedures recognizes that the molecular properties of a drug, such as 
the molecular weight, may substantially limit the potential for adverse 
health effects. NIOSH may consider molecular weight along with the 
other intrinsic molecular properties of a drug that affect the hazard a 
drug poses. While some large molecular weight drugs may have low 
bioavailability by relevant routes of exposure, other factors in the 
characterization of the hazard are considered as well. 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. 
Blinatumomab continues to be proposed for placement and other 
monoclonal antibodies that have properties meeting the NIOSH definition 
of a hazardous drug will remain on the List.
Periodicity
    Three commenters offered opinions on the timeliness of the List, 
which NIOSH has attempted to publish every 2 years since 2010.
    Comment: The List seems to be heavily weighted toward older drugs.

[[Page 25444]]

    NIOSH response: The List is about 4 years behind the introduction 
of new drugs when it is periodically updated because there are several 
steps in the review process. NIOSH appreciates that a timelier List 
might be helpful and is working toward that end. The current List 
created by NIOSH requires an extensive review process that does not 
readily allow more frequent publication. That said, when NIOSH becomes 
aware of new drugs with MSHI, NIOSH identifies such drugs on the web 
page for the current List to immediately alert stakeholders. The 
inclusion of MSHI makes such drugs automatically hazardous under the 
NIOSH definition and thus, the extensive review process is not 
required.
    Comment: FDA-approved drugs should be reviewed in real time or 
NIOSH should provide ``off-cycle'' updates to the List.
    NIOSH response: The List is updated any time NIOSH is aware that a 
drug manufacturer has added special handling information to the patient 
information for a specific drug. 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. NIOSH's extensive review process only allows for 
periodic updates of hazardous drugs that do not have MSHI.
Methodology/Process
    Seven commenters asked questions and offered suggestions about the 
procedures themselves.
    Comment: The methodology used to develop the list of drugs proposed 
for placement on the List was not the same as the methodology used in 
previous years.
    NIOSH response: In 2004, NIOSH used lists from several 
organizations as examples of hazardous drugs. In 2010, NIOSH first 
updated the List based on the NIOSH definition of a hazardous drug. 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. The draft Procedures reflects 
peer review and public comment; the list of drugs proposed for 
placement on the List has been updated based on the revised draft 
Procedures.
    Comment: NIOSH should conduct or commission a meta-analysis or 
systematic review, ``[i]n the absence of published literature 
synthesizing the body of clinical knowledge'' about a specific drug.
    NIOSH response: A systematic review is a significant undertaking 
requiring the prior publication or dissemination of multiple studies 
relating to a specific drug. In very few cases, if any, would 
sufficient studies be available to conduct a formal meta-analysis 
relating to a specific drug. NIOSH will consider conducting a 
systematic review if such studies become available relating to the 
hazard that a specific drug may pose in healthcare settings.
    Comment: What is the mechanism for evaluating investigational new 
drugs (i.e., drugs used in preclinical and clinical research but not 
yet FDA-approved)?
    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. 
Accordingly, the List is derived only from drugs approved by FDA's 
Center for Drug Evaluation and Research. NIOSH does not review drugs 
that are not yet approved for use in humans. NIOSH does not review 
biologics reviewed by the FDA Center for Biologics Evaluation and 
Research.
    Comment: Peer reviews should be conducted before the close of the 
public comment period to allow public commenters time to review them. 
Not allowing public commenters to review peer reviews before submitting 
their own comments to the docket is ``in conflict with the principle of 
transparency'' established in the OMB Final Information Quality 
Bulletin for Peer Review (70 FR 2664, Jan. 14, 2005).
    NIOSH response: NIOSH views peer review and public comment as two 
distinct, often complementary, tools in ensuring both quality and 
transparency in influential scientific information products. 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. . .'' whereas public comment, 
including stakeholder review, often provides NIOSH with crucial 
feedback on how a project or publication may impact the interests of 
employees, stakeholder organizations, or other parties. While the 
Bulletin recognizes the benefit of both forms of input to agencies, it 
provides agencies with broad discretion in determining how to implement 
peer review, including timing as it relates to public comment, if 
applicable. NIOSH does not offer peer reviews for public comment for 
any scientific publications because the technical and scientific review 
conducted by independent peer reviewers are not NIOSH products.
    Comment: The draft Policy and Procedures should provide the drug 
manufacturer with ``transparent documentation as to the basis of adding 
a drug to the List.'' Without a thorough understanding of the basis for 
adding a drug, the drug manufacturer may not be able to formulate a 
request for reconsideration of the drug.
    NIOSH response: The rationale for proposing the placement of each 
drug to the List is provided in the Federal Register notice preceding 
the final List publication. The manufacturer or any other stakeholder 
is invited to comment on the sufficiency of the explanation of the 
basis for adding a drug to the List.
    Comment: Providing sufficient information to rebut a NIOSH 
determination to add or not add a drug to the List is difficult for 
healthcare organizations.
    NIOSH response: For reevaluation of a listed drug, NIOSH does not 
require requestors to provide a complete analysis of the available 
evidence. The requestor need only provide some new information that is 
relevant to the issue of whether the drug does or does not meet the 
NIOSH definition of a hazardous drug or the decision to place a drug on 
a particular table in the List. NIOSH will begin the reevaluation 
process for any request to add or remove a drug that provides some new 
supporting evidence by searching for additional hazard identification 
(toxicity) and hazard characterization information about the drug that 
is relevant to the criteria set out in the NIOSH definition of a 
hazardous drug.
Criteria Clarification
    Six commenters were critical of the methodology NIOSH described for 
adding drugs to the List and asked that NIOSH clarify the language in 
certain sections of the draft Policy and Procedures.
    Comment: NIOSH should include the professional qualifications of 
the NIOSH staff who perform these evaluations.
    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. 
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. Additionally, peer reviews provide the 
Agency with a review of its science; peer reviewers and their 
credentials are identified in the NIOSH Peer Review Agenda.

[[Page 25445]]

    Commenters: NIOSH should identify the criteria used to evaluate 
study quality and strength, and describe how they are used to 
critically appraise the quality and risk of bias and other limitations 
of individual studies; arbitrate conflicting information; and 
synthesize the totality of animal and human studies data in support of, 
or opposition to, the listing of a drug as ``hazardous.''
    NIOSH response: The majority of these evaluations are based on the 
information provided in the drug package insert; thus, NIOSH relies on 
the quality of science generated by a drug manufacturer, subsequently 
reviewed by FDA during the drug approval process, and then published in 
the drug package insert. 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. In 
the case of a drug being reevaluated, conclusions about study quality 
would be discussed in a Federal Register notice.
    Comment: While NIOSH describes several Bradford Hill criteria \6\ 
used to evaluate information from human studies in footnote 44 of the 
draft Policy and Procedures, no rationale is offered to explain why 
many of the original nine Bradford Hill criteria are not used. 
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. NIOSH should 
clarify the criteria described in the footnote and explain how evidence 
against these various criteria is evaluated, how each independent line 
of evidence is systematically and critically appraised, how the quality 
and risk of bias of individual studies is evaluated, how conflicting 
information is arbitrated, and how the totality of the data is 
synthesized.
---------------------------------------------------------------------------

    \6\ Aschengrau A, Seage GR [2018], Essentials of Epidemiology in 
Public Health. 4th Edition, (Burlington, MA: Jones & Bartlett).
---------------------------------------------------------------------------

    NIOSH response: NIOSH uses the subset of Bradford Hill criteria 
which are most useful for evaluating human study results on hazardous 
drugs. The most important criteria for the review of human studies are 
strength of association, temporality, plausibility, and biological 
gradient.
    Comment: In the draft Policy and Procedures footnote 45, NIOSH 
lists criteria used to evaluate information from animal studies. 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. 
Furthermore, animal studies must be evaluated for the recovery/
reversibility of effects and the pharmacological relevance of the 
species studied. NIOSH must add criteria for animal studies to include 
the recovery/reversibility of adverse effects and the pharmacological 
relevance of the test species.
    NIOSH response: NIOSH has not conducted a formal meta-analysis or 
systematic review for any drug currently on the List. In very few 
cases, if any, would sufficient studies be available to conduct a 
formal meta-analysis relating to a specific drug. Accordingly, NIOSH 
primarily uses information available in the package inserts to make 
determinations about whether to place a drug on the List. NIOSH may 
conduct a meta-analysis or systematic review when reevaluating the 
placement of a drug already on the List, if the available evidence 
warrants such a review. In that case, important criteria for animal 
studies include strength of association; consistency between studies; 
relevance of the model system and routes of exposure; the duration, 
reversibility, and recoverability of the observed effects; and 
concordance of those effects with effects in humans. If a meta-analysis 
or systematic review is warranted for a reevaluation, NIOSH would 
consider these criteria on a case-by-case basis. Under the draft 
Procedures, NIOSH's rationale, including a description of any meta-
analysis or systematic review if performed, and final determination 
would be described in a notice published in the Federal Register.
    Comment: It is unclear how NIOSH interprets evidence of increasing 
progression or severity with increased dose, and how the value for 
``low dose'' was derived. Specifically, whether NIOSH conducts 
categorical regression analyses to evaluate dose-response data for 
severity. 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.
    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 [mu]g/m\3\ after applying 
appropriate uncertainty factors.\7\ OELs in this range are typically 
established for potent or toxic drugs in the pharmaceutical industry. 
NIOSH is adding text in footnote 16 of the draft Procedures to clarify 
and emphasize the derivation.
---------------------------------------------------------------------------

    \7\ See supra note 3.
---------------------------------------------------------------------------

    Comment: NIOSH should clarify how close chemical analogs are 
identified, and whether NIOSH establishes site concordance across 
analogs and how evidence for and against the absence of concordance is 
interpreted. Similar questions were raised about animal studies.
    NIOSH response: NIOSH examines chemical analogs based on 
similarities in a drug's structure and toxicity profile compared with 
other drugs on the List. Often the mechanism of action for the drug 
being assessed is known and can be compared to other drugs of a similar 
structure/activity. 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.
    Comment: Hazardous drugs should also be identified by UNII code 
(the unique ingredient identifier used by FDA and USP) on the List.
    NIOSH response: There are several methods for identifying active 
pharmaceutical ingredient compounds, including Chemical Abstract 
Service Registry number (CAS) and UNII. At this time, NIOSH has chosen 
not to list any of the identification numbers but is considering doing 
so in the future. NIOSH encourages public input on the question of 
which ingredient identifier may be the most useful for the List.
Editorial Suggestions
    Two commenters offered editorial suggestions for clarifying 
language in the draft; although the comments are not summarized here, 
changes were made to the revised draft Procedures as appropriate.

[[Page 25446]]

C. Draft Procedures: Summary of Changes

    NIOSH considered peer review and public comment received in 
response to the February 2018 FRN, and significantly revised the draft 
Policy and Procedures; that document is now called Procedures. These 
changes now reflected in the draft Procedures for Developing the NIOSH 
List of Hazardous Drugs in Healthcare Settings (draft Procedures) 
include the clarification of some language and streamlining the 
procedures NIOSH uses to determine the hazard potential of a specific 
drug. Most importantly, the definition of the term ``hazardous drug'' 
would now acknowledge that ``hazard characterization'' is an important 
factor for drugs under consideration. Section C of the draft 
Procedures, which includes the evaluation criteria, would be expanded 
to include new clauses 4 and 5 to allow NIOSH to consider additional 
factors beyond the intrinsic toxicity of the drug molecule in 
determining whether to place the drug on the List. The draft Procedures 
is in the docket for this activity.

III. The NIOSH List of Hazardous Drugs in Healthcare Settings, 2020

A. Public Comment Summaries and NIOSH Responses

    As discussed extensively in the notice published February 14, 2018, 
NIOSH identified 275 potentially hazardous drugs between January 2014 
and December 2015 (83 FR 6563). Of the 275 drugs identified during that 
timeframe, two had special handling information specified by the 
manufacturer (MSHI) and were automatically placed on the List. 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. After 
considering the peer and stakeholder reviews, NIOSH determined that 20 
drugs and one class of drugs exhibit toxicity that meets the NIOSH 
definition of a hazardous drug and proposed them for placement on the 
List. The two drugs with MSHI that were placed on the List and the 20 
drugs and one drug class proposed for placement on the List were 
identified in the February 14, 2018 notice, along with NIOSH's 
rationale for each proposed addition. A new peer review was not 
conducted. Public comments on the drugs and drug class proposed for 
placement on the List in 2018 are summarized and answered below.
Do Not Place Drug on the List
    Comment: Botulinum toxins, including abobotulinumtoxinA and 
onabotulinumtoxinA, should not be placed on the List. Botulinum toxins 
do not meet the criteria for placement on the List; abotulinumtoxinA 
and rimabotulinumtoxinB did not have labeling changes during the search 
period January 2014 through December 2015, and changes to the labels 
for onabotulinumtoxinA and incobotulinumtoxinA do not meet the criteria 
for organ toxicity at low doses or teratogenicity or other 
developmental toxicity. Moreover, NIOSH is not properly weighing the 
low therapeutic index of the drug against the relatively low risk of 
handling the drug by healthcare workers who are knowledgeable about 
safe handling. According to the safety data sheets for botulinum 
toxins, no engineering controls or respiratory protective devices are 
required for safe handling.
    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. 
However, after consideration of input from the public and stakeholders, 
NIOSH has decided to review the toxicity and the hazards related to 
occupational exposure to botulinum toxins. Therefore, at this time 
NIOSH is no longer proposing to place the class of botulinum toxins on 
the 2020 List. Any additional information from any interested party 
that will assist with further reviews of the botulinum toxins will be 
reviewed for potential placement on the List in the future.
    Comment. Darbepoetin alfa should not be placed on the List. This 
drug poses no risk to healthcare workers; the evidence supporting its 
addition is not based on occupational exposure. The large molecular 
size limits dermal absorption and aerosolization. The drug's mechanism 
of action does not indicate DNA damage.
    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. In addition, darbepoetin alfa did not meet the NIOSH 
criteria for a hazardous drug based on any other toxicity endpoint. 
Accordingly, darbepoetin alfa is no longer proposed for placement on 
the 2020 List.
    Comment: Dihydroergotamine should not be placed on the List. The 
safety data sheet for this drug indicates that it does not pose a 
heightened risk to healthcare workers.
    NIOSH response: NIOSH has determined that dihydroergotamine has 
demonstrated reproductive toxicity in experimental animals. 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. 
Accordingly, NIOSH proposes to place dihydroergotamine on the List.
    Comment: Exenatide should not be placed on the List. NIOSH did not 
take into account the real risk of occupational exposure or the 
mechanism of action of this relatively large molecule. The size of the 
molecule limits dermal absorption and aerosolization.
    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. NIOSH has 
determined that exenatide extended-release caused a dose-related and 
treatment-duration-dependent increase in the incidence of thyroid C-
cell tumors (adenomas and/or carcinomas) at clinically relevant 
exposures in both genders of rats. In mice, doses near the maximum 
recommended human dose lead to increased neonatal death. 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. Accordingly, NIOSH 
proposes to place exenatide on the List. Polypeptides of this size and 
larger have been shown to have bioavailability through relevant routes 
of exposure. Because dosage forms can change and new dosage forms may 
be approved, dosage form is not considered in making List placement 
determinations.
    Comment: Interferon beta-1b should not be placed on the List, or, 
in the alternative, it should only be placed on Table 3. 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. Data evaluation submitted to the docket by the 
manufacturer demonstrates that interferon beta-1b is not causally 
associated with spontaneous abortion or with any ``patterns or signals 
suggesting pregnancy outcomes.'' Research on

[[Page 25447]]

populations who have received interferon beta-1b throughout pregnancy 
have demonstrated no difference in spontaneous abortions or birth 
weight compared to population comparators.
    NIOSH response: The manufacturer provided information indicating 
that multiple evaluations of pregnancy registries did not provide any 
signals suggesting negative pregnancy outcomes associated with 
interferon beta-1b. Accordingly, NIOSH has determined that interferon 
beta-1b does not meet the criteria for a hazardous drug and is no 
longer proposing to place it on the List.
    Comment: Ivabradine should not be placed on the List. This drug is 
administered as a coated tablet, self-administered by the patient at 
home; as such, ivabradine poses no risk to healthcare workers.
    NIOSH response: NIOSH has determined that reproductive effects were 
observed in pregnant rats at doses near the equivalent maximum 
recommended human dose. Drugs are placed on the List based on their 
intrinsic properties. Because dosage forms can change and new dosage 
forms may be approved, dosage form is not considered in making List 
placement determinations. Accordingly, NIOSH continues to propose 
placing ivabradine on the List.
    Comment: Olaparib should not be placed on the List because the risk 
to direct occupational healthcare worker exposure is anticipated to be 
minimal when handling intact olaparib capsules.
    NIOSH response: NIOSH has determined that teratogenicity occurred 
in rats at doses approximately 0.3 percent of therapeutic doses in 
humans. Accordingly, NIOSH proposes to place olaparib on the List. 
Because dosage forms can change and new dosage forms may be approved, 
dosage form is not considered in making List placement determinations.
    Comment: Osimertinib should not be placed on the List. Embryo-fetal 
toxicity is shown to happen at dose exposure 1.5 times the recommended 
ingested human dose of 80 mg; it is unlikely that a healthcare worker 
would accidentally be exposed to osimertinib during handling at levels 
found to cause embryo-fetal harm. 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.
    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. Therefore, NIOSH no longer proposes to place osimertinib on 
the List.
    Comment: Triazolam should not be placed on the List.
    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. However, NIOSH did not independently evaluate 
triazolam. After review, NIOSH now finds that the information in the 
package insert for this drug does not support a determination that it 
presents a hazard to healthcare workers and is no longer proposing to 
place it on the List.
Place Drug on the List
    Comment: NIOSH indicated that two drugs--daratumumab and 
dinutuximab--demonstrated insufficient toxicity information available 
to meet the NIOSH definition of a hazardous drug. Both drugs should be 
placed on the List because information available in the respective 
package inserts indicates that both drugs may cause teratogenic 
effects. NIOSH should provide the rationale for not proposing their 
placement on the List.
    NIOSH response: As presented in the 2018 FRN, daratumumab and 
dinutuximab were reviewed and did not meet the NIOSH criteria for a 
hazardous drug because the available information about each drug's 
toxicity was insufficient to support placement on the List. There are 
no human studies relating to the developmental effects of daratumumab 
or dinutuximab. No animal studies have been performed regarding 
developmental effects of daratumumab or dinutuximab. Accordingly, NIOSH 
is not proposing to place these two drugs on the List.
    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. 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.
    NIOSH response: As presented in the 2018 FRN, NIOSH reviewed 
cetuximab, ibrutinib, ipilimumab, necitumumab, nintedanib, nivolumab, 
palbociclib, panitumumab, ramucirumab, and ruxolitinib for placement on 
the List and, for each, the available information showed a toxic effect 
that does not meet the NIOSH definition of a hazardous drug. 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. 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. If new 
information becomes available about any of these drugs, NIOSH will 
reevaluate them in a future update to the List.
    Comment: Eight drugs were approved by FDA prior to December 2015, 
but do not appear on the 2016 List and were not proposed for placement 
on the List in the February 2018 FRN. The drugs and rationales for each 
of them include the following:

------------------------------------------------------------------------
 
------------------------------------------------------------------------
Fosamprenavir.....................  Carcinogenicity: Cited studies
                                     demonstrated an increased incidence
                                     of various oncologic presentations
                                     (hepatocellular adenoma/carcinoma,
                                     interstitial cell hyperplasia, and
                                     uterine endometrial
                                     adenocarcinoma), in multiple animal
                                     species (rat and mice) at exposure
                                     lower than human doses (0.7-1.4
                                     fold in rats and 0.3-0.7 fold in
                                     mice compared to a human dosing).
Gefitinib.........................  Carcinogenicity/teratogenicity:
                                     Cited studies demonstrated an
                                     increased incidence of
                                     hepatocellular adenomas in mice.
                                     The package insert also cites
                                     gefitinib as exhibiting
                                     teratogenicity.
Idelalisib........................  Genotoxicity: Cited studies
                                     demonstrated genotoxicity in male
                                     rats at high doses (2 grams/
                                     kilogram).
Lapatinib.........................  Reproductive toxicity/
                                     teratogenicity: The FDA classifies
                                     lapatinib as pregnancy category D
                                     indicating positive evidence of
                                     human fetal risk. Cited studies in
                                     the package insert also demonstrate
                                     impaired fertility in rats.
Midostaurin.......................  Reproductive toxicity: Cited studies
                                     in the package insert demonstrated
                                     reproductive toxicity in male and
                                     female rates.
Nicotine..........................  Carcinogenicity/genotoxicity: Cited
                                     studies in the package insert
                                     demonstrated an increased incidence
                                     of tumors in hamsters and rats.
                                     Genotoxicity has been noted in
                                     Chinese hamster ovary cells.

[[Page 25448]]

 
Pembrolizumab.....................  Teratogenicity: The package insert
                                     contains a warning of embryofetal
                                     toxicity when administered to
                                     pregnant women. Manufacturer
                                     recommendation: that females of
                                     reproduction potential use
                                     effective contraception during and
                                     for four months after completing
                                     therapy.
Talimogene laherparepvec..........  Reproductive toxicity: The package
                                     insert contains MSHI stating,
                                     ``Healthcare providers who are
                                     immunocompromised or pregnant
                                     should not prepare or administer
                                     IMLYGIC and should not come into
                                     direct contact with the IMLYGIC
                                     injection sites, dressings, or body
                                     fluids of treated patients'' due to
                                     the risk of transmission of
                                     talimogene laherparepvec and
                                     herpetic infection.
------------------------------------------------------------------------

    NIOSH response: Each of these drugs has either been previously 
reviewed and found not to meet the NIOSH definition of a hazardous 
drug, falls outside the scope of the List, or is slated for review in 
the future. NIOSH's findings about each drug are as follows:

------------------------------------------------------------------------
 
------------------------------------------------------------------------
Fosamprenavir.....................  This drug was reviewed by NIOSH for
                                     a previous update to the List and
                                     it did not meet the criteria for a
                                     hazardous drug. The available
                                     information showed this drug has a
                                     toxic effect that does not meet the
                                     NIOSH definition of hazardous drug.
                                     No new information has been
                                     reported that would meet the NIOSH
                                     criteria for a hazardous drug. If
                                     new information becomes available,
                                     NIOSH will reevaluate it in a
                                     future update to the List.
Gefitinib.........................  This drug was reviewed by NIOSH for
                                     a previous update to the List and
                                     it did not meet the criteria for a
                                     hazardous drug. However, because
                                     new safety information was recently
                                     added to the package insert, this
                                     drug is scheduled to be reviewed
                                     for the update after the 2020 List
                                     update.
Idelalisib........................  This drug was reviewed by NIOSH and
                                     presented in the 2018 FRN; it did
                                     not meet the criteria for a
                                     hazardous drug. The available
                                     information does not demonstrate or
                                     support a determination that the
                                     drug meets the NIOSH definition of
                                     hazardous drug. No new information
                                     has been reported that would meet
                                     the NIOSH criteria for a hazardous
                                     drug. If new information becomes
                                     available, NIOSH will reevaluate it
                                     in a future update to the List.
Lapatinib.........................  This drug was reviewed by NIOSH for
                                     a previous update to the List. The
                                     available information showed this
                                     drug has a toxic effect that does
                                     not meet the NIOSH definition of
                                     hazardous drug. No new information
                                     has been reported that would meet
                                     the NIOSH criteria for a hazardous
                                     drug. If new information becomes
                                     available, NIOSH will reevaluate it
                                     in a future update to the List.
Midostaurin.......................  This drug was approved by FDA in
                                     2017. This drug is scheduled to be
                                     reviewed for the next List update.
Nicotine..........................  Because drugs sold over the counter
                                     are not contemplated in this
                                     activity, this drug has not been
                                     and will not be reviewed for
                                     placement on the List.
Pembrolizumab.....................  This drug was reviewed by NIOSH and
                                     presented in the 2018 FRN; the
                                     available information shows a toxic
                                     effect that does not meet the NIOSH
                                     definition of hazardous drug. It is
                                     scheduled to be re-reviewed for the
                                     next update to the List, because
                                     new information has been added to
                                     the package insert.
Talimogene laherparepvec..........  This oncolytic viral therapy product
                                     is outside the scope of NIOSH's
                                     definition of a hazardous drug
                                     because it is approved by FDA's
                                     Center for Biologics Evaluation and
                                     Research. 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
                                     List.
------------------------------------------------------------------------

Move From One Table on the List to Another
    Comment: The hormonal agents in Table 1 of the 2016 List that are 
exclusively reproductive risks, including estrogens (estrogen agonist-
antagonists such as tamoxifen and antiestrogens such as anastrozole, 
exemestane, and letrozole), gonadotropins (leuprolide and triptorelin), 
antigonadotrophins (degarelix), and progestins (megestrol) should be 
moved to Table 2 or 3.
    Comment: Monoclonal antibodies do not have a cytotoxic mechanism of 
action and, as such, do not pose the same level of occupational risk or 
toxicity as conventional antineoplastic drugs. Those monoclonal 
antibodies that are not directly cytotoxic or conjugated with a 
cytotoxic agent should be moved from Table 1 to another place on the 
List.
    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. As such, they should be moved from 
Table 1 to another place on the List.
    NIOSH response: After scientific review and consideration of input 
from peer reviewers and public commenters, NIOSH is proposing a 
reorganization of the List. As cancer therapy has changed from 
primarily cytotoxic drugs to non-cytotoxic and targeted therapies, 
there is sometimes a mismatch in general recommendations for safe 
handling and the hazardous nature of the drugs. In light of these 
changes, NIOSH proposes a new List structure, described in the preamble 
to the List, which is available for review in the docket for this 
activity. In accordance with the new structure, many of the hormonal 
agents on the 2016 List have been moved to Table 2. Hormonal agents 
that are classified by NTP as ``known to be a human carcinogen'' or by 
IARC as ``carcinogenic'' or ``probably carcinogenic'' will be 
identified in Table 1.
Remove Drug From List
    Comment: Bacillus Calmette-Guerin (BCG) should be removed from the 
List.
    NIOSH response: BCG, a vaccine approved by the FDA Center for 
Biologics Evaluation and Research, was included in the original 2004 
Alert and `grandfathered' into the List. 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.
Drugs Handled Inconsistently
    Comment: The drugs ibrutinib and blinatumomab, both antineoplastic 
monoclonal antibodies, are treated inconsistently in the February 2018 
FRN. 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. NIOSH should consider whether reliance on the 
AHFS Class 10:00 (antineoplastic agents) alone ``is enough to 
necessitate Table 1

[[Page 25449]]

inclusion even if a drug does need to be on the NIOSH list.''
    NIOSH response: In response to input from peer reviewers and 
external comments and following scientific review, NIOSH proposes a 
reorganization of the tables in the draft 2020 List in a manner that 
may address at least some of the concerns expressed. 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. Furthermore, 
some drugs carry multiple AHFS code classifications and are not just 
antineoplastic drugs. Therefore, when antineoplastic drugs are grouped, 
as they were in earlier versions of Table 1, drugs that required 
different levels of protection were grouped together (non-cytotoxic 
drugs with cytotoxic drugs). NIOSH determined that grouping all 
antineoplastic drugs together in one table is no longer the most useful 
or informative for the user. 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.
    Comment: Azole antifungal drugs are being treated inconsistently. 
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. Thus, neither was proposed 
for placement on the List in the February 2018 FRN.
    NIOSH response: NIOSH has evaluated each drug individually and not 
by class of drug. Two very similar drugs may have substantially 
different toxicities and at different doses. Fluconazole meets the 
NIOSH criteria for a hazardous drug while the other two, ketoconazol 
and itraconazole, do not. Animal data on the developmental effects of 
fluconazole suggest developmental changes in rats at doses less than 
the equivalent maximum human recommended dose of 400 mg/day. In humans 
receiving 400 mg/day or higher developmental effects consistent with 
animal data have been observed and epidemiological data suggest a risk 
of spontaneous abortions and congenital abnormalities in infants whose 
mothers were treated with 150 mg/day fluconazole. Data on the 
developmental effects of itraconazole and ketoconazole suggest 
developmental toxicity has only been observed in doses greater than the 
maximum human recommended dose.
Add New Category of Drugs
    Comment: Add a new category for drugs that sublime and offer 
information about proper handling, including the conditions under which 
sublimation (transition of a solid substance to a gas) happens as well 
as the need to filter and exhaust the work area where such drugs are 
used. The List should also indicate that hazardous drugs that do not 
sublime may be exhausted through a HEPA filter back into the work area.
    NIOSH response: Sublimation depends on the drug form and is not an 
inherent toxicity property of the drug. Accordingly, drugs that sublime 
should be handled using risk management strategies relevant to the 
conditions of use. Although assessing specific controls for specific 
exposure situations is beyond the scope of the List, information about 
the use of respiratory protection in the handling of hazardous drugs is 
found in the draft risk management document, Managing Hazardous Drug 
Exposures: Information for Healthcare Settings, which is available in 
the docket for this activity.
    Comment: The List should identify those hazardous drugs that are 
both cytotoxic and cytostatic as well as volatile. The drugs pose the 
greatest risk to healthcare workers, ``based on a combination of 
volatility and dose-related toxic potential of those vapors.''
    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. Because this 
issue is a matter of delivery form, rather than inherent toxicity, it 
is currently beyond the scope of the List. NIOSH will consider 
identifying hazardous drugs that are known to be volatile in future 
updates to the List.

B. Draft NIOSH List of Hazardous Drugs in Healthcare Settings, 2020: 
Summary of Changes

    In February 2018, NIOSH proposed adding 21 drugs (including one 
class of drugs) to the List. After evaluating public comments, NIOSH 
made the following determination:
    [ssquf] 13 drugs are proposed for placement on the List
    [ssquf] 3 drugs are automatically added to the List because they 
have MSHI in the package insert (2 drugs identified in the 2018 FRN and 
another recently-approved by FDA)
    [ssquf] 7 drugs proposed for placement on the List in the 2018 FRN 
are no longer considered in this action
    The 13 drugs proposed for placement on the List are presented for 
public comment in the table below, along with the rationale for their 
placement on the List.
    Two drugs included in the 2018 FRN, inotuzumab ozogamicin and 
trabectedin, have MSHI and are automatically added to the 2016 List. 
One additional drug, polatuzumab vedotin, was approved by FDA's Center 
for Drug Evaluation and Research in July/August 2019 and its package 
insert includes MSHI provided by the drug's manufacturer. Because drugs 
with MSHI are automatically placed on the List and are not subject to 
public or peer review, polatuzumab vedotin was added to the 2016 List 
in September 2019 and will appear in the 2020 List.\8\ These three 
drugs do not appear below because they are not subject to public 
comment.
---------------------------------------------------------------------------

    \8\ See https://www.cdc.gov/niosh/docs/2016-161/default.html for 
all drugs with special handling information added to the 2016 List.
---------------------------------------------------------------------------

    The following seven drugs that were proposed for placement on the 
List in the February 2018 FRN are no longer proposed for placement on 
the List, for the reasons discussed above in Sections II.B. and III.B: 
bevacizumab, botulinum toxins, darbepoetin alfa, interferon beta-1b, 
osimertinib, trastuzumab, and triazolam.

  Drugs Proposed for Placement on the NIOSH List of Hazardous Drugs in
                        Healthcare Settings, 2020
------------------------------------------------------------------------
 Generic drug name a and AHFS    Rationale c and proposed location d on
           class b                              the List
------------------------------------------------------------------------
Blinatumomab.................  Rationale
AHFS Class: Antineoplastic...  Organ toxicity at low doses:
                                neurotoxicity at low doses in patients
                                in clinical studies.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.

[[Page 25450]]

 
Ceritinib....................  Rationale
AHFS Class: Antineoplastic...  Developmental toxicity: embryo-fetal
                                toxicity at low doses in rats and
                                rabbits.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Clobazam.....................  Rationale
AHFS Class: Antiepileptic....  Reproductive toxicity and Developmental
                                toxicity: embryo-fetal mortality and
                                other harm at low doses in rats and
                                rabbits, present in human breast milk.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Cobimetinib..................  Rationale
AHFS Class: Antineoplastic...  Reproductive toxicity and Developmental
                                toxicity: increased post-implantation
                                loss, including total litter loss in
                                rats at low doses; post-implantation
                                loss and fetal malformations in humans.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Dihydroergotamine............  Rationale
AHFS Class: 5-                 Reproductive toxicity: oxytocic
 hydroxytryptamine (HT)         properties at low doses in humans.
 receptor binder.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Exenatide....................  Rationale
AHFS Class: Antidiabetic.....  Carcinogenicity and Developmental
                                toxicity: thyroid C-cell tumors in rat
                                studies; adverse fetal effects in rats
                                and mice.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Isotretinoin.................  Rationale
AHFS Class: Retinoid.........  Developmental toxicity: severe fetal
                                malformations at any dose in humans.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Ivabradine...................  Rationale
AHFS Class: Hyperpolarization- Developmental toxicity: embryo-fetal
 activated cyclic nucleotide-   toxicity and teratogenicity at low doses
 gated (HCN) blocker.           in rats.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Lenvatinib...................  Rationale
AHFS Class: Antineoplastic...  Developmental toxicity: embryo-fetal
                                toxicity at low doses in rats and
                                rabbits; abortifacient in rabbits at low
                                doses.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Miltefosine..................  Rationale
AHFS Class: Antibiotic.......  Developmental toxicity: fetal death and
                                teratogenicity at low doses in rats and
                                rabbits.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Olaparib.....................  Rationale
AHFS Class: Antineoplastic...  Carcinogenicity and Developmental
                                toxicity: myelodysplastic syndrome/acute
                                myeloid leukemia in patients in clinical
                                studies; embryo-fetal toxicity, post
                                implantation loss, malformations at low
                                doses in rats.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Sonidegib....................  Rationale
AHFS Class: Antineoplastic...  Reproductive toxicity and Developmental
                                toxicity: embryo-fetal toxicity,
                                teratogenesis, and spontaneous abortions
                                at low doses in rabbits.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
Urofollitropin...............  Rationale
AHFS Class: Ovulation          Developmental toxicity: drug is known to
 stimulator.                    cause fetal harm in patients.
                               Proposed Location
                               Table 2: No MSHI, not classified as known
                                or probable carcinogen by NTP or IARC.
------------------------------------------------------------------------
\a\ FDA-approved drug (January 2014-December 2015).
\b\ AHFS (American Hospital Formulary Service) Pharmacologic-Therapeutic
  Classification system.
\c\ See Procedures section IV.
\d\ NIOSH proposes that the List include only two tables. Table 1
  includes only those drugs that contain MSHI in the package insert; and/
  or meet the NIOSH definition of a hazardous drug and are classified by
  the NTP as ``known to be a human carcinogen,'' or classified by the
  IARC as ``carcinogenic'' or ``probably carcinogenic.'' Table 2
  includes those drugs that meet the NIOSH definition of a hazardous
  drug but are not drugs that have MSHI or are classified by the NTP as
  ``known to be a human carcinogen,'' or classified by the IARC as
  ``carcinogenic'' or ``probably carcinogenic.''


[[Page 25451]]

C. NIOSH List of Hazardous Drugs in Healthcare Settings, 2020--Title, 
Reorganization, and Removals

    NIOSH has retitled and reorganized the List in response to comments 
received. Many of the drugs currently used to fight cancer function 
differently than those previously used. Antineoplastic drugs are no 
longer all cytotoxic, genotoxic, and highly hazardous chemicals. 
Therefore, when drugs are grouped by their function (i.e., 
antineoplastic), as they were in earlier versions of Table 1, drugs 
that required different protective measures were grouped together (non-
cytotoxic drugs with cytotoxic drugs). NIOSH has determined that 
grouping all antineoplastic drugs together in one table is no longer 
the most useful or informative for users. Therefore, NIOSH has 
regrouped the tables by hazard. 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.''

    Additional changes to the List, including those drugs proposed for 
removal from the List, are described in detail in the draft NIOSH List 
of Hazardous Drugs in Healthcare Settings, 2020, which is available for 
review in the docket for this activity.

IV. Risk Management for Hazardous Drugs in Healthcare Settings

    In the 2016 List, Table 5 provided information on recommended 
exposure controls for hazardous drugs based on formulations. In order 
to clarify that the List is a hazard identification tool, NIOSH has 
removed this table from the document. In its place, NIOSH has developed 
a new, comprehensive document on risk management strategies entitled, 
Managing Hazardous Drug Exposures: Information for Healthcare Settings, 
which includes a revision of this table on control approaches to safe 
handling of hazardous drugs. The new risk management document is 
available for review in the docket for this activity.
    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. Independent peer reviewers are being consulted as 
well; their charge is available on the NIOSH website \9\ and includes 
the following questions. NIOSH encourages public comment on these 
questions.
---------------------------------------------------------------------------

    \9\ NIOSH Peer Review Agenda, https://www.cdc.gov/niosh/review/peer/isi/healthsafetyrisks.html.
---------------------------------------------------------------------------

    1. Please provide feedback on the overall document:
    a. What additional information would improve its usefulness and 
why?
    b. What changes could be made to improve the utility of the 
information?
    c. What information is redundant, incorrect, missing, or not 
needed? Please explain.
    2. 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.
    3. Please provide any additional studies or scientific information 
that support or validate the use of the NIOSH recommended control 
strategies or alternative strategies to control exposures to hazardous 
drugs.
    4. Please provide any additional studies or scientific information 
that support or validate evidence-based strategies or approaches for 
controlling exposures to hazardous drugs that are different from those 
that NIOSH has proposed.
    5. NIOSH has provided its proposed recommendations and related 
information about controlling hazardous drugs in the Table of Control 
Approaches in Chapter 8.
    a. What additional information would improve the usefulness of this 
table and why?
    b. What structural or format changes could be made to improve the 
utility of this table?
    c. What information is redundant, incorrect, missing, or not 
needed? Please explain.
    6. What improvements could be made to this risk management 
information to make it more useful to employers and healthcare workers? 
Please provide specific examples.
    7. Please provide information about your professional experience, 
if any, of implementing control strategies for exposures to hazardous 
drugs in healthcare or similar settings. Please describe what you found 
to be most or least effective and why. Include relevant publications if 
available.
    8. Please provide any additional studies or scientific information 
related to the use of a medical surveillance program as an additional 
approach to protect workers in healthcare settings. Information of 
particular interest includes considerations for design and 
implementation of a medical surveillance program, data analysis, and 
communication of results to participants.

John J. Howard,
Director,National Institute for Occupational Safety and Health, Centers 
for Disease Control and Prevention.
[FR Doc. 2020-09332 Filed 4-30-20; 8:45 am]
BILLING CODE 4163-18-P