[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]
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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.
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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\
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\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.
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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\
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\2\ See https://www.cdc.gov/niosh/topics/hazdrug/peer-review-plan.html for the peer review plan for the draft Policy and
Procedures.
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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.
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\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.
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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\
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\4\ See USP, FAQs: <800 Hazardous Drugs--Handling in
Healthcare Settings, https://www.usp.org/frequently-asked-questions/hazardous-drugs-handling-healthcare-settings.
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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.
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\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.''
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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.
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\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