[Federal Register Volume 86, Number 245 (Monday, December 27, 2021)]
[Notices]
[Pages 73402-73405]
[FR Doc No: 2021-27922]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-93829; File No. SR-CboeBZX-2021-084]

Self-Regulatory Organizations; Cboe BZX Exchange, Inc.; Notice of
Filing and Immediate Effectiveness of a Proposed Rule Change To Amend
its Fee Schedule

December 20, 2021.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(``Act''),\1\ and Rule 19b-4 thereunder,\2\ notice is hereby given that
on December 10, 2021, Cboe BZX Exchange, Inc. (``Exchange'') filed with
the Securities and Exchange Commission (``Commission'') the proposed
rule change as described in Items I and II below, which Items have been
prepared by the Exchange. The Commission is publishing this notice to
solicit comments on the proposed rule change from interested persons.
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    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
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I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    Cboe BZX Exchange, Inc. (the ``Exchange'' or ``BZX'' or ``BZX
Equities'') proposes to amend its Fee Schedule. The text of the
proposed rule change is provided in Exhibit 5.
    The text of the proposed rule change is also available on the
Exchange's website (http://markets.cboe.com/us/equities/regulation/rule_filings/bzx/), at the Exchange's Office of the Secretary, and at
the Commission's Public Reference Room.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the Exchange included statements
concerning the purpose of and basis for the proposed rule change and
discussed any comments it received on the proposed rule change. The
text of these statements may be examined at the places specified in
Item IV below. The Exchange has prepared summaries, set forth in
sections A, B, and C below, of the most significant aspects of such
statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

1. Purpose
    The Exchange proposes to amend its fee schedule as follows: (1)
Modify the Add/Remove Volume Tiers, (2) adopt a new Non-Displayed Add
Volume Tier, (3) modify Tier 2 of the Step-Up Tiers, and (4) eliminate
the Total Volume Tier. The Exchange proposes to implement the proposed
change to its fee schedule on December 1, 2021.\3\
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    \3\ The Exchange initially filed the proposed fee changes on
December 1, 2021 (SR-BZX-2021-081). On December 10, 2021, the
Exchange withdrew that filing and submitted this proposal.
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    The Exchange first notes that it operates in a highly competitive
market in which market participants can readily direct order flow to
competing venues if they deem fee levels at a particular venue to be
excessive or incentives to be insufficient. More specifically, the
Exchange is only one of 16 registered equities exchanges, as well as a
number of alternative trading systems and other off-exchange venues
that do not have similar self-regulatory responsibilities under the
Exchange Act, to which market participants may direct their order flow.
Based on publicly available information,\4\ no single registered
equities exchange has more than 16% of the market share. Thus, in such
a low-concentrated and highly competitive market, no single equities
exchange possesses significant pricing power in the execution of order
flow. The Exchange in particular operates a ``Maker-Taker'' model
whereby it pays credits to Members that add liquidity and assesses fees
to those that remove liquidity. The Exchange's fee schedule sets forth
the standard rebates and rates applied per share for orders that
provide and remove liquidity, respectively. Additionally, in response
to the competitive environment, the Exchange also offers tiered pricing
which provides Members opportunities to qualify for higher rebates or
reduced fees where certain volume criteria and thresholds are met.
Tiered pricing provides an incremental incentive for Members to strive
for higher tier levels, which provides increasingly higher benefits or
discounts for satisfying increasingly more stringent criteria.
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    \4\ See Cboe Global Markets, U.S. Equities Market Volume
Summary, Month-to-Date (November 24, 2021), available at https://markets.cboe.com/us/equities/market_statistics/.
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Add/Remove Volume Tiers
    Pursuant to footnote 1 of the Fee Schedule, the Exchange currently
offers Add/Remove Volume Tiers (tiers 1 through 5) that provide Members
an opportunity to receive an enhanced rebate from the standard rebate
for liquidity adding orders that yield fee codes B,\5\ V,\6\ and Y \7\
and meet certain required volume-based criteria. Specifically, the
Tiers are as follows:
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    \5\ Orders yielding Fee Code ``B'' are displayed orders adding
liquidity to BZX (Tape B).
    \6\ Orders yielding Fee Code ``V'' are displayed orders adding
liquidity to BZX (Tape A).
    \7\ Orders yielding Fee Code ``Y'' are displayed orders adding
liquidity to BZX (Tape C).
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     Tier 1 offers an enhanced rebate of $0.0025 per share for
qualifying orders (i.e., yielding fee codes B, V, or Y) where a Member
has an ADAV \8\ as a percentage of TCV \9\ equal to or greater than
0.08% or where a Member has an ADAV equal to or greater than 8 million
shares.
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    \8\ ``ADAV'' means average daily added volume calculated as the
number of shares added per day and ``ADV'' means average daily
volume calculated as the number of shares added or removed,
combined, per day. ADAV and ADV are calculated on a monthly basis.
    \9\ ``TCV'' means total consolidated volume calculated as the
volume reported by all exchanges and trade reporting facilities to a
consolidated transaction reporting plan for the month for which the
fees apply.
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     Tier 2 offers an enhanced rebate of $0.0027 per share for
qualifying orders (i.e., yielding fee codes B, V, or Y) where a Member
has an ADAV as a percentage of TCV equal to or greater than 0.15% or
where a Member has an ADAV equal to or greater than 15 million shares.
     Tier 3 offers an enhanced rebate of $0.0029 per share for
qualifying orders (i.e., yielding fee codes B, V, or Y) where a Member
has an ADAV as a percentage of TCV equal to or greater than 0.35%

or where a Member has an ADAV equal to or greater than 35 million
shares.
     Tier 4 offers an enhanced rebate of $0.0030 per share for
qualifying orders (i.e., yielding fee codes B, V, or Y) where a Member
has an ADAV as a percentage of TCV equal to or greater than 0.60% or
where a Member has an ADAV equal to or greater than 60 million shares.
     Tier 5 offers an enhanced rebate of $0.0031 per share for
qualifying orders (i.e., yielding fee codes B, V, or Y) where a Member
has an ADAV as a percentage of TCV equal to or greater than 1.00% or
where a Member has an ADAV equal to or greater than 100 million shares.
    The Exchange now proposes to modify existing Tiers 1 and 2, add a
new Tier 2, and renumber existing Tiers 2 through 5. Specifically, as
proposed the Tiers would provide for the following:
     Proposed Tier 1 would offer an enhanced rebate of $0.0020
per share (instead of $0.0025 per share) for qualifying orders (i.e.,
yielding fee codes B, V, or Y) where a Member has an ADAV as a
percentage of TCV equal to or greater than 0.08% [sic] or where a
Member has an ADAV equal to or greater than 10 million shares (instead
of 8 million shares).
     Proposed Tier 2 would offer an enhanced rebate of $0.0025
per share for qualifying orders (i.e., yielding fee codes B, V, or Y)
where a Member has an ADAV as a percentage of TCV equal to or greater
than 0.20% or where a Member has an ADAV equal to or greater than 20
million shares.
     Proposed Tier 3 (current Tier 2) would offer an enhanced
rebate of $0.0027 per share for qualifying orders (i.e., yielding fee
codes B, V, or Y) where a Member has an ADAV as a percentage of TCV
equal to or greater than 0.25% (instead of 0.15%) or where a Member has
an ADAV equal to or greater than 25 million shares (instead of 15
million).
     Proposed Tiers 4 through 6 would have the same criteria
and provide the same enhanced rebate as existing Tiers 3 through 5,
respectively. The only proposed change is to modify the Tier numbers of
Tier 3 through 5 to Tier 4 through 6, respectively.
    Although the proposed changes to the thresholds of proposed Tiers 1
and 3 result in more stringent criteria, Members still have an
opportunity to receive an enhanced rebate if they meet the applicable
tier threshold. Moreover, the proposed changes are designed to
encourage Members to increase their displayed liquidity in Tape A, B
and C securities on the Exchange, thereby contributing to a deeper and
more liquid market, which benefits all market participants and provides
greater execution opportunities on the Exchange.
Non-Displayed Add Volume Tiers
    Pursuant to footnote 1 of the Fee Schedule, the Exchange currently
offers Non-Displayed Add Volume Tiers (tiers 1 through 4) that provide
Members an opportunity to receive an enhanced rebate from the standard
rebate for liquidity adding orders that yield fee codes HB,\10\ HV,\11\
and HY \12\ and meet certain required volume-based criteria.
Specifically, the Add Volume Tiers are as follows:
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    \10\ Orders yielding Fee Code ``HB'' are non-displayed orders
adding liquidity to BZX (Tape B).
    \11\ Orders yielding Fee Code ``HV'' are non-displayed orders
adding liquidity to BZX (Tape A).
    \12\ Orders yielding Fee Code ``HY'' are non-displayed orders
adding liquidity to BZX (Tape C).
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     Non-Displayed Add Volume Tier 1 offers an enhanced rebate
of $0.0018 per share for qualifying orders (i.e., yielding fee codes
HB, HI,\13\ HV, or HY) where a Member adds an ADV equal to or greater
than 0.05% of the TCV.
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    \13\ Orders yielding Fee Code ``HI'' are non-displayed orders
adding liquidity to BZX that receive price improvement.
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     Non-Displayed Add Volume Tier 2 offers an enhanced rebate
of $0.0020 per share for qualifying orders (i.e., yielding fee codes
HB, HI, HV, or HY) where a Member adds an ADV equal to or greater than
0.10% of the TCV.
     Non-Displayed Add Volume Tier 3 offers an enhanced rebate
of $0.0025 per share for qualifying orders (i.e., yielding fee codes
HB, HI, HV, or HY) where a Member adds an ADV equal to or greater than
0.15% of the TCV.
     Non-Displayed Add Volume Tier 4 offers an enhanced rebate
of $0.0029 per share for qualifying orders (i.e., yielding fee codes
HB, HI, HV, or HY) where a Member adds an ADV equal to or greater than
0.35% of the TCV.
    Now, the Exchange proposes to introduce a new Non-Displayed Add
Volume Tier 4 and renumber existing Non-Displayed Add Volume Tier 4 to
Tier 5. Specifically, proposed Non-Displayed Add Volume Tier 4 is as
follows:
     Proposed Non-Displayed Add Volume Tier 4 offers an
enhanced rebate of $0.00275 per share for qualifying orders (i.e.,
yielding fee codes HB, HI, HV, or HY) where a Member adds an ADV equal
to or greater than 0.20% of the TCV.
    The proposed change is designed to give Members an additional
opportunity to receive an enhanced rebate for orders meeting the
applicable threshold. Further, the proposed change is designed to
encourage Members to increase their non-displayed volume adding
liquidity on the Exchange, contributing to a deeper and more liquid
market, which benefits all market participants and provides greater
execution opportunities on the Exchange.
Step-Up Tiers
    Pursuant to footnote 2 of the Fee Schedule, the Exchange currently
offers Step-Up Tiers (tiers 1 and 2) that provide Members an
opportunity to receive an enhanced rebate from the standard rebate for
liquidity adding orders that yield fee codes B, V, and Y where they
increase their relative liquidity each month over a predetermined
baseline. Tier 2 of the Step-Up Tiers provides an enhanced rebate of
$0.0032 per share to a Member that (1) has a Step-Up Add TCV \14\ from
June 2021 equal to or greater than 10 million shares; and (2) has an
ADV equal to or greater than 0.30% of the TCV or the Member has an ADV
equal to or greater than 35 million. The Exchange notes that step-up
tiers are designed to encourage Members that provide displayed
liquidity on the Exchange to increase their order flow, which would
benefit all Members by providing greater execution opportunities on the
Exchange. Now the Exchange proposes to amend criteria (1) of the
current criteria for Step-Up Tier 2 to provide an alternative means of
satisfying the first prong. Particularly, the Exchange proposes to
provide under criteria (1) that a Member must have a Step-Up ADAV from
June 2021 equal to or greater than 10 million shares or, alternatively,
a Member must have a Step-Up Add TCV from June 2021 equal to or greater
than 0.10%. The Exchange believes that the tier as proposed will
further incentivize increased order flow to the Exchange, which may
contribute to a deeper, more liquid market to the benefit of all market
participants by creating a more robust and well-balanced market
ecosystem. Step-Up Tier 2, as modified, continues to be available to
all Members and would provide Members an opportunity to receive an
enhanced rebate.
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    \14\ ``Step-Up Add TCV'' means ADAV as a percentage of TCV in
the relevant baseline month subtracted from current ADAV as a
percentage of TCV.
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Total Volume Tiers
    The Exchange also proposes to eliminate the Total Volume Tier 1,
which is the only Tier under Total Volume Tiers and is currently
described under footnote 3 of the fee schedule. Particularly, this tier
applies to orders yielding fee code B, V, or Y and

provides a $0.0033 per share rebate to Members that have an ADV greater
than or equal to 1.40% of the TCV. No Member has reached this tier in
several months and the Exchange therefore no longer wishes to, nor is
it required to, maintain such a tier.
2. Statutory Basis
    The Exchange believes that the proposed rule change is consistent
with the objectives of Section 6 of the Securities Exchange Act of 1934
(the ``Act''),\15\ in general, and furthers the objectives of Section
6(b)(4) and 6(b)(5),\16\ in particular, as it is designed to provide
for the equitable allocation of reasonable dues, fees and other charges
among its Members, issuers and other persons using its facilities. The
Exchange operates in a highly competitive market in which market
participants can readily direct order flow to competing venues if they
deem fee levels at a particular venue to be excessive or incentives to
be insufficient. The proposed rule changes reflect a competitive
pricing structure designed to incentivize market participants to direct
their order flow to the Exchange, which the Exchange believes would
enhance market quality to the benefit of all Members, and thus is in
the public interest. The Exchange notes that relative volume-based
incentives and discounts have been widely adopted by exchanges,
including the Exchange, and are reasonable, equitable and non-
discriminatory because they are open to all members on an equal basis
and provide additional benefits or discounts that are reasonably
related to (i) the value to an exchange's market quality and (ii)
associated higher levels of market activity, such as higher levels of
liquidity provision and/or growth patterns. Additionally, as noted
above, the Exchange operates in highly competitive market. The Exchange
is only one of several equity venues to which market participants may
direct their order flow, and it represents a small percentage of the
overall market. It is also only one of several maker-taker exchanges.
Competing equity exchanges offer similar tiered pricing structures,
including schedules of rebates and fees that apply based upon members
achieving certain volume and/or growth thresholds, as well as assess
similar fees or rebates for similar types of orders, to that of the
Exchange. These competing pricing schedules, moreover, are presently
comparable to those that the Exchange provides, including the pricing
of comparable criteria and/or fees and rebates.
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    \15\ 15 U.S.C. 78f.
    \16\ 15 U.S.C. 78f(b)(4) and (5).
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    The Exchange believes the proposed changes to the Add/Remove Volume
Tiers, Non-Displayed Add Volume Tiers, and Step-Up Tiers are reasonable
because each tier, as modified, continues to be available to all
Members and provide Members an opportunity to receive an enhanced
rebate. The Exchange also believes that the proposed enhanced rebates
continue to be commensurate with the proposed criteria. That is, the
rebates reasonably reflect the difficulty in achieving the applicable
criteria as amended. The Exchange believes the proposed changes to the
Add/Remove Volume Tiers, Non-Displayed Add Volume Tiers, and Step-Up
Tiers represent an equitable allocation of rebates and is not unfairly
discriminatory because all Members are eligible for those tiers and
would have the opportunity to meet a tier's criteria and would receive
the proposed rebate if such criteria is met. Without having a view of
activity on other markets and off-exchange venues, the Exchange has no
way of knowing whether this proposed rule change would definitely
result in any Members qualifying for the proposed tier. While the
Exchange has no way of predicting with certainty how the proposed tiers
will impact Member activity, the Exchange anticipates that at least
five Members will be able to satisfy the criteria proposed under the
Add/Remove Volume Tier 1, one Member will be able to satisfy the
criteria proposed under the Add/Remove Volume Tier 3, one Member will
be able to satisfy the criteria proposed under the Non-Displayed Tier
4, and one Member will be able to satisfy the criteria proposed under
the Step-Up Tier 2. The Exchange does not expect any Member to
immediately satisfy the criteria proposed under the Add Volume Tier 2;
however, the Exchange believes the proposed rebate incentivizes Members
to meet the tier's criteria in the future. The Exchange also notes that
proposed tier/rebate will not adversely impact any Member's ability to
qualify for other reduced fee or enhanced rebate tiers. Should a Member
not meet the proposed criteria under the modified tier, the Member will
merely not receive that corresponding enhanced rebate.
    Finally, the Exchange believes the proposed amendment to remove the
Total Volume Tier is reasonable because no Member has achieved this
tier in several months. Moreover, the Exchange is not required to
maintain this tier and Members still have a number of other
opportunities and a variety of ways to receive enhanced rebates for
displayed liquidity, including the enhanced rebates under the Add
Volume Tiers under footnote 1 of the fees schedule. The Exchange
believes the proposal to eliminate this tier is also equitable and not
unfairly discriminatory because it applies to all Members.

B. Self-Regulatory Organization's Statement on Burden on Competition

    The Exchange does not believe that the proposed rule change will
impose any burden on competition that is not necessary or appropriate
in furtherance of the purposes of the Act. Rather, as discussed above,
the Exchange believes that the proposed changes would encourage the
submission of additional order flow to a public exchange, thereby
promoting market depth, execution incentives and enhanced execution
opportunities, as well as price discovery and transparency for all
Members. As a result, the Exchange believes that the proposed changes
further the Commission's goal in adopting Regulation NMS of fostering
competition among orders, which promotes ``more efficient pricing of
individual stocks for all types of orders, large and small.'' \17\
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    \17\ Securities Exchange Act Release No. 51808, 70 FR 37495,
37498-99 (June 29, 2005) (S7-10-04) (Final Rule).
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    The Exchange believes the proposed rule changes do not impose any
burden on intramarket competition that is not necessary or appropriate
in furtherance of the purposes of the Act. Particularly, the proposed
tier changes apply to all Members equally in that all Members continue
to be eligible for the Add Volume, Non-Displayed Add Volume, and Step-
Up Tiers, have a reasonable opportunity to meet the tiers' criteria and
will receive the corresponding additional rebates if such criteria are
met. Additionally, the proposed tier changes are designed to attract
additional order flow to the Exchange. The Exchange believes that the
updated tier criteria would incentivize market participants to direct
liquidity adding order flow to the Exchange, bringing with it
additional execution opportunities for market participants and improved
price transparency. Greater overall order flow, trading opportunities,
and pricing transparency benefits all market participants on the
Exchange by enhancing market quality and continuing to encourage
Members to send orders, thereby contributing towards a robust and well-
balanced market ecosystem.
    Next, the Exchange believes the proposed rule change does not
impose any burden on intermarket competition that is not necessary or
appropriate in

furtherance of the purposes of the Act. As previously discussed, the
Exchange operates in a highly competitive market. Members have numerous
alternative venues that they may participate on and direct their order
flow, including 15 other equities exchanges and off exchange venues and
alternative trading systems. Additionally, the Exchange represents a
small percentage of the overall market. Based on publicly available
information, no single equities exchange has more than 16% \18\ of the
market share. Therefore, no exchange possesses significant pricing
power in the execution of order flow. Indeed, participants can readily
choose to send their orders to other exchange and off-exchange venues
if they deem fee levels at those other venues to be more favorable.
Moreover, the Commission has repeatedly expressed its preference for
competition over regulatory intervention in determining prices,
products, and services in the securities markets. Specifically, in
Regulation NMS, the Commission highlighted the importance of market
forces in determining prices and SRO revenues and, also, recognized
that current regulation of the market system ``has been remarkably
successful in promoting market competition in its broader forms that
are most important to investors and listed companies.'' \19\ The fact
that this market is competitive has also long been recognized by the
courts. In NetCoalition v. Securities and Exchange Commission, the D.C.
Circuit stated as follows: ``[n]o one disputes that competition for
order flow is `fierce.' . . . As the SEC explained, `[i]n the U.S.
national market system, buyers and sellers of securities, and the
broker-dealers that act as their order-routing agents, have a wide
range of choices of where to route orders for execution'; [and] `no
exchange can afford to take its market share percentages for granted'
because `no exchange possesses a monopoly, regulatory or otherwise, in
the execution of order flow from broker dealers'. . ..''.\20\
Accordingly, the Exchange does not believe its proposed fee change
imposes any burden on competition that is not necessary or appropriate
in furtherance of the purposes of the Act.
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    \18\ Supra note 3.
    \19\ See Securities Exchange Act Release No. 51808 (June 9,
2005), 70 FR 37496, 37499 (June 29, 2005).
    \20\ NetCoalition v. SEC, 615 F.3d 525, 539 (D.C. Cir. 2010)
(quoting Securities Exchange Act Release No. 59039 (December 2,
2008), 73 FR 74770, 74782-83 (December 9, 2008) (SR-NYSEArca-2006-
21)).
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C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants, or Others

    The Exchange neither solicited nor received comments on the
proposed rule change.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    The foregoing rule change has become effective pursuant to Section
19(b)(3)(A) of the Act \21\ and paragraph (f) of Rule 19b-4 \22\
thereunder. At any time within 60 days of the filing of the proposed
rule change, the Commission summarily may temporarily suspend such rule
change if it appears to the Commission that such action is necessary or
appropriate in the public interest, for the protection of investors, or
otherwise in furtherance of the purposes of the Act.
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    \21\ 15 U.S.C. 78s(b)(3)(A).
    \22\ 17 CFR 240.19b-4(f).
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IV. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. Comments may be submitted by any of
the following methods:

Electronic Comments

     Use the Commission's internet comment form (http://www.sec.gov/rules/sro.shtml); or
     Send an email to [email protected]. Please include
File Number SR-CboeBZX-2021-084 on the subject line.

Paper Comments

     Send paper comments in triplicate to Secretary, Securities
and Exchange Commission, 100 F Street NE, Washington, DC 20549-1090.

All submissions should refer to File Number SR-CboeBZX-2021-084. This
file number should be included on the subject line if email is used. To
help the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's internet website (http://www.sec.gov/rules/sro.shtml).
Copies of the submission, all subsequent amendments, all written
statements with respect to the proposed rule change that are filed with
the Commission, and all written communications relating to the proposed
rule change between the Commission and any person, other than those
that may be withheld from the public in accordance with the provisions
of 5 U.S.C. 552, will be available for website viewing and printing in
the Commission's Public Reference Room, 100 F Street NE, Washington, DC
20549 on official business days between the hours of 10:00 a.m. and
3:00 p.m. Copies of the filing also will be available for inspection
and copying at the principal office of the Exchange. All comments
received will be posted without change. Persons submitting comments are
cautioned that we do not redact or edit personal identifying
information from comment submissions. You should submit only
information that you wish to make available publicly. All submissions
should refer to File Number SR-CboeBZX-2021-084 and should be submitted
on or before January 18, 2022.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\23\
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    \23\ 17 CFR 200.30-3(a)(12).
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Jill M. Peterson,
Assistant Secretary.
[FR Doc. 2021-27922 Filed 12-23-21; 8:45 am]
BILLING CODE 8011-01-P


[Federal Register Volume 76, Number 189 (Thursday, September 29, 2011)]
[Notices]
[Page 60505]
[FR Doc No: 2011-25116]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-N-0690]

Center for Drug Evaluation and Research, Approach to Addressing
Drug Shortage; Public Workshop; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is opening a comment
period for the notice of public workshop published in the Federal
Register of July 28, 2011 (76 FR 45268). In that notice, FDA announced
a public workshop regarding the approach of the Center for Drug
Evaluation and Research to addressing drug shortages. FDA is opening a
comment period in light of public interest in this topic and in order
to gain additional insight about the causes and impact of drug
shortages, and possible strategies for preventing or mitigating drug
shortages.

DATES: Either electronic or written comments will be accepted after the
workshop until December 23, 2011.

ADDRESSES: Submit electronic comments to http://www.regulations.gov.
Submit written comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Christine Moser or Lori Benner, Center
for Drug Evaluation and Research, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 22, Rm. 6202, Silver Spring, MD 20993-0002,
301-796-1300.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA held a public workshop regarding CDER's current approach to
addressing drug shortages. Given the increasing number of drug
shortages and the attendant safety concerns for the public's health, it
is important to discuss the causes of these shortages, as well as
strategies to address them. This public workshop focused on collecting
information and gaining perspective from professional societies,
patient advocates, industry, consumer groups, health care
professionals, researchers, and other interested persons. The topics
discussed: How CDER becomes aware of drug shortages, Reasons behind
drug shortages, Determination of medically necessary products, CGMP
(current good manufacturing practice) and other compliance issues,
Actions taken when a drug shortage occurs, and Outcomes of mitigated
drug shortages. Additional discussions included the public health
impact of drug shortages and what measures can be taken to prevent the
occurrence of a drug shortage. The Agency encouraged professional
societies, patient advocates, industry, consumer groups, health care
professionals, researchers, and other interested persons to attend this
public workshop.

II. Transcripts

    Please be advised that as soon as a transcript is available, it
will be accessible at http://www.regulations.gov, approximately 45 days
after the public workshop. It may be viewed at the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD. A transcript will also be available in either
hardcopy or on CD-ROM, after submission of a Freedom of Information
request. Written requests are to be sent to the Division of Freedom of
Information (ELEM-1029), Food and Drug Administration, 12420 Parklawn
Dr., Element Bldg., Rockville, MD 20857.

III. Comments

    Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. It is no
longer necessary to send two copies of mailed comments. Identify
comments with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday.

    Dated: September 26, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-25116 Filed 9-28-11; 8:45 am]
BILLING CODE 4160-01-P


## clean and commented
dochlmod <- function(dat.merge, modat0, fitout = NULL, runmod = T) {

    require(mgcv)
    require(rMR)
    require(mgcv)
    load("modairtemp.rda")  # model of mean air temperature from tempmod.R
    source("binv.R")
    source("logtick.exp.R")

    dat.merge$site.id.c <- factor(dat.merge$site.id.c)

    ## set number of MCMC chains here
    nchains <- 6

    # drop littoral duplicates
    dat.merge <- subset(dat.merge, sample.type == "MICX")
    dat.merge.sav <- dat.merge
    # select variables used in the model
    dat.merge <- dat.merge[, c("site.id.c", "doc.result", "therm.sav", "chl",
                               "domean", "tempmean","tbot",
                               "do.hyp.fail", "do.hyp.pass",
                               "yday.x", "st.nla2012","year", "tmax",
                               "index.lat.dd", "index.lon.dd",
                               "index.site.depth",
                               "elevation", "area.ha", "tmean.pt",
                               "tmin.pt")]

    sitemean <- function(x, site, varname,dolog = F) {
        if (! dolog) {
            xm <- tapply(x, site, mean, na.rm = T)
        }
        else {
            xm <- tapply(x, site, function(x) mean(log(x), na.rm = T))
        }
        return(xm)
    }

    ## compute mean values of lake characteristics and merge
    varlist <- c("doc.result", "index.lat.dd", "tmean.pt", "tmin.pt",
                 "index.lon.dd", "elevation", "area.ha", "index.site.depth")
    matout <- matrix(NA, ncol = length(varlist),
                     nrow = length(levels(dat.merge$site.id.c)))
    dolog <- c(T, rep(F, times = 7))
    for (i in 1:length(varlist)) {
        matout[,i] <- sitemean(dat.merge[, varlist[i]],
                               dat.merge$site.id.c, dolog = dolog[i])
    }
    dat.mean <- data.frame(levels(dat.merge$site.id.c), matout)
    names(dat.mean) <- c("site.id.c", "docmean", "Lat", "Temp", "TempMin",
                         "Lon", "Elev", "Area", "Depth")
    dat.mean$LakeRatio <- (dat.mean$Area*10000)^0.25/dat.mean$Depth

    ## model tempmin and fill in missing values
    df2 <- na.omit(dat.mean[, c("Elev", "Lat", "Lon", "TempMin")])
    mod <- gam(TempMin ~ s(Lat, Lon, k = 50) + Elev, data = df2)
    predout <- predict(mod, dat.mean[, c("Lat", "Lon", "Elev")])
    dat.mean$TempMin <- predout

    dat.merge<-merge(dat.merge, dat.mean,by = "site.id.c")

    ## compute mean depth below thermocline
    dat.merge$hyp.depth <-dat.merge$Depth - dat.merge$therm.sav
    incvec <- dat.merge$hyp.depth < 0
    incvec[is.na(incvec)] <- F
    dat.merge$hyp.depth[incvec] <- NA # drop sites with negative hyp depth
    hypdepth.mn <- tapply(dat.merge$hyp.depth, dat.merge$site.id.c, mean,
                          na.rm = T)
    dftemp <- data.frame(site.id.c = names(hypdepth.mn),
                         hypdepth.mn = as.vector(hypdepth.mn))
    dat.merge <- merge(dat.merge, dftemp, by = "site.id.c")

    ## drop missing data
    incvec <- ! is.na(dat.merge$hyp.depth) & ! is.na(dat.merge$domean) &
        ! is.na(dat.merge$chl) & ! is.na(dat.merge$docmean)
    dat.merge <- dat.merge[incvec,]

    ## set bottom temperature less than 4 to 4 for the purposes
    ## of calculating beginning DO
    incvec <- dat.merge$TempMin < 4
    incvec[is.na(incvec)] <- F
    dat.merge$TempMin[incvec] <- 4

    ## get beginning DO concentration at turnover
    dosat <- DO.saturation(rep(5, times = nrow(dat.merge)),
                           dat.merge$TempMin, elevation.m = dat.merge$Elev,
                           salinity = rep(0, times = nrow(dat.merge)),
                           salinity.units = "pp.thou")

    dat.merge$maxDO <- 5/dosat

    ## select lakes that seasonally stratify based on lake ratio
    dat.merge <- subset(dat.merge, LakeRatio < 3)

    ## drop 7 partial profiles depth > 25 m and number of measurements < 16
    incvec <- (dat.merge$do.hyp.pass + dat.merge$do.hyp.fail < 16) &
        dat.merge$hyp.depth > 25
    dat.merge <- dat.merge[!incvec,]

    ## ND alkaline lake dropped, WA super saturated lake, IN metalimnetic DO max
    ## these are big outliers in the model
    droplist <- c("NLA12_ND-R17", "NLA12_WA-R10", "NLA12_IN-131")
    for (i in droplist) {
        incvec <- dat.merge$site.id.c == i
        if (sum(incvec) == 1){
            dat.merge <- dat.merge[!incvec,]
        }
    }

    ## compute adjusted latitude for finding dimictic lakes
    lat0 <- seq(0, 90, by = 10)
    adj <- c(0.27, 0.31, 0.34, 0.39, 0.46, 0.54, 0.68, 0.89, 1.3, 2.4)
    dat.merge$adjloc <- approx(lat0, adj, dat.merge$Lat)$y
    dat.merge$adjlat <- dat.merge$Lat + dat.merge$adjloc*dat.merge$Elev/100

    dat.merge <- subset(dat.merge, adjlat > 40) # drop monomictic lakes

    ## standardize variables for model
    dat.merge$chl <- log(dat.merge$chl)
    varlist <- c("hypdepth.mn", "docmean", "chl", "yday.x", "Temp")
    mnsav <- apply(dat.merge[, varlist], 2, mean)
    sdsav <- apply(dat.merge[, varlist], 2, sd)

    for (i in varlist) {
        dat.merge[,paste(i, "sc", sep = ".")] <- (dat.merge[,i] - mnsav[i])/sdsav[i]
    }

    dat.merge$site.id.c <- factor(dat.merge$site.id.c)
    dat.merge$sitenum <- as.numeric(dat.merge$site.id.c)

    ## sitedata
    dfsite <- unique.data.frame(dat.merge[, c("sitenum", "hypdepth.mn.sc",
                                           "docmean.sc","maxDO",
                                           "Lat", "Temp.sc")])
    dfsite <- dfsite[order(dfsite$sitenum),]

    # output chl and DOm data
    dffull0 <- dat.merge
#    save(dffull0, file = "dffull0.rda")

    ## split data into missing (DO < 2) or observed
    incvec <- dat.merge$domean < 2
    dftemp1 <- dat.merge[!incvec,]
    dftemp2 <- dat.merge[incvec,]

    df1 <- modat0

    ## get mean air temperature at MO lakes using Lat, Lon, and Elev
    df1$Lon <- df1$Long
    df1$Elev <- df1$elev*0.3048
    df1$Temp <- predict(modairtemp, df1)

    ## standardize MO data by nla vals
    df1$chlmean.sc <- (df1$chlmean - mnsav["chl"])/sdsav["chl"]
    df1$docmean.sc <- (df1$docmean - mnsav["docmean"])/sdsav["docmean"]
    df1$yday.sc <- (df1$yday - mnsav["yday.x"])/sdsav["yday.x"]
    df1$depth.hm.sc<- (df1$depth.hm - mnsav["hypdepth.mn"])/sdsav["hypdepth.mn"]
    df1$Temp.sc <- (df1$Temp - mnsav["Temp"])/sdsav["Temp"]

    ## get state average value for Temp and elev to inform maxDO for MO data
    dftemp.state <- unique.data.frame(dat.merge.all[, c("site.id.c",
                                                        "st.nla2012")])
    dftemp.state <-merge(dftemp.state, dat.mean[, c("site.id.c", "TempMin",
                                                    "Elev")])
    incvec <- dftemp.state$st.nla2012 == "MO"
    mo.mn <- apply(dftemp.state[incvec, c("TempMin", "Elev")], 2, mean)
    dosat.mo <- DO.saturation(5,
                           mo.mn["TempMin"], elevation.m = mo.mn["Elev"],
                           salinity = 0,
                           salinity.units = "pp.thou")
    mo.maxDO <- 5/dosat.mo

    ## set up site ids
    df1$id <- factor(as.character(df1$id))
    df1$sitenum <- as.numeric(df1$id)
    df1$idyear <- factor(df1$idyear)
    df1$siteyrnum <- as.numeric(df1$idyear)

    lookup0 <- unique.data.frame(df1[, c("siteyrnum", "Temp.sc")])
    lookup0 <- lookup0[order(lookup0$siteyrnum),]

    dfsite0 <- unique.data.frame(df1[, c("sitenum", "depth.hm.sc", "chlmean.sc",
                                         "docmean.sc", "Temp.sc")])
    dfsite0 <- dfsite0[order(dfsite0$sitenum),]

    datstan <- list(n = c(nrow(dftemp1), nrow(dftemp2), nrow(dat.merge)),
                    nsite = nrow(dfsite),
                    chl = dat.merge$chl.sc,
                    temp = dfsite$Temp.sc,
                    depth = dfsite$hypdepth.mn.sc,
                    doc = dfsite$docmean.sc,
                    dmax = dfsite$maxDO,
                    t1 = dftemp1$yday.x.sc,
                    t2 = dftemp2$yday.x.sc,
                    domean = dftemp1$domean,
                    sitenum = dat.merge$sitenum,
                    sitenum1 = dftemp1$sitenum,
                    sitenum2 = dftemp2$sitenum,
                    n0 = nrow(df1),
                    t0 = df1$yday.sc,
                    domean0 = df1$domean.all,
                    dmax0 = mo.maxDO,
                    nsite0 = max(dfsite0$sitenum),
                    chl0 = dfsite0$chlmean.sc,
                    temp0 = as.vector(lookup0$Temp.sc),
                    depth0 = dfsite0$depth.hm.sc,
                    doc0 = dfsite0$docmean.sc,
                    sitenum0 = df1$sitenum,
                    nsiteyr0 = max(df1$siteyrnum),
                    siteyrnum0 = df1$siteyrnum)

    print(str(datstan))

    modstan <- '
         data {
             int n[3];                    // N above 2, below 2, and all
             int nsite;                   // number of samples
             vector[n[3]] chl;            // sample Chl

             vector[nsite] temp;          // mean air temperature
             vector[nsite] depth;         // depth below thermocline
             vector[nsite] doc;           // mean doc
             vector[nsite] dmax;          // maximum DO

             vector[n[1]] t1;             // sample day above 2s
             vector[n[2]] t2;             // sample day below 2s
             vector[n[1]] domean;         // mean DO
             int sitenum[n[3]];           // sitenums for different samples
             int sitenum1[n[1]];
             int sitenum2[n[2]];

             int n0;                      // N samples for MO
             vector[n0] t0;               // sampling day for MO
             vector[n0] domean0;          // mean DO for MO
             real dmax0;                  // maximum DO for MO
             int nsite0;                  // N sites
             int nsiteyr0;                // N site-year
             vector[nsiteyr0] temp0;      // Air temperature
             vector[nsite0] chl0;         // Chl
             vector[nsite0] depth0;       // depth below thermocline
             vector[nsite0] doc0;         // mean DOC
             int sitenum0[n0];
             int siteyrnum0[n0];

         }
         parameters {
             real muchl;                       // model for mean site chl
             real<lower =0> sigchl[2];         // variance terms for chl model
             vector[nsite] etachl;

             real mud[4];                      // Coefficients for VOD model
             vector<upper = 2>[n[2]] domean2;  // Estimates for censored DO

             real<upper = 0> b[2];             // Coefficients for strat day model
             real<lower = 0> sigt;             // Variance in strat day model
             vector[nsite] etat;
             vector[nsiteyr0] etat0;
             real<lower = 0> sigt0;

             real<lower = 0> sig;              // variance in predicted DO
             real<lower = 0> sig0;             // variance in predicted DO MO
             real<lower = 0> sigd;            // variance in VOD
             vector[nsite0] etad;
         }
         transformed parameters {
             vector[nsite] chlsite;
             vector[nsite] tstart;
             vector[n[1]] dopred1;
             vector[n[2]] dopred2;
             vector[nsiteyr0] tstart0;

             vector[n0] dopred0;
             vector[nsite0] d2;

             chlsite = muchl + etachl*sigchl[1];

             tstart = b[1] + b[2]*temp + etat*sigt;  // strat day model
             tstart0 = b[1] + b[2]*temp0 + etat0*sigt0;

             // VOD model
             d2 = -exp(mud[1]) + mud[2]*chl0 + mud[3]*depth0+mud[4]*doc0 + etad*sigd;

             // Predictions of mean DO
             dopred0 = dmax0 +d2[sitenum0] .* (t0 - tstart0[siteyrnum0]);
             dopred1 = dmax[sitenum1] + (-exp(mud[1]) + mud[2]*chlsite[sitenum1] +
                            mud[3]*depth[sitenum1] + mud[4]*doc[sitenum1]).*
                            (t1 - tstart[sitenum1]);
             dopred2 = dmax[sitenum2] + (-exp(mud[1]) + mud[2]*chlsite[sitenum2] +
                            mud[3]*depth[sitenum2] + mud[4]*doc[sitenum2]).*
                            (t2 - tstart[sitenum2]);
         }
         model {
             muchl ~ normal(0,3);
             sigchl ~ cauchy(0,3);
             etachl ~ normal(0,1);

             sig ~ cauchy(0,3);

             // Priors for strat day based on Demers and Kalff coef scaled
             // Scaled by centering applied to mean annual temeprature
             b[1] ~ normal(-3.6, 2);
             b[2] ~ normal(-0.71, 0.4);
             // Priors for variance in strat day based on Demers and Kalff
             // scaled
             sigt ~ normal(0.78, 0.3);
             sigt0 ~ normal(0.78, 0.3);

             etat ~ normal(0,1);
             etat0 ~ normal(0,1);

             mud ~ normal(0,2);

             etad ~ normal(0,1);
             sigd ~ cauchy(0,2);

             sig0 ~ cauchy(0,3);

             // sampling statements
             chl ~ normal(chlsite[sitenum], sigchl[2]);
             domean ~ normal(dopred1,  sig);
             domean2 ~ normal(dopred2, sig);
             domean0 ~ normal(dopred0, sig0);

         }
         generated quantities {
             vector[n[1]] dop;     // predictive posterior national
             vector[n0] do0p;      // predictive posterior MO
             for (i in 1:n[1]) dop[i] = normal_rng(dopred1[i], sig);
             for (i in 1:n0) do0p[i] = normal_rng(dopred0[i], sig0);
         }
     '

    if (runmod) {
        require(rstan)
        rstan_options(auto_write = TRUE)
        nchains <- 6
        options(mc.cores = nchains)

        fit <- stan(model_code = modstan, data = datstan,
                    iter = 900, chains = nchains, warmup = 300,
                    control = list(max_treedepth = 15,
                                   adapt_delta = 0.9), thin = 2)

        return(fit)
    }
    else {
        ## plot median posterior prediction vs. observation
        varout <- extract(fitout, pars = c("do0p", "dop"))
        dopmed <- apply(varout$dop, 2, median)
        do0pmed <- apply(varout$do0p, 2, median)
        dev.new()
        par(mar = c(4,4,1,1), mfrow = c(1,2), mgp = c(2.3,1,0),
            bty = "l")
        plot(dopmed, dftemp1$domean, xlab = "Predicted DO",
             ylab = "Observed DO", pch = 21, col = "grey39",
             bg = "white", main = "NLA")
        abline(0,1)
        plot(do0pmed, df1$domean.all, xlab = "Predicted DO",
             ylab = "Observed DO", pch = 21, col= "grey39",
             bg = "white", main = "MO")
        abline(0,1)
    }
}

## runmod variable set to T to run simulation and set to F to
##  run post processing.
fitout <- dochlmod(dat.merge.all, modat0, runmod = T)
## post process
dochlmod(dat.merge.all, modat0, fitout, runmod = F)