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Case 1:12-cv-01842-RBW Document 15 Filed 03/06/13 Page 1 of 13
UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF COLUMBIA
__________________________________________
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CUMBERLAND PHARMACEUTICALS INC.,
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Plaintiff,
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v.
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Civil Action No. 12-1842 (RBW)
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FOOD AND DRUG ADMINISTRATION, et al., )
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Defendants.
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__________________________________________)
FEDERAL DEFENDANTS’ REPLY MEMORANDUM IN SUPPORT OF MOTION
TO DISMISS OR, IN THE ALTERNATIVE, FOR SUMMARY JUDGMENT AND
OPPOSITION TO PLAINTIFF’S CROSS-MOTION FOR SUMMARY JUDGMENT
INTRODUCTION
As the government explained in its opening brief, FDA determined that the original
Acetadote formulation was not withdrawn for safety or efficacy reasons, and approved
InnoPharma’s application to market that formulation. In arriving at these decisions, FDA
considered an extensive amount of data and engaged in robust scientific analysis and discussion,
and during this review one component of the agency changed an initial view it had expressed.
The decision-making process resulted in a well-reasoned agency decision that is more than
adequately supported by the administrative record and deserving of this Court’s deference.
Nothing in Cumberland’s opposition and cross-motion for summary judgment calls into
question FDA’s decisions. To support its assertion that the original Acetadote formulation was
withdrawn for safety reasons, Cumberland tries to shift the Court’s focus away from the
agency’s final decision to isolated portions of the administrative record. Specifically,
Cumberland relies heavily on statements from one agency component’s initial memorandum,
largely ignoring a subsequent, lengthier memorandum in which that initial recommendation was
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changed. This later memorandum was based not only on a reexamination of previously
considered information, but also consideration of new and more extensive, scientifically
important information. Cumberland also continues to argue that the agency had and has
significant safety concerns about the original Acetadote formulation, even though FDA approved
Cumberland’s application for that product in 2004, Cumberland marketed it for nearly eight
years (including for some period of time after the new formulation was introduced), and the
agency now has concluded that it was not withdrawn for safety reasons.
Cumberland has much to gain from its attack on the agency’s decisions. Its exclusivity to
market the original Acetadote formulation has expired, but it retains exclusivity to market the
new Acetadote formulation without EDTA. InnoPharma and — potentially — other companies
are free to compete with Cumberland by marketing the original Acetadote formulation.
Although Cumberland has substantial financial reasons for trying to persuade this Court to
overturn FDA’s decision, Cumberland has not provided any sound reason for this Court to do so.
Accordingly, the federal defendants’ motion to dismiss or, in the alternative, for summary
judgment should be granted, and plaintiff’s motion should be denied.
ARGUMENT
I.
FDA Reasonably Concluded that the Original Acetadote Formulation
Was Not Withdrawn for Safety or Effectiveness Reasons
Cumberland’s primary argument is that the original formulation of its Acetadote product
was withdrawn from sale for safety reasons, and FDA’s conclusion to the contrary was arbitrary
and capricious. Memorandum of Points and Authorities in Opposition to Defendants’ Motion to
Dismiss and in Support of Plaintiff’s Cross-Motion for Summary Judgment (“Cumb. Mem.”) at
12-20. In making this argument, however, Cumberland selects isolated portions of the
administrative record, ignoring the record as a whole and the final decision reached by FDA.
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The final decision here is embodied in FDA’s citizen petition response. AR FDA 456–63. In
that document, the agency explained: “After a thorough review of the relevant scientific data,
FDA has determined that the original, EDTA-containing formulation of Acetadote was not
withdrawn from sale for reasons of safety or efficacy.” Id. at 459. The citizen petition response
provides multiple, well-reasoned grounds for FDA’s conclusion.
Two of the issues raised by Cumberland in its citizen petition and addressed by FDA in
its citizen petition response are not raised in this litigation. The first is the association of EDTA
with drops in serum calcium levels. Id. at 460. After analyzing this issue, FDA concluded that
“the amount of EDTA in the originally approved Acetadote formulation . . . is too small to have
a clinically significant impact on serum calcium levels.” Id. The second is Bayer’s withdrawal
of its EDTA-containing formulation of the drug Leukine. Id. 461. Cumberland argued in its
petition that Bayer’s formulation had been withdrawn because it was associated with an increase
in adverse events. Id. FDA attributed these adverse events to the interaction of EDTA with the
active ingredient in Leukine and concluded that the same concern is not relevant to Acetadote.
Id. Cumberland does not challenge either of these conclusions.
Cumberland instead focuses on the postmarketing study it agreed to conduct, contending
that at one time FDA had safety concerns about its original formulation. Cumb. Mem. at 12-14.
FDA reviewed the relevant data and records relating to Cumberland’s post-marketing
commitment “to evaluate the potential benefit of [EDTA] on the stability of the drug product.”
AR FDA 460. Cumberland’s final report relating to this post-marketing commitment concluded
that EDTA does not enhance the stability of acetylcysteine; it in no way indicated that the
presence of EDTA rendered the original Acetadote formulation unsafe. See AR FDA 1355.
Consistent with the findings of that report, Cumberland’s own press release announcing the
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approval of the new formulation stated that the new product could be prepared “without
compromising the potency, solubility or stability of the product,” but is silent as to safety. Id. at
6, 460. Thus, although FDA noted a “theoretical” safety concern with EDTA, id. at 461, it did
not find, upon a review of all the relevant data — and eight years of experience with Cumberland
marketing the original Acetadote formulation — that the original formulation of Acetadote had
been withdrawn from sale for safety reasons.
In support of its argument that “safety concerns” led to the change in the original
Acetadote formulation, Cumberland repeatedly cites a “Medical Officer’s Consult Review” from
July 2011, which describes the initial position of FDA’s Division of Gastroenterology and Inborn
Errors Products (“DGIEP”). Cumb. Mem. at 3, 7–8, 13-15, 17, citing AR FDA 563-66.
However, this is neither DGIEP’s final position nor the agency’s final decision. Indeed, FDA’s
final decision rejects the notion that the original Acetadote formulation was withdrawn for safety
reasons, and this decision is fully supported in the record.
Cumberland argues that FDA did not explain why DGIEP’s initial position was not
adopted as the agency’s final decision. Cumb. Mem. at 15. However, the record contains a
thorough explanation of why the position outlined in the July 1, 2011, memorandum was rejected
by DGIEP and FDA. DGIEP provided three grounds for its initial position: 1) the FDA
reviewer of the investigational new drug application for acetylcysteine speculated that certain
adverse (anaphylactic) reactions were due to the delivery of acetylcysteine and/or EDTA; 2) two
reports in the literature showed that EDTA is associated with allergic reactions when used in
other drug production formulations (i.e., apomorphine and propofol); and 3) safety concerns
about EDTA resulted in the 2008 US market withdrawal of the EDTA-containing product
Leukine. AR FDA 564.
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In a 28-page memorandum dated October 26, 2012, DGIEP reconsidered and reversed its
initial recommendation. Id. at 513-41. Regarding the first concern about the association of
anaphylactic reactions, DGIEP considered a memorandum from FDA’s Office of Surveillance
and Epidemiology (“OSE”) and the labeling of the original and new formulations of Acetadote.
Id. at 519–21. Based on this additional information, DGIEP concluded that the anaphylactic
reactions associated with Acetadote could not be attributed to EDTA and that, in any event, the
labeling of both the original and new formulations of Acetadote carried the same adequate
warnings for these adverse events. Id. at 521–22.
Regarding its second concern about literature reports associating allergic reactions with
EDTA-containing apomorphine and propofol, DGIEP examined, for the first time, three clinical
studies involving EDTA-containing propofol and a prior FDA clinical review of EDTAcontaining propofol. See id. at 525–33. DGIEP could not determine from the three clinical
studies that an adverse reaction could be attributed EDTA. Id. at 528–531. FDA’s clinical
review of EDTA-containing propofol concluded that no adverse events attributable to EDTA
were recorded during five clinical trials. Id. at 532–33. DGIEP also explained that the
hypersensitivity of EDTA in apomorphine occurred when delivered by subcutaneous route,
whereas Acetadote is administered intravenously. Id. at 521, 534.
Regarding DGIEP’s third initial concern about the withdrawal of Leukine, DGIEP
reviewed the Leukine regulatory record and concluded that the adverse events were attributable
to an interaction between EDTA and Leukine’s active ingredient. Id. at 534; see also id. at 461.
DGIEP noted that there was no similar evidence for the original Acetadote formulation. Id.
In addition to re-examining these three bases for its initial conclusion, DGIEP evaluated
other factors that support the conclusion that the original Acetadote formulation was not
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withdrawn for safety reasons. For example, DGIEP evaluated whether the amount of EDTA in
the original Acetadote formulation would cause significant drops in serum calcium levels, id. at
517–19; whether the EDTA in the original formulation could cause nephrotoxicity signals, id. at
522–25; and whether the safety profile of other currently marketed injectable products containing
EDTA (e.g., Endrate/Versenate, Emend, Aloxi) suggested that adverse events associated with
those products were attributable to EDTA, id. at 526, 532, 533. DGIEP’s thorough examination
of the information available to it both prior to and after the initial July 2011 recommendation led
DGIEP to reasonably conclude that the original formulation was not withdrawn for safety
reasons.
Cumberland also contends that DGIEP reached a different result in its October 26, 2012,
memorandum “by answering a different question”— that is, whether the agency erroneously
approved the original formulation. See Cumb. Mem. at 9. The record reflects, however, that
DGIEP answered the same question that it addressed in its July 1, 2011, memorandum—that is,
whether Cumberland withdrew the original Acetadote formulation for safety reasons. See, e.g.,
AR FDA 517 (“DGIEP has concluded . . . that Acetadote with EDTA was not discontinued for
reasons of safety.”); id. at 539–40 (“[N]one of these concerns rises to the level that would enable
us to conclude that the old formulation of Acetadote (with EDTA) was withdrawn for reasons of
safety.”).
Cumberland states that DGIEP “did not point to any new information from Cumberland
regarding the withdrawal.” Cumb. Mem. at 9. However, DGIEP’s October 26, 2012,
memorandum explicitly states that it took into account new information from Cumberland,
including Cumberland’s citizen petition and comments submitted to that petition’s docket. See
AR FDA 513. In addition, DGIEP considered other extensive new information that was not
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available to DGIEP at the time it provided its initial memorandum, including comments
submitted to Leydig’s citizen petition docket; OSE’s September 5, 2012, memorandum;
discussions from two internal FDA meetings; and FDA’s clinical review of the safety of EDTA
in propofol formulations. See id. at 513–16.
Cumberland criticizes DGIEP for looking to “extraneous factors,” such as the benefit of
having two separate suppliers of acetylcysteine injection to cover a potential drug shortage.
Cumb. Mem. at 15. This factor, however, was not articulated in the agency’s final decision, i.e.,
the citizen petition response. DGIEP was simply (and harmlessly) pointing out the indisputable
fact that it is preferable to have multiple sources, rather than a single source, for a drug product
that treats life-threatening conditions. See AR FDA 515–16, 540.
Cumberland also argues that the DGIEP memorandum inappropriately noted the fact that
Cumberland did not recall the original Acetadote formulation after receiving approval for the
new formulation. Cumb. Mem. at 16. Cumberland complains that the agency does not always
request a recall if a formulation is withdrawn for safety reasons. Id. DGIEP was just noting that
a recall would have been consistent with a finding that the old formulation was withdrawn for
safety reasons; it was not suggesting that all products withdrawn for safety reasons must be
recalled. See AR FDA 515. In any event, FDA did not rely on this point to support its final
conclusion that the original Acetadote formulation was not withdrawn for safety reasons.
Cumberland argues that the agency erroneously sought support for its safety assessment
“from the fact that several other products currently on the market contain EDTA” because the
“only issue for FDA to determine was whether the original formulation of Acetadote was
withdrawn for safety reasons.” Cumb. Mem. at 17. In its citizen petition response, FDA noted
that EDTA is contained in many other drug products currently on the market that are approved as
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safe and effective, including some, such as Versenate, which contain much higher quantities of
EDTA per dose. AR FDA 461. The agency’s experience with various quantities of EDTA in
other drug products is clearly relevant to the agency’s assessment as to whether the presence and
specific amount of EDTA in the original Acetadote formulation suggests that the product was
withdrawn for safety reasons. Indeed, Cumberland recognized the relevance of other approved
EDTA-containing products by relying on such products to justify the presence of EDTA in its
original Acetadote formulation. Id. at 535, 1694.20–1694.21, 1708–09.
Cumberland complains that FDA does not explain why the inconclusive data from FDA’s
Adverse Events Reporting System (“AERS”) would not lead FDA to conclude that the original
Acetadote formulation was withdrawn for reasons of safety. Cumb. Mem. at 18. FDA reviewed
data from AERS to determine whether the EDTA in the original Acetadote formulation was
associated with allergic reactions, including anaphylaxis. AR FDA 460–61. The data did not
demonstrate that the adverse events were attributable to the EDTA in the original formulation.
Id. at 460. FDA found that the adverse events alternatively could be attributed to acetylcysteine
or to the multisystem organ pathology associated with the underlying acetaminophen overdose.
Id. at 460–61. Accordingly, the agency concluded that the AERS data do not provide a
reasonable basis upon which to conclude that the original Acetadote formulation was withdrawn
for safety reasons. Id. at 461. Although the AERS data were inconclusive, other factors
supported the determination that the original Acetadote formulation was not withdrawn for safety
reasons, such as the determination that the amount of EDTA in the original Acetadote
formulation would not have a clinically significant impact on serum calcium levels. Unlike in
the two Ninth Circuit cases cited by Cumberland in which the agencies relied primarily on
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inconclusive data, see Cumb. Mem. at 19, FDA supported its decision not only on the AERS
data, but also various other factors described in the citizen petition response.
Cumberland also argues that FDA should have concluded that the original Acetadote
formulation was withdrawn for safety reasons because OSE allegedly “noted that the incidence
of allergic reactions with Acetadote had decreased since the introduction of the EDTA-free
formulation.” Cumb. Mem. at 18. Cumberland cites certain pages from the October 26, 2012,
DGIEP memorandum to support its assertion that OSE noted this alleged “decrease” in adverse
event reports. Id. (citing AR FDA 514–15, 519, 539). But neither OSE nor DGIEP stated that
the incidence of allergic reactions in patients had decreased once the EDTA-containing
formulation had been withdrawn. In reviewing the data, OSE found that were 61 adverse events
reported for Acetadote up to October 2011 (Acetadote had been approved in 2004). AR FDA
664-65. This included all types of adverse events, including skin allergic reactions, and OSE
noted that there had been two reports of skin allergic reactions for Acetadote after January 7,
2011, the approval date for EDTA-free Acetadote formulation. Id. at 665. The two postapproval reports were not compared to the number of pre-approval reports of skin allergic
reactions, and thus it was not possible to conclude that there had been a decrease in the incidence
of allergic skin reactions after introduction of the EDTA-free formulation. Moreover, both the
original and new Acetadote formulations were on the market after January 7, 2011, see AR FDA
519, so even if there had been a decrease, it could not be attributed to an EDTA-free formulation.
Cumberland argues that the agency’s final decision does not deserve deference because
FDA “did not elevate the issue” whether the original Acetadote formulation was withdrawn for
safety reasons to a supervisor or higher-order decisionmaker, citing Graceway Pharmaceuticals,
LLC. v. Sebelius, 783 F. Supp. 2d 104 (D.D.C. 2011). See Cumb. Mem. at 19–20. This
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argument is without merit. Unlike in Graceway, FDA did not need to “elevate” any
disagreement between DGIEP and other components of the agency because the DGIEP scientists
and managers did their own new round of research, and ultimately agreed that DGIEP’s initial
recommendation was not supported by adequate scientific evidence. See AR FDA 513–41. If
anything, the facts supporting deference in this case are even more compelling than those in
Graceway: here, the agency did not need to resolve disagreement between separate agency
components because the scientists who made the initial recommendation changed their opinion
based upon, among other things, consideration of a significant amount of new information.
Also citing Graceway, 783 F. Supp. 2d at 113, Cumberland argues that the agency’s
decision does not deserve deference because here FDA ignored the opinion of its own experts.
Cumb. Mem. at 20. This argument is also meritless. The final agency decision at issue here is
the citizen petition response, and that decision was signed by Dr. Janet Woodcock, the Director
of the Center for Drug Evaluation and Research, who has the “final word in responding to the
plaintiff’s Citizen Petition,” Graceway, 783 F. Supp. 2d at 113. Included in the record of the
final decision are the initial position of DGIEP and the later decision of that component, after it
reconsidered its initial position. See AR FDA 513-41. DGIEP’s memoranda were not ignored,
but were considered — among other things — by the final decisionmaker. See AR FDA 460–61.
II.
FDA Properly Granted InnoPharma A Waiver and Approved
its Application Duplicating the Original Acetadote Formulation
Cumberland argues that in approving InnoPharma’s Abbreviated New Drug Application
(“ANDA”), FDA incorrectly waived the regulatory requirement that the ANDA contain the same
inactive ingredients as the reference listed drug (“RLD”). Cumb. Mem. at 20. As pointed out in
defendants’ memorandum in support of their motion to dismiss, the Food, Drug, and Cosmetic
Act (“FDCA”) requires ANDAs to contain the same active ingredient as the RLD, but allows for
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differences in inactive ingredients unless the inactive ingredients are unsafe. U.S. Mem. at 5-6,
citing 21 U.S.C. §§ 355(j)(2)(A)(ii), 355(j)(4)(H). An FDA regulation generally requires that for
injectable products the ANDA must contain the same inactive ingredients as the RLD. U.S.
Mem. at 6 (citing 21 C.F.R. § 314.94(a)(9)(iii)). This regulatory requirement can be waived,
however, see id. (citing 21 C.F.R. § 314.99(b)), so long as any difference in inactive
ingredient(s) does not render the product unsafe. See 21 U.S.C. § 355(j)(4)(H).
In its citizen petition response, FDA explained that it “may approve an ANDA for
acetylcysteine injection that duplicates the original Acetadote formulation.” AR FDA 462. FDA
stated that a waiver under 21 C.F.R. § 314.99 is appropriate “[b]ecause the original Acetadote
formulation meets the statutory safety standard with respect to inactive ingredients.” Id. FDA
consequently granted InnoPharma a waiver under 21 C.F.R. § 314.99 and approved
InnoPharma’s ANDA. See AR FDA 1851–55.
Cumberland argues that the appropriate standard is not whether the original Acetadote
formulation meets the statutory safety standard, but whether the ANDA is less safe than the new
formulation of the RLD. Cumb. Mem. at 21. This is not correct. FDA properly asked whether
EDTA rendered the original Acetadote formulation unsafe for use under the conditions described
in the labeling proposed for the drug. Here FDA properly applied the statutory standard by
asking whether the original Acetadote formulation was unsafe and upon answering that question
in the negative, reasonably granted InnoPharma a waiver and approved its ANDA. See 21
U.S.C. § 355(j)(4)(H). In any event, the record makes clear that FDA did not consider
InnoPharma’s ANDA less safe than the new formulation.
Cumberland also argues that FDA acted contrary to its own regulation, 21 C.F.R.
§ 314.127(a)(8)(ii)(B), by not requiring InnoPharma to demonstrate that its acetylcysteine
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product was as safe as Cumberland’s version because when there is a “difference in antioxidant,
buffer or preservative” the ANDA must contain “sufficient information to demonstrate that the
difference does not affect the safety or efficacy of the drug product.” Cumb. Mem. at 22
(quoting 21 C.F.R. § 314.127(a)(8)(ii)(B)). However, this aspect of the regulation does not apply
to InnoPharma’s ANDA because the EDTA in the original Acetadote formulation is not acting as
a “preservative, buffer, or antioxidant.” See AR FDA 462; see also U.S. Mem. at 6. If EDTA
did act as an antioxidant, buffer, or preservative, there would be no need for a waiver. See U.S.
Mem. at 6, 23 n.2. In such a situation, differences in an antioxidant, buffer, or preservative are
permitted by regulation if “the differences do not affect the safety or efficacy of the proposed
drug product.” 21 C.F.R. § 314.94(a)(9)(iii); see also U.S. Mem. at 6; 21 C.F.R. §
314.127(a)(8)(ii)(B). Information in the record here sufficiently demonstrates that EDTA does
not affect the safety or efficacy of the drug product. See 21 U.S.C. § 355(j)(4)(H). 1
CONCLUSION
For the foregoing reasons, federal defendants’ motion to dismiss or, in the alternative, for
summary judgment should be granted, and Cumberland’s motion should be denied.
1
When the waiver provision is applicable, 21 C.F.R. § 314.99 permits the waiver of any
regulatory requirement regarding inactive ingredients, as long as the statutory standard is met —
as it was here. See AR FDA 462 & n.18.
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Of Counsel:
Respectfully submitted,
WILLAIM B. SCHULTZ
Acting General Counsel
STUART F. DELERY
Principal Deputy Assistant Attorney General
ELIZABETH H. DICKINSON
Associate General Counsel,
Food and Drug Division
MAAME EWUSI-MENSAH FRIMPONG
Deputy Assistant Attorney General
MICHAEL S. BLUME
Director
ERIC M. BLUMBERG
Deputy Chief Counsel, Litigation
_____/s/______________
DRAKE CUTINI
Senior Litigation Counsel
Consumer Protection Branch
U.S. Department of Justice
P.O. Box 386
Washington, DC 20044
Tel: 202-307-0044
Fax: 202-514-8742
[email protected]
JULIE A. DOHM
Associate Chief Counsel, Litigation
U.S. Department of Health & Human Services
Office of the General Counsel
10903 New Hampshire Avenue
White Oak 31 Room 4582
Silver Spring, MD 20993-0002
301-796-8732
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