1 

Office of Orphan Products Development 

Food and Drug Administration 

10903 New Hampshire Avenue 

WO32-5271 

Silver Spring, MD 20993 

May 1, 2023 

Sidley Austin LLP 

Counsel to Jazz Pharmaceuticals, Inc.

1501 K Street, N.W. 

Washington, D.C. 20005 

Attention: Sean C. Griffin and Kwaku A. Akowuah 

Re: Determination that Xywav’s (NDA 212690) unexpired orphan-drug exclusivity (“ODE”)

does not block approval of Lumryz (NDA 214755) 

Dear Mr. Griffin and Mr. Akowuah: 

We have considered the submissions described in greater detail herein from Jazz 

Pharmaceuticals, Inc. (“Jazz”) and Sidley Austin LLP (“Sidley”) as counsel to Jazz. FDA’s 

Office of Orphan Products Development (“OOPD” or “we”) provides the response below. 

I. Introduction

Herein, this analysis evaluates whether the ODE for Xywav (calcium, magnesium, potassium, 

and sodium oxybates) blocks the approval of NDA 214755 for Lumryz (sodium oxybate) for 

extended-release oral suspension submitted by Avadel CNS Pharmaceuticals, LLC (“Avadel”) 

for the treatment of cataplexy or excessive daytime sleepiness (“EDS”) in adults with narcolepsy. 

Xywav became eligible for ODE for the treatment of cataplexy or EDS in patients 7 years of age 

and older with narcolepsy because its sponsor, Jazz, demonstrated at the time of approval that 

Xywav was clinically superior to Xyrem, which was previously approved for the same 

indication. Under section 527(a) of the Federal Food, Drug, & Cosmetic Act (“FD&C Act”), the 

ODE for Xywav prevents FDA from approving a new drug product that is the “same drug” as 

Xywav for the same use or indication until its exclusivity expires on July 21, 2027.1

 By 

regulation, a drug is the “same drug” as Xywav if it contains the same active moiety (oxybate) 

1 Section 527(a) of the FD&C Act; see also 21 CFR § 316.31. See also FDA, Clarification of Orphan-Drug 

Exclusivity Following Catalyst Pharms., Inc. v. Becerra, 88 Fed. Reg. 4086 (Jan. 24, 2023).

FDA-OOPD-May23-POSTING-000001
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for the same use or indication (the treatment of cataplexy or EDS in patients 7 years of age and 

older with narcolepsy)2 unless the new drug product is clinically superior to Xywav.

3

 For the 

reasons described below, we conclude that Lumryz is clinically superior to Xywav and is thus 

not considered to be the “same drug” as Xywav within the meaning of 21 CFR § 316.3(b)(14) 

and section 527(a) of the FD&C Act. Therefore, Xywav’s ODE does not block approval of 

NDA 214755 for Lumryz for the treatment of cataplexy or EDS in adults with narcolepsy. 

We also conclude that Lumryz is eligible for its own term of ODE because it is clinically 

superior to both Xywav and Xyrem. Under section 527(c)(1) of the FD&C Act, if FDA has 

previously approved a drug that is otherwise the same drug for the same use or indication, the 

subsequent drug may be eligible for its own term of ODE if the sponsor demonstrates that its 

product is clinically superior to every such previously approved drug.4 As set forth below, we 

have determined that Avadel has demonstrated Lumryz’s clinical superiority to every previously 

approved oxybate drug for the same use or indication, i.e., both Xywav and Xyrem. Therefore, 

Lumryz is eligible for its own term of ODE for the treatment of cataplexy or EDS in adults with 

narcolepsy. 

OOPD consulted with agency sleep experts and the Division of Neurology 1 (“DN1”) in making 

this determination,5

 and their scientific thinking and expert opinions have been integral to this 

decision. As discussed below, FDA’s determination is based on careful consideration of the 

relevant scientific, legal, and regulatory issues raised and the materials submitted by outside 

parties. On December 15, 2020, Avadel submitted to OOPD and to the file for NDA 214755 an 

“exclusivity claim.”6 On July 14, 2021, Avadel submitted to OOPD and to the file for NDA 

214755 a supplement to its “exclusivity claim.”7 On July 21, 2021, Avadel sent a letter to 

OOPD and to FDA’s Office of Chief Counsel (“OCC”) presenting arguments why Lumryz’s 

NDA should be eligible for approval notwithstanding Xywav’s ODE.

8

 On October 25, 2021, 

Latham & Watkins LLP as counsel to Avadel sent OCC a letter presenting arguments about the 

approvability of Lumryz’s NDA.9 On August 30, 2022, Avadel sent a letter to OOPD with 

additional arguments about clinical superiority.10 

2 The indication for Lumryz is “the treatment of cataplexy or EDS in adults with narcolepsy,” which is not coextensive with, but falls entirely within, the scope of Xywav’s ODE because Xywav’s ODE includes a broader age 

range.

3 21 CFR § 316.3(b)(14).

4 Section 527(c)(1) of the FD&C Act; see also 21 CFR § 316.34(c). 5 See Mahadevappa Hunasikatti MD FCCP and Nargues Weir MD FCCP FAASM ATSF, Consult request on 

Lumryz (Apr. 29, 2023) [hereinafter Sleep Expert Consult]; DN1, Office of Orphan Products Development Consult 

Request #16-5302 at (May 1, 2023) [hereinafter DN1 Lumryz Consult]. 6 Avadel, Exclusivity Claim (Dec. 15, 2020). 7 Avadel, Exclusivity Claim – Supplemental Information in Demonstration of Clinical Superiority of FT218 (Jul. 14, 

2021). 8 Letter from Jerad G. Seurer to Nicole Wolanski and Mark Raza, Approval and Orphan Drug Exclusivity for FT218 

(sodium oxybate for extended-release oral suspension) (Jul. 21, 2021). 9 Letter from John R. Manthei to Elizabeth Dickinson, Lumryz (sodium oxybate) for extended-release oral 

suspension (NDA 214755) (Oct. 25, 2021). 10 Letter from Jennifer Gudeman to Sandra Retzky, Orphan Drug Considerations for LUMRYZ (sodium oxybate) for

Extended-Release Oral Suspension – DRU 2016-5302 (Aug. 30, 2022). 

FDA-OOPD-May23-POSTING-000002
3 

In addition to the submissions OOPD received from Avadel and its counsel, OOPD received 

submissions from Jazz. On September 16, 2021, Jazz sent a letter to OOPD presenting 

arguments why Lumryz is not clinically superior to Xywav (“Jazz’s September 2021 Letter”).

11 

On December 6, 2022, Sidley as counsel to Jazz sent OCC a letter presenting arguments why 

Lumryz is not clinically superior to Xywav (“Sidley Letter”) and requested a meeting with 

OCC.

12 On January 18, 2023, FDA met with Sidley during which Sidley presented a slide deck

(“Sidley Slides”).

13 In this analysis, the arguments presented in Jazz’s September 2021 Letter, 

the Sidley Letter, and the Sidley Slides are collectively referred to as Jazz’s arguments.14 

II. Legal Background 

A. Orphan-Drug Designation (“ODD”)

Congress enacted the Orphan Drug Act in 1983 to provide incentives for the development of 

drugs for rare diseases or conditions that would not otherwise be developed due to the small 

patient population and lack of profitability of such drugs.15 Section 526 of the FD&C Act 

defines a “rare disease or condition,” in relevant part, as any disease or condition that affects less 

than 200,000 persons in the United States.16 To be eligible for ODD incentives — including tax 

credits for qualified clinical testing, exemption from the application user fee, and, potentially, 

ODE — the sponsor of a drug must request ODD for a rare disease or condition under section 

526 of the FD&C Act, and FDA must grant ODD.17 FDA’s regulations at 21 CFR Part 316 lay 

out the requirements for an ODD submission.18 A sponsor of a drug that is “otherwise the same 

as an already approved drug may seek and obtain ODD for the subsequent drug for the same rare 

disease or condition if it can present a plausible hypothesis that its drug may be clinically 

superior to the first drug.”19

11 Letter from Dennis Ahern to Sandra Retzky, Considerations Regarding Clinical Superiority for Oxybate Products

(Sep 16, 2021) [hereinafter Jazz’s September 2021 Letter].

12 Letter from Sean C. Griffin to Shoshana Hutchinson, Orphan Drug Exclusivity for NDA 212690 (Dec. 6, 2022) 

[hereinafter Sidley Letter].

13 See Sidley, Presentation to the Office of Chief Counsel of behalf of Jazz Pharmaceuticals, Inc. (Jan. 18, 2023) 

[hereinafter Sidley Slides]. This meeting was listening only for FDA. 14 We also note that on November 29, 2022, TREND Community, a patient advocacy organization, sent a letter to 

OOPD presenting arguments and patient testimonials why there is a need for a once-nightly oxybate therapy. Letter 

from Maria Picone to FDA (Nov. 29, 2022). Then on January 2, 2023, Clete A. Kushida, M.D., Ph.D. sent a letter 

to OOPD to present arguments that Lumryz is clinically superior to the existing oxybate therapies, Xyrem and 

Xywav. Letter from Clete A. Kushida to Sandra Retzky (Jan. 3, 2023). These letters did not serve as a basis for

FDA’s decision.

15 Pub. L. No. 97-414, 96 Stat. 2049 (1983). 16 See section 526(a)(2)(A) of the FD&C Act. 17 See section 526(a)(1) of the FD&C Act. A sponsor must request ODD prior to submitting a marketing application 

for the drug for the relevant disease.

18 See, e.g., 21 CFR §§ 316.20-21. 19 21 CFR § 316.20(a).

FDA-OOPD-May23-POSTING-000003
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B. ODE

One important incentive Congress provided in the Orphan Drug Act for sponsors developing 

drugs for rare diseases is the potential for a drug to become eligible for ODE. Section 527(a) 

states, in relevant part: 

Except as provided in subsection (b), if the Secretary- 

(1) approves an application filed pursuant to section 505, or 

(2) issues a license under section 351 of the Public Health Service Act

for a drug designated under section 526 for a rare disease or condition, the Secretary 

may not approve another application . . . or issue another license . . . for the same drug 

for the same disease or condition for a person who is not the holder of such approved 

application or of such license until the expiration of seven years from the date of the 

approval of the approved application or the issuance of the license. . . . 

In short, ODE prevents FDA from approving or licensing the same drug for the same use or 

indication for a person who is not the holder of such approved application or of such license until 

the expiration of seven years from the date of approval or licensure.20 

The statute provides two exceptions to ODE at section 527(b), under which FDA may approve 

an application for the same drug as a drug with ODE for the same use or indication. First, FDA 

may approve such an application if the agency finds that the sponsor of the drug with ODE 

cannot “ensure the availability of sufficient quantities of the drug to meet the needs of persons 

with the disease or condition.”21 Second, FDA may also approve such an application if the 

sponsor of the drug with ODE consents to the approval of the application.22 

As explained below, FDA interprets section 527(a) in two contexts: 1) to determine whether a 

drug is eligible for ODE and 2) to determine whether certain pending drugs may be approved 

during an approved drug’s unexpired ODE (i.e., the scope of ODE). 

i. Eligibility for ODE

An orphan-designated drug becomes eligible for ODE under section 527(a) of the FD&C Act 

once FDA approves or licenses it for the designated rare disease or condition, subject to the 

additional condition of clinical superiority in section 527(c) of the FD&C Act, when applicable. 

Section 527(c)(1) states: 

If a sponsor of a drug that is designated under section 526 and is otherwise the same, as 

determined by the Secretary, as an already approved or licensed drug is seeking exclusive 

approval or exclusive licensure described in subsection (a) for the same rare disease or 

condition as the already approved drug, the Secretary shall require such sponsor, as a 

20 See section 527(a) of the FD&C Act; see also, e.g., 21 CFR §§ 316.31, 316.34, 316.3(b)(14). 21 Section 527(b)(1) of the FD&C Act. 22 Section 527(b)(2) of the FD&C Act.

FDA-OOPD-May23-POSTING-000004
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condition of such exclusive approval or licensure, to demonstrate that such drug is 

clinically superior to any already approved or licensed drug that is the same drug. 

 

When applicable, FDA requires the sponsor of a subsequent drug to demonstrate clinical 

superiority to all (i.e., each and every) previously approved drugs with the same active moiety 

for the same indication or use to be eligible for its own term of ODE.23 

Section 527(c)(2) of the FD&C Act defines “clinically superior” for the purposes of meeting the 

condition of clinical superiority in section 527(c)(1) to mean “the drug provides a significant 

therapeutic advantage over and above an already approved or licensed drug in terms of greater 

efficacy, greater safety, or by providing a major contribution to patient care.”24 The orphan-drug 

regulations at 21 CFR § 316.3(b)(3) define “clinically superior” as follows:

Clinically superior means that a drug is shown to provide a significant therapeutic 

advantage over and above that provided by an approved drug (that is otherwise the same 

drug) in one or more of the following ways: 

(i) Greater effectiveness than an approved drug (as assessed by effect on a 

clinically meaningful endpoint in adequate and well controlled clinical trials). 

Generally, this would represent the same kind of evidence needed to support a 

comparative effectiveness claim for two different drugs; in most cases, direct 

comparative clinical trials would be necessary; or

(ii) Greater safety in a substantial portion of the target populations, for example, 

by the elimination of an ingredient or contaminant that is associated with 

relatively frequent adverse effects. In some cases, direct comparative clinical 

trials will be necessary; or

(iii) In unusual cases, where neither greater safety nor greater effectiveness has 

been shown, a demonstration that the drug otherwise makes a major contribution 

to patient care.25

Section 527(c) of the FD&C Act was enacted by Congress under the FDA Reauthorization Act 

of 2017 (“FDARA”), and the applicability of the section was clarified in the Consolidated 

Appropriations Act, 2021 (2020). Prior to FDARA, FDA had relied upon its regulations to 

require a drug that is otherwise the same drug as a previously approved drug for the same use or 

indication to demonstrate clinical superiority to the previously approved drug for it to be eligible 

for ODE. See, e.g., 21 CFR § 316.34(c) stating that “If a drug is otherwise the same drug as a 

previously approved drug for the same use or indication, FDA will not recognize orphan-drug 

exclusive approval if the sponsor fails to demonstrate upon approval that the drug is clinically 

superior to the previously approved drug.” See also 21 CFR § 316.3(b)(3) & § 316.3(b)(14). In 

23 21 CFR § 316.3(b)(14) defines “same drug” to mean, in relevant part, “a drug that contains the same active moiety

as a previously approved drug and is intended for the same use . . . except that if the subsequent drug can be shown 

to be clinically superior to the first drug, it will not be considered to be the same drug.” Further discussion of this 

definition appears in the subsequent subsection. 

24 Section 527(c)(2) of the FD&C Act. 25 21 CFR § 316.3(b)(3).

FDA-OOPD-May23-POSTING-000005
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response to court losses on the specific issue of whether FDA could impose such a clinical 

superiority requirement as a precondition for eligibility for ODE, Congress amended the statute

to give the agency explicit statutory authority to do so. 

Section 527(c)(1) states that if a sponsor “is seeking exclusive approval or exclusive licensure 

described in subsection (a)” for an otherwise same drug that has already been approved or 

licensed for the same disease or condition, “as a condition of such exclusive approval or 

licensure,” the sponsor must demonstrate “that such drug is clinically superior to any already 

approved or licensed drug that is the same drug.” As the text demonstrates, section 527(c) only 

concerns potential eligibility of a subsequent drug for its own period of ODE and does not 

address whether a subsequent drug’s approval is blocked by another drug’s ODE even where 

clinical superiority of the subsequent drug has been shown. As described further below, the 

blocking effect of ODE of a previously approved drug is instead described in 527(a) of the 

FD&C Act.

ii. Scope of ODE

As explained above, under section 527(a) of the FD&C Act, ODE prevents FDA from approving 

or licensing the same drug for the same use or indication for a person who is not the holder of 

such approved application or of such license until the expiration of seven years from the date of 

approval or licensure. FDA looks to the definition of “same drug” at 21 CFR § 316.3(b)(14) in 

determining whether a subsequent drug is the same drug for the same indication or use as a 

previously approved drug with unexpired ODE. That regulation defines “same drug” to mean, in 

relevant part, “a drug that contains the same active moiety as a previously approved drug and is 

intended for the same use . . . except that if the subsequent drug can be shown to be clinically 

superior to the first drug, it will not be considered to be the same drug.”26 Thus, under FDA’s 

validly promulgated and longstanding regulations, the “same drug” definition has a chemical and 

clinical component. In the 1992 Final Rule for the orphan-drug regulations, FDA explained that 

“two drugs would be considered the same drug if the principal, but not necessarily all, structural 

features of the two drugs were the same, unless the subsequent drug were shown to be clinically 

superior” and that “either differences in active moiety or clinical superiority will be sufficient to 

make two micromolecular drugs different.”27 Accordingly, if the sponsor of the subsequent drug 

for the same indication or use can demonstrate that its drug has a different active moiety28 or is 

clinically superior29 to the drug with ODE (i.e., the “first drug”), the subsequent drug will not be 

considered to be the “same drug” as the drug with ODE, and that drug’s ODE will not block 

approval of the application for the subsequent drug for the same indication or use.30 

Interpreting section 527(a) of the FD&C Act in this manner does not create an exception to ODE 

analogous to those codified at section 527(b) of the FD&C Act that were discussed above; the 

26 21 CFR § 316.3(b)(14). 27 See FDA, Orphan Drug Regulations, Final Rule, 57 Fed. Reg. 62076, 62078 (Dec. 29, 1992) [hereinafter 1992 

Final Rule].

28 See 21 CFR § 316.3(b)(2) for orphan-drug definition of “active moiety.” 29 See 21 CFR § 316.3(b)(3) defining “clinically superior.” 30 1992 Final Rule, 57 Fed. Reg. at 62078 (“Assuming that a subsequent drug's marketing application is otherwise 

approvable, FDA will not interpret the Orphan Drug Act to block approval of any drug proved to be clinically 

superior to a drug with currently effective exclusive marketing rights.”).

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7 

exceptions at 527(b) concern instances where FDA determines that a drug is the same drug for 

the same indication or use but is approvable nonetheless despite another same drug’s unexpired 

ODE. Drugs that are approved under the exceptions at section 527(b) would be chemically and 

clinically the same as the drug with unexpired ODE and would not include clinically superior 

drugs. 

In summary, for a determination under section 527(a) as to whether a drug’s unexpired ODE 

blocks approval of a subsequent drug, FDA compares the subsequent drug to the drug with 

unexpired ODE. In circumstances in which the subsequent drug contains the same active moiety 

for the same indication or use as the drug with unexpired ODE, FDA determines whether the 

subsequent drug is clinically superior to the drug with ODE. If it is clinically superior, the 

subsequent drug is not considered to be the “same drug,” and thus its approval for the same 

indication or use is not blocked. By contrast, for a determination under section 527(c) of the 

FD&C Act as to whether a subsequent drug with the same active moiety for the same indication 

or use as a previously approved drug is eligible under section 527(a) for its own term of ODE, 

FDA compares the subsequent drug to all such previously approved drugs, even if ODE for those 

drugs has expired. If the subsequent drug is clinically superior to each, then it is eligible for its 

own term of ODE. 

C. Clinical Superiority 

As explained above, section 527(c)(2) of the FD&C Act defines clinically superior to mean that 

“the drug provides a significant therapeutic advantage over and above an already approved or 

licensed drug in terms of greater efficacy, greater safety, or by providing a [MCTPC],” and 21 

CFR § 316.3(b)(3) defines clinically superior to mean that “a drug is shown to provide a 

significant therapeutic advantage over and above that provided by an approved drug (that is 

otherwise the same drug) in one or more of the following ways:” greater effectiveness, greater 

safety, or a MCTPC (emphasis added). In both definitions, the subsequent drug must provide a 

significant therapeutic advantage “over and above” an already approved drug in just one way—

greater efficacy, greater safety, or by providing a MCTPC—to be considered clinically superior. 

Neither the plain reading of the statute nor that of the regulation imposes an additional 

requirement that in order to provide a significant therapeutic advantage in one of the three 

measures, the drug must also be at least comparable in the other two measures. 

There is at least one instance in which FDA determined that a subsequent drug is clinically 

superior based on greater efficacy even though the drug was less safe in one measure than the 

previously approved drug with ODE. Specifically, FDA considered whether different interferon 

beta products for relapsing remitting multiple sclerosis (“RRMS”) were clinically superior to one 

another. This situation involved three interferon beta products for the same use. The first 

interferon beta for treatment of RRMS, Betaseron, was approved on July 23, 1993, and was 

eligible for ODE until July 23, 2000. During Betaseron’s period of ODE, a different sponsor, 

Biogen, sought marketing approval for another interferon beta product for RRMS called Avonex. 

FDA determined that Biogen demonstrated that Avonex was clinically superior to Betaseron 

because Avonex was safer due to elimination of skin necrosis at injection sites.31 As a result, 

31 FDA, Memorandum, Clinical Superiority of Biogen’s interferon product, Avonex, DRU-1991-627 (Apr. 16, 

1996).

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Avonex was a different drug than Betaseron under the orphan-drug regulations, and Betaseron’s 

ODE did not block its approval. On May 17, 1996, FDA approved Avonex for RRMS, and it 

was eligible for its own term of ODE until May 17, 2003. Subsequently, during Avonex’s period 

of ODE, a third sponsor, Serono, sought approval for an interferon beta product for RRMS called 

Rebif. Serono demonstrated that Rebif was more effective than Avonex based on a study 

showing that patients taking Rebif were less likely to experience multiple sclerosis exacerbations 

than patients taking Avonex.32 However, Rebif patients experienced skin necrosis at injection 

sites that Avonex patients did not (i.e., the same adverse event that was present with Betaseron 

that led to the determination that Avonex was clinically superior to Betaseron based on safety).33 

FDA concluded that Rebif was clinically superior to Avonex based on greater effectiveness, and 

that the safety considerations of Rebif compared to Avonex were “not directly relevant” to the 

clinical superiority determination.34 In making its decision, FDA explained the following: 

[T]he regulations do not state that clinical superiority must be based on overall risk 

benefit being deemed superior for the subsequent product compared to the prior product. 

In fact, the regulations indicate that only a selected aspect may constitute a sufficient 

basis to reach a conclusion of clinical superiority. That is, the aspects not selected by the 

sponsor for focus (e.g., safety when efficacy is selected; efficacy when safety is selected) 

do not require a comparative assessment. The regulations require neither that all aspects 

of known efficacy nor all aspects of safety be shown to be superior. Nor do the 

regulations indicate that other aspects of safety or efficacy be shown “comparable” when 

only one specific aspect of safety or efficacy is shown to be superior.35

FDA also stated:

There is no additional requirement that the subsequent product, although clinically 

superior in one parameter, must also be shown to be at least equal in all others. This 

would set an inappropriate and nearly impossible burden (in terms of clinical trial design) 

on the sponsor of a second product. A more meaningful standard is a significant 

therapeutic benefit in terms of increased effectiveness and adequate safety, or increased 

safety and adequate effectiveness. The balancing of risks and benefits embodied in a drug 

product as a whole is done when the agency determines whether the drug may be 

approved for the particular use.36

D. MCTPC

32 See FDA, BLA STN 103780/0 Comparative Study of Rebif to Avonex and Orphan Exclusivity at 20 (Mar. 7, 2002) 

[hereinafter CBER Rebif memo].

33 Id. 34 Id. 35 Id. at 3-4. See also id. at 10-11 (“Orphan drug regulations do not state that all known clinical actions of a product 

must be shown superior to the competitor.”); id. at 20 (“[T]he orphan drug regulations do not require that safety be 

superior or even identical between two drugs when a clinical efficacy comparison is employed for the demonstration 

of being not the ‘same drug.’”). 

36 FDA, Memorandum, OOPD Analysis of Exclusivity Issues Raised in the Serono BLA for Rebif at 3 (Mar. 7, 2002) 

[hereinafter OOPD Rebif memo]. 

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Because of the diverse ways in which drugs may qualify as clinically superior (and therefore not 

the “same drug”) under the law, FDA evaluates clinical superiority on a case-by-case basis.37 

Specifically, with respect to MCTPC, to preserve the statutory incentive to develop orphan 

drugs, the agency has stated that MCTPC is “intended to constitute a narrow category.”38 

Regarding how to demonstrate a MCTPC, the agency has also stated: 

• “There is no way to quantify such superiority in a general way. The amount and kind 

of superiority needed would vary depending on many factors, including the nature 

and severity of the disease or condition, the quality of the evidence presented, and 

diverse other factors.”39

• “The following factors, when applicable to severe or life-threatening diseases, may in 

appropriate cases be taken into consideration when determining whether a drug 

makes a major contribution to patient care: convenient treatment location; duration of 

treatment; patient comfort; reduced treatment burden; advances in ease and comfort 

of drug administration; longer periods between doses; and potential for selfadministration.”40

• MCTPC “determinations can be complex and encompass consideration of a number 

of factors that potentially implicate safety and effectiveness, which are evaluated on a 

case-by-case basis for each drug product.”41 

Relative effectiveness and safety of the drug may be relevant in assessing whether a drug makes 

a MCTPC, and a drug must meet FDA’s safety and effectiveness standards to obtain approval, 

but, as explained above, nothing in the statute or regulation requires comparable effectiveness 

and safety. In the Rebif example noted above, FDA stated with respect to MCTPC: 

This analysis may involve multiple aspects of the drug product, since the benefit to the 

patient is likely to be greater convenience or less discomfort, and the very term “major 

contribution to patient care” implies a more global assessment. So, for example, an 

assessment of the safety or effectiveness of the new form of the subsequent product might 

be considered in determining whether the drug made a major contribution to patient care. 

However, even in this instance, there can not [sic] be an infinite number of comparison 

criteria if this provision of the regulation is to be meaningful.42

For example, if the administration of a drug were changed from intravenous (IV) to oral, FDA 

would consider, if appropriate, whether any adverse events diminished the advantage of the 

37 See FDA, Orphan Drug Regulations, Proposed Rule, 56 Fed. Reg. 3338, 3340 (Jan. 29, 1991) [hereinafter 1991 

Proposed Rule] (“The content of this evidence [needed for a demonstration of clinical superiority] will depend on 

the nature of the superiority claimed.”); see also 1992 Final Rule, 57 Fed. Reg. at 62079 (stating that a major 

contribution to patient care “determination will have to be made on a case-by-case basis.”). 38 1991 Proposed Rule, 56 Fed. Reg. at 3343. 39 1992 Final Rule, 57 Fed. Reg. at 62078. 40 FDA, Orphan Drug Regulations, Final Rule, 78 Fed. Reg. 35117, 35125 (Jun. 12, 2013) [hereinafter 2013 Final 

Rule]. 

41 Id. at 35124. 42 CBER Rebif memo, supra note 32, at 3.

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10 

change in administration from IV or oral. In that respect, safety concerns could inform the 

MCTPC analysis, but a safety concern present in a subsequent drug that was not present in the 

previous drug would not automatically defeat a MCTPC finding. That determination would be 

made on a case-by-case basis and depend upon the nature of the safety concern weighed against 

the benefits of the MCTPC. 

III. Factual Background 

This matter involves three different drug products that contain the same active moiety 

(oxybate)43 for the treatment of cataplexy or EDS in patients with narcolepsy. Jazz is the current 

sponsor of Xyrem (sodium oxybate) and Xywav (calcium, magnesium, potassium, and sodium 

oxybates). Avadel is the sponsor of Lumryz (sodium oxybate). 

A. Normal Sleep and Narcolepsy

 

The following background concerning normal sleep and narcolepsy is based on OOPD’s 

consultation with two board certified sleep experts in FDA (“Sleep Expert Consult”).44 

Adequate sleep is essential for humans as it physically and psychologically restores bodily 

functions.45 Without adequate sleep, humans function poorly and may die prematurely.46

Chronic sleep loss, sometimes called sleep debt, is well known to cause reduced performance, 

increased risk for accidents and death, and detrimental effects on both psychological and 

physical health.47 

Normal sleep architecture is characterized in adults as a progression of 90 to 120 minute sleep 

cycles starting with non-REM Stage 1 sleep (NREM or N1 sleep), then non-REM Stage 2 

(NREM or N2) sleep, then non-REM Stage 3 (NREM or N3) sleep, and ending in Rapid Eye 

Movement (REM or Stage R) sleep.48 Rapid eye movements and dreaming occur during Stage 

R.49 After Stage R, the normal adult has a very brief return to Stage Wake (Stage W), in the 

transition of going from cycle to cycle, though this awakening is not typically remembered, is 

normal and does not contribute to sleep fragmentation, sleep loss, or daytime sleepiness.50 The 

43 The active moiety oxybate may also be referred to as gamma-hydroxybutyrate (GHB). 44 Sleep Expert Consult, supra note 5. These physicians are boarded in (1) internal medicine; (2) pulmonology; (3) 

critical care medicine; (4) and sleep. One of the consultants continues to see patients in a sleep clinic. Statements in 

this subsection of the document are based on statements in this consult. 45 Kiran Maski, Insufficient sleep: Evaluation and management, UpToDate (May 23, 2022), 

https://www.uptodate.com/contents/insufficient-sleep-evaluation-and-management. 46 Chiara Cirelli, Insufficient sleep: Definition, epidemiology, and adverse outcomes, UpToDate (Oct 10, 2022), 

https://www.uptodate.com/contents/insufficient-sleep-definition-epidemiology-and-adverse-outcomes. 47 Id. 48 Douglas Kirsch, Stages and architecture of normal sleep, UpToDate (Sep 12, 2022), 

https://www.uptodate.com/contents/stages-and-architecture-of-normal-sleep. 49 James A. Rowley & M. Safwan Badr, Chapter 1: Normal Sleep, in Essentials of Sleep Medicine 3, at 5 (M. 

Safwan Badr & Jennifer L. Martin eds., 2nd ed. 2022). 50 Mary A. Carskadon & William C. Dement, Monitoring and staging humas sleep, Chapter 2—Normal Human 

Sleep: An Overview, in Principles and practice of sleep medicine at 12 (M.H. Kryger et al., eds., 5th ed. 2011); see 

also Rowley, supra note 49, at 5 (Fig. 1.2).

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normal sleep cyclical pattern typically repeats four to five times per night.51 Cycling progression 

through these stages is the basic structural organization of normal sleep and is called “sleep 

architecture.”52

Each sleep stage has unique features. Stage N1 sleep is light sleep (easily arousable), Stage N2 

sleep is intermediate in depth (less light sleep), and Stage N3 is deep sleep, otherwise known as 

restorative sleep, slow-wave sleep (SWS), or delta sleep.53 Brain activity is low during Stage N3 

sleep, and importantly, many recovery functions in the body occur only in this stage of 

sleep.54 Normally, the sleep cycles progress through the night with increasing time in Stage N3 

during initial sleep cycles and increasing REM sleep in each later sleep cycle during the night.55 

Stage N3 sleep has a unique and important role in restoring the mind and body.56 With sleep 

loss or deprivation or interruption, one enters Stage N3 sleep earlier and with increased quantity 

during the night.57 Thus, the body attempts to achieve sleep equilibrium by rapidly restoring this 

critical stage of sleep.58 On polysomnography (PSG)—a diagnostic full sleep study with an 

electroencephalogram (EEG)—REM sleep is a time of active brain EEG waves and 

physiological instability characterized by somewhat irregular heart rate and breathing patterns.59 

REM is associated with paralysis of all muscles except the essential respiratory muscles (e.g., the 

diaphragm).60

When an arousal occurs (e.g., when waking up to take medication during the night after falling 

asleep), there is a shift in an EEG pattern—one that leads to a longer Stage W with alertness or 

consciousness, even if not remembered.61 That duration of time in Stage W is prolonged and 

will adversely impact a clinical measure called Wake After Sleep Onset (WASO)—a metric of 

how much wakefulness happens in a night of sleep.62 In treating sleep disorders, including 

narcolepsy, the goal is to maximize the time in sleep and minimize wake time (i.e., minimize 

WASO).63 Disruption of sleep leads to the inability to enter Stage N3, or disruption of N3, and 

such individuals will revert back to Stage W and subsequently progress to Stage N1 sleep and so 

51 Kirsch, supra note 48. 52 Rowley, supra note 49, at 5. 53 Carskadon, supra note 50, at 11. 54 Derk-Jan Dijk, Regulation and Functional Correlates of Slow Wave Sleep, Supp. To Vol. 5 No. 2 Journal of 

Clinical Sleep Medicine, S6, at S6 (2009). 55 Carskadon, supra note 50, at 11. 56 Lixia Chen et al., The association between sleep architecture, quality of life, and hypertension in patients 

with obstructive sleep apnea, 27 Sleep and Breathing 191, at 192 (2023). 57 Kirsch, supra note 48; see also Carskadon, supra note 50, at 15. 58 See Sleep Expert Consult, supra note 5, at 4. 59 Ye Zhang et al., Polysomnographic nighttime features of narcolepsy: A systematic review and meta-analysis, 58 

Sleep Medicine Reviews at 1 (2021); see also David W. Carley & Sarah S. Farabi, Physiology of Sleep, 29 Diabetes 

Spectr. 5, at 6; see also Kirsch, supra note 48; see also Carskadon, supra note 50, at 3-4. 60 Rowley, supra note 49 at 5. 61 Kirsch, supra note 48; see also Pierre Philip et al., Sleep Fragmentation in Normals: A Model for Sleepiness 

Associated with Upper Airway Resistance Syndrome, 17 Sleep 242, at 244-245 (1994). 62 Eric Suni, Wakefulness After Sleep Onset, Sleep Foundation (updated Jan. 18, 2023),

https://www.sleepfoundation.org/sleep-studies/wakefulness-after-sleep-onset. 63 See Sleep Expert Consult, supra note 5, at 5. 

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forth.64 The disruption changes sleep architecture and will increase WASO.65 This disruption is 

something to be avoided in the narcoleptic patient, if possible.66 

Narcolepsy is a disorder of REM intrusion into wakefulness.67 Sudden REM sleep onset during 

wakefulness causes loss of motor tone (i.e., sleep paralysis) along with a dream like state called 

cataplexy.68 REM intrusion can also occur during sleep, disrupting the normal sleep architecture 

described above.69 Individuals with narcolepsy “generally fall asleep rapidly but can 

spontaneously awaken several times during the night and have difficulty returning to sleep. This 

sleep maintenance insomnia seems paradoxical in a disorder characterized by daytime sleepiness, 

and it may reflect a low threshold to transition from sleep to wakefulness.”70 REM intrusion in 

sleep shifts sleep stages and prevents sleep continuity (also called sleep consolidation), 

fragments normal sleep architecture, and prevents sufficient deep sleep (i.e., prevents N3 

restorative sleep from occurring because the sleep stages keep shifting to lighter sleep).71 Often 

Stage N1 increases at the debt of Stage N3 sleep given the increased number of shifts between 

sleep stages.72 This results in daytime sleepiness with the consequences of sleep fragmentation 

or sleep deprivation (i.e., altered sleep architecture which may affect daytime performance).73 

EDS is the most common and chronic symptom of narcolepsy.74 Per Scammell: “[t]he 

sleepiness may be so severe that patients with narcolepsy can rapidly doze off with little 

warning; these episodes are commonly referred to as ‘sleep attacks.’”75 Another symptom of 

narcolepsy, cataplexy, is an “emotionally-triggered transient muscle weakness” that can cause a 

patient to collapse.76 

For narcolepsy, the goals of therapy are “to achieve ‘normal’ alertness during conventional 

waking hours or to maximize alertness at important times of the day, (e.g., during work, school, 

or while driving),” and to the extent possible, promote normal sleep at night.77 Management of 

narcolepsy is multimodal and includes non-pharmacologic and pharmacologic treatment.78 Nonpharmacologic care, including “sleep hygiene,” is “critical to obtaining adequate, quality sleep 

64 Richard Berry et al., The AASM Manual for the Scoring of Sleep and Associated Events, Rules, Terminology and 

Technical Specifications, American Academy of Sleep Medicine (AASM) (2020), version 2.6 at 22-33. 65 See Sleep Expert Consult, supra note 5, at 6. 66 Id. 67 Thomas E Scammell, Clinical features and diagnosis of narcolepsy in adults, UpToDate (Jul. 12, 2022), 

https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-narcolepsy-in-adults. 68Id. 69 Imran Ahmed & Michael Thorpy, Chapter 15: Narcolepsy and Idiopathic Hypersomnia, in Essentials of Sleep 

Medicine 327, at 328 (M. Safwan Badr & Jennifer L. Martin eds., 2nd ed. 2022). 70 Scammell, Clinical, supra note 67. 71 Michelle T. Cao & Christian Guilleminault, Chapter 90: Narcolepsy: Diagnosis and Management, in Neurologic 

Disorders 873, at 873; see also Zhang, supra note 59 at 11. 72 Sleep Expert Consult, supra note 5, at 6. 73 Id. at 6-7. 74 Scammell, Clinical, supra note 67; see also Cao, supra note 71, at 873. 75 Scammell, Clinical, supra note 67. 76 Id. 77 Thomas E Scammell, Treatment of narcolepsy in adults, UpToDate (Nov. 14, 2022), 

https://www.uptodate.com/contents/treatment-of-narcolepsy-in-adults. 78 Kiran Maski et al., Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine

clinical practice guideline, 17 Journal of Clinical Sleep Medicine 1881, at 1892 (2021).

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on an ongoing basis.”79 Sleep hygiene means consistent sleep scheduling, a bedtime routine of 

personal care, napping, daily exercise, and a sleep environment conducive to sleep without 

interruptions.80

In addition to behavioral changes promoting good sleep hygiene, most patients with narcolepsy 

also require pharmacotherapy.81 Oxybate salts are one class of drugs that improves symptoms of 

EDS and decreases episodes of cataplexy.82 Per Scammell, especially for patients with severe 

and disabling sleepiness: 

Oxybates have a different mechanism of action than other narcolepsy 

medications and act primarily through consolidating nighttime sleep. Although 

risks and side effects, as well as cost, may be higher with oxybates, they can 

offer the best chance of optimal symptom control with monotherapy. For 

patients with a good response to oxybates, other wake-promoting medications 

may be able to be tapered.83

As explained above, “consolidating nighttime sleep” means ensuring sleep continuity through the 

normal stages of sleep architecture. Therefore, oxybate products are intended to decrease 

nocturnal arousals (also known as nighttime or nocturnal awakenings) to decrease sleep 

fragmentation that leads to poor quality sleep. Importantly, as explained in more detail below, 

the effectiveness of Xyrem and Xywav wanes during the night, so their labeling recommends 

that patients awaken for a second dose. Lumryz, as a once nightly formulation, will eliminate 

such nocturnal arousal, thus minimizing disturbances and decreasing sleep fragmentation. 

B. Regulatory History of Oxybate Products for Narcolepsy 

On November 7, 1994, FDA granted ODD to Jazz’s predecessor Orphan Medical, Inc. for 

oxybate84 for the treatment of narcolepsy. On July 17, 2002, FDA approved Xyrem for the 

treatment of cataplexy associated with narcolepsy, and Xyrem was eligible for ODE for the 

treatment of cataplexy associated with narcolepsy until July 17, 2009. On November 18, 2005, 

FDA approved Xyrem for a new indication, the treatment of EDS in patients with narcolepsy, 

and Xyrem was eligible for a new term of ODE for the treatment of EDS in patients with 

narcolepsy until November 18, 2012. Both of those periods of ODE have since expired. Finally, 

on October 26, 2018, FDA approved Xyrem for the treatment of cataplexy or EDS in pediatric 

patients 7 years of age and older with narcolepsy. Prior to this approval, the safety and 

effectiveness of Xyrem in pediatric patients had not been established, and therefore this approval 

79 Maski, Insufficient, supra note 45. 80 See National Sleep Foundation, 10 Tips for a Better Night’s Sleep, https://www.thensf.org/sleep-tips/; see also

American Academy of Sleep Medicine, How to sleep better,

https://aasm.org/resources/pdf/products/howtosleepbetter web.pdf; see also Ahmed, supra note 69 at 340. 81 Timothy I. Morgenthaler et al., Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of 

Central Origin, 30 Sleep 1705 at 1705-1711 (2007). 82 Scammell, Treatment, supra note 77. 83 Id. (emphasis added). 84 We note that ODD letters and the ODD database often refer to the generic name of the drug the sponsor uses in its 

request for designation rather than the active moiety, but the ODD applies to the active moiety (here, oxybate for the 

treatment of narcolepsy). 

FDA-OOPD-May23-POSTING-000013
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expanded the indication to a new patient population. Xyrem was eligible for ODE for the 

treatment of cataplexy or EDS in pediatric patients 7 years of age and older with narcolepsy, 

which will run until October 26, 2025.85

Xyrem has a concentration of 0.5 grams (g)/milliliter (mL) of sodium oxybate, equivalent to 

0.413 g/mL of oxybate.86 Xyrem is taken in 2 doses at night, the first dose at bedtime with the 

second dose taken 2.5 to 4 hours later.87 For adults, the initial starting dose is 4.5 g per night, 

which can be increased in increments of 1.5 g per night at weekly intervals to a maximum of 9 g 

per night.88 The maximum dose of 9 g contains approximately 1,640 milligrams (mg) of 

sodium.89 This amount can make up a large portion of the maximum daily recommended 

sodium (for example, CDC guidelines recommend less than 2,300 mg of sodium each day as part 

of a healthy eating pattern).90 Due to its high sodium content, Xyrem’s labeling includes a 

Warning and Precaution on use of the drug in patients sensitive to high sodium intake and 

recommends consideration of the amount of daily sodium intake in each dose of Xyrem for 

patients sensitive to sodium intake (e.g., those with heart failure, hypertension, or renal 

impairment).91 The sodium warning is listed last of eight warnings, and warnings are listed in 

order of relative clinical significance.92

Subsequently, Jazz developed a low-sodium alternative to Xyrem called Xywav. Xywav 

consists of 4 active ingredients, all of which have oxybate as the active moiety: calcium oxybate 

(0.234 g/mL), potassium oxybate (0.130 g/mL), magnesium oxybate (0.096 g/mL), and sodium 

oxybate (0.040 g/mL) — equivalent to 0.413 g/mL of oxybate, the same as Xyrem.93 The total 

salt concentration is 0.5 g/mL.94 Also like Xyrem, the recommended starting dosage for Xywav 

in adults is 4.5 g per night administered orally, divided into two doses, one at bedtime with the 

second dose to be taken 2.5 to 4 hours later.95 Xywav can be titrated by increments of up to 1.5 

g per night per week to the recommended maximum dosage of 9 g per night.96 At the maximum 

85 Pediatric exclusivity extends Xyrem’s ODE until April 26, 2026. 86 Xyrem FDA-Approved Labeling at Section 3 (Apr. 2023), available at: 

https://www.accessdata.fda.gov/drugsatfda docs/label/2023/021196s042lbl.pdf [hereinafter Xyrem 2023 Labeling]. 87 Id. at section 2.1. Note that the labeling describes dosage “per night” regardless of whether the patient primarily 

sleeps during the day or night. This analysis will also use the word “night” to refer to the patient’s bedtime. 88 Id. at section 2.1. 89 Id. at section 5.8. 90 See CDC, About Sodium, available at: https://www.cdc.gov/salt/food htm. 91 Xyrem 2023 Labeling, supra note 86, at section 5.8. The warning states, “Xyrem has a high salt content. In 

patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment), consider the 

amount of daily sodium intake in each dose of Xyrem. Table 3 provides the approximate sodium content per Xyrem 

dose.”

92 See FDA, Guidance for Industry, Warnings and Precautions, Contraindications, and Boxed Warning Sections of 

Labeling for Human Prescription Drug and Biological Products — Content and Format at 7 (Oct. 2011) (available 

at: https://www fda.gov/regulatory-information/search-fda-guidance-documents/warnings-and-precautionscontraindications-and-boxed-warning-sections-labeling-human-prescription) (“The order in which adverse reactions 

are presented in the WARNINGS AND PRECAUTIONS section should reflect the relative clinical significance of 

the adverse reactions”).

93 Xywav FDA-Approved Labeling at section 3 (Apr. 2023), available at:

https://www.accessdata.fda.gov/drugsatfda docs/label/2023/212690s011lbl.pdf [hereinafter Xywav 2023 Labeling]. 94 Id. 95 Id. at section 2.1. 96 Id. 

FDA-OOPD-May23-POSTING-000014
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dose for adults, the sodium content of Xywav is 131 mg.97 Therefore, unlike Xyrem, there are 

no Warnings and Precautions in Xywav’s labeling related to that drug’s use in patients sensitive 

to high sodium intake. 

Because the active moiety in Xywav is also oxybate, Xywav is covered by Jazz’s ODD for 

oxybate for the treatment of narcolepsy. On July 21, 2020, FDA approved Xywav for the 

treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy. In order for 

Xywav to be eligible for ODE, Jazz was required to demonstrate that Xywav was clinically 

superior to Xyrem.98 OOPD determined that Xywav was clinically superior to Xyrem because 

the reduced sodium in Xywav provides greater safety in a substantial portion of the target 

population.99 Specifically, at the effective daily dose of 6 g to 9 g, Xyrem adds approximately 

1,100 mg to 1,640 mg of sodium to each patient’s daily sodium intake, compared to Xywav, 

which adds only 87 to 131 mg of sodium to each patient’s daily sodium intake for the same 

recommended daily dose.100 OOPD concluded, “the differences in the sodium content of the two 

products at the recommended doses will be clinically meaningful in reducing cardiovascular 

morbidity in a substantial proportion of patients for whom the drug is indicated.”101 OOPD 

noted that whether sodium content of Xyrem increases cardiovascular risks in patients with 

narcolepsy has never been specifically or adequately investigated; however, the general base of 

knowledge about the effects of sodium support that the amount of sodium in Xyrem would 

increase cardiovascular risks in patients with narcolepsy.102 

Because FDA found Xywav to be clinically superior to Xyrem, Xywav was eligible for ODE.103

On June 24, 2021, OOPD sent a letter to Jazz stating that it is eligible for ODE for Xywav for the 

treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy, effective as 

of the July 21, 2020, approval of NDA 212690.104 Xywav’s ODE for this indication will run 

until July 21, 2027.

97 NDA 212690 Clinical Review at 7 (available at: 

https://www.accessdata.fda.gov/drugsatfda docs/nda/2020/212690Orig1s000MedR.pdf). 98 Section 527(c)(1) of the FD&C Act. 99 See FDA, Exclusivity Memorandum DRU-1994-858, Xywav (calcium, magnesium, potassium, and sodium 

oxybates) at 6 (Sep. 30, 2021) [hereinafter Xywav Exclusivity Memo]. During OOPD’s assessment of Xywav’s 

clinical superiority over Xyrem, OOPD received and considered two letters from Jazz containing arguments why 

Xywav is clinically superior to Xyrem. See letter from Arthur Merlin d’Estreux to Janet Maynard, Orphan Drug 

Exclusivity for JZP-258, NDA No. 212690 (Apr. 24, 2020); see also letter from Robert Iannone to Janey Maynard, 

Request to Expedite Recognition of Orphan Drug Exclusivity for XYWAV (NDA 212690) (Apr. 19, 2021). 

Additionally, OOPD received and considered a letter from Avadel providing arguments why Xywav is not clinically 

superior to Xyrem. See letter from Jennifer Gudeman to Janet Maynard, Sodium Oxybate for the Treatment of 

Narcolepsy (Dec. 8, 2020). OOPD also consulted with the Division of Neurology 1 (“DN1”) in the Center for Drug 

Evaluation and Research (“CDER”). See DN1, Consult Request NDA 212690 Xywav (Nov. 27, 2020) [hereinafter 

DN1 2020 Xywav Consult]; See also DN1, Consult Request NDA 212690 Xywav (Mar. 8, 2021). 100 Xywav Exclusivity Memo, supra note 99, at 3. 101 FDA, Clinical Superiority Findings, available at https://www fda.gov/industry/designating-orphan-productdrugs-and-biological-products/clinical-superiority-findings. 102 Xywav Exclusivity Memo, supra note 99, at 5. 103 See section 527(c) of the FD&C Act. 104 Letter from Nicole Wolanski to Jazz Pharmaceuticals, Inc., Orphan-Drug Exclusivity Letter DRU-1994-858

(June 24, 2021). OOPD also responded to Avadel’s letter to explain that we considered their arguments before 

concluding that Xywav was eligible for ODE. See letter from Nicole Wolanski to Jennifer Gudeman, Sodium 

Oxybate for the Treatment of Narcolepsy (Jun. 24, 2021).

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17 

dose. 112 DNP’s response supported OOPD’s conclusion that there was a plausible hypothesis 

that Lumryz may be clinically superior to Xyrem based on providing greater safety or by making 

a MCTPC over Xyrem.113 Therefore, on January 8, 2018, FDA granted Avadel’s request for

ODD for oxybate for treatment of narcolepsy.114

On December 15, 2020, Avadel submitted NDA 214755 for Lumryz. On July 18, 2022, FDA 

tentatively approved Lumryz for the treatment of cataplexy or EDS in adults with narcolepsy. 

The Tentative Approval Letter stated, “This letter does not address whether any orphan drug 

exclusivity (ODE) recognized for Xyrem under NDA 021196 or for Xywav (calcium, 

magnesium, potassium, and sodium oxybates) oral solution under NDA 212690 affects the 

approvability of Avadel’s application.”115 On March 1, 2023, Avadel submitted an amendment 

to NDA 214755 requesting final approval.

IV. Discussion

A. Applicability of the Clinical Superiority Standard

Xywav currently has ODE for the treatment of cataplexy or EDS in patients 7 years of age and 

older with narcolepsy, and as such, FDA may not approve another sponsor’s marketing 

application for the same drug for the same use or indication until its exclusivity expires on July 

21, 2027.

116 Lumryz contains the same active moiety as Xywav (oxybate), and Avadel is 

seeking approval for Lumryz for an indication covered by Xywav’s unexpired ODE (the 

treatment of cataplexy or EDS in adults with narcolepsy). Under the orphan-drug regulations, 

Lumryz is the “same drug” as Xywav unless Lumryz is clinically superior to Xywav.117 If 

Lumryz is clinically superior to Xywav, then it is not the “same drug” as Xywav, and Xywav’s 

ODE will not block Lumryz’s approval.

118 

112 Id. at 8-9. 113 FDA, Review of Amended Request for Orphan Drug Designation for sodium oxybate, DRU-2016-5302 at 4-6 

(Dec. 21, 2017). The standard for ODD is a “plausible hypothesis” that the subsequent drug may be clinically 

superior to the first drug. When FDA grants ODD to a drug that is otherwise the same drug as a previously approved 

drug for the same rare disease or condition based on a plausible hypothesis of clinical superiority, that means FDA 

agrees that the sponsor “may be able to produce a clinically superior drug,” not that the sponsor has provided 

evidence that its drug in fact would be clinically superior. See 1991 Proposed Rule, 56 Fed. Reg. at 3340. This is a 

lower standard than is required to demonstrate clinical superiority for the purposes of determining whether a drug’s 

ODE blocks approval of another drug or determining eligibility for ODE. 114 Letter from Debra Y. Lewis to The Weinberg Group Inc., Designation letter for sodium oxybate, DRU-2016-

5302 (Jan. 8, 2018). See also supra note 84. 115 Letter from Teresa Buracchio to Marla E. Scarola, Tentative Approval Letter (Jul. 18, 2022). 116 Section 527(a) of the FD&C Act; 21 CFR §§ 316.31 & 316.3(b)(14). 117 21 CFR § 316.3(b)(14). 118 Jazz asserts that for FDA to approve Lumryz, Lumryz must be clinically superior to Xywav. See Sidley Letter, 

supra note 12, at 5-8. We agree with this conclusion but note that Jazz at one point appears to arrive at this 

conclusion based on an incorrect interpretation of the law, citing to section 527(c) of the FD&C Act (the condition 

of clinical superiority to be eligible for ODE) as an exception to ODE. See, e.g., id. at 7 (“Thus, section 527(c)(1) 

provides that a later-in-time applicant can break through unexpired exclusivity (or obtain new exclusivity) only by 

demonstrating that its proposed drug will be ‘clinically superior to any already approved or licensed drug that is the 

same drug.’ 21 U.S.C. § 360cc(c)(1) . . .”). Later, Jazz changed its position during the meeting between Sidley and 

OCC. See Sidley Slides, supra note 13, at 10 (stating that section 527(c) cannot be read as a third exception to ODE 

FDA-OOPD-May23-POSTING-000017
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Avadel is not seeking approval for Lumryz for an indication covered by Xyrem’s unexpired 

ODE.119 Upon approval, in order to be eligible for its own term of ODE, an orphan-designated 

drug must be clinically superior to all otherwise same drugs previously approved for the same 

use or indication.120 Accordingly, if Lumryz is clinically superior to Xywav and Xyrem, then it 

will be eligible for its own term of ODE. 

i. Clinical superiority can overcome ODE

As explained above, the definition of “same drug” in the orphan-drug regulations states that if a 

subsequent drug that has the same active moiety and is for the same use as a previously approved 

drug “can be shown to be clinically superior to the first drug, it will not be considered to be the 

same drug.”121 Accordingly, if a subsequent drug is clinically superior to a drug with ODE that 

has the same active moiety and is for the same indication or use, approval of the subsequent drug 

is not blocked by that drug’s ODE. Jazz provides three arguments why FDA cannot apply the 

definition of “same drug” here to determine that Lumryz is a different drug than Xywav, and 

thus not blocked by Xywav’s ODE. 

First, Jazz argues that Depomed and Eagle struck down FDA’s definition of “same drug.”122 As 

a threshold matter, Depomed and Eagle concerned a different set of facts and a distinct legal 

issue. Those cases addressed FDA’s authority to require a demonstration of clinical superiority 

as a condition for eligibility for ODE prior to the addition of section 527(c) to the FD&C Act. 

Jazz acknowledges this, stating, “Section 527(c) thus addresses the specific factual scenario at 

issue in Depomed, Eagle, and United Therapeutics by providing that subsequent periods of ODE 

cannot be obtained without proof of clinical superiority.”123 Thus, the holdings of these cases 

concern eligibility for ODE, not the scope of ODE (i.e., what ODE blocks). The district court in 

Eagle Pharms explicitly stated: “[t]he scope of Bendeka’s exclusivity is an issue that the FDA 

must determine in the first instance.”124

and that section 527(c) addresses only serial grants of exclusivity). Section 527(c) only concerns potential eligibility 

of a subsequent drug (like Lumryz) for its own period of ODE; it does not address whether a subsequent drug’s 

(Lumryz’s) approval is blocked by Xywav’s ODE. See section II.B of document for further explanation. 119 Avadel is only seeking approval for the treatment of cataplexy or EDS in the adult population with narcolepsy, 

and Xyrem’s ODE only blocks approval of the same drug for the treatment of cataplexy or EDS in the pediatric 

population. Jazz acknowledges that “[. . .] the unexpired ODE for XYREM is not at issue (because Avadel’s 

proposed labeling omits pediatric use).” Sidley Slides, supra note 13, at 7. 120 Section 527(c)(1) of the FD&C Act. 121 21 CFR § 316.3(b)(14)(i); see also similar language in 316.3(b)(14)(ii). 122 Sidley Letter, supra note 12, at 6; see also Sidley Slides, supra note 13, at 14. 123 Sidley Slides, supra note 13, at 10. 124 Eagle Pharms., Inc. v. Azar, No. CV 16-790 (TJK), 2018 WL 3838223, at *3 (D.D.C. Aug. 1, 2018). See also id. 

at *2 (“But the Order did not adopt Eagle’s (or any other party’s) interpretation of the scope of Bendeka’s 

exclusivity.”); id. (“And as Defendants repeatedly and correctly assert, the scope of Bendeka's exclusivity was not 

before the Court in this litigation. See, e.g., Defs.’ Mot. at 7 (‘Eagle repeatedly emphasized that the scope of 

exclusivity for Bendeka was a separate issue from the existence of any such exclusivity, indicating that only the

latter was properly before this Court.’). Rather, the issue was whether Bendeka should enjoy orphan-drug 

exclusivity at all. Accordingly, that was the only issue that the Court’s Opinion and Order addressed, as Defendants 

acknowledge. See id. at 2, 9; Defs.’ Reply at 2. And doing so did not require the Court to address whether Bendeka 

is the same drug as Treanda under either the FDA’s regulations or the statute.”). See also FDA, Dear Applicants for 

FDA-OOPD-May23-POSTING-000018
19 

Jazz nonetheless points to several quotations from the cases in looking for support, but these 

quotations do not speak directly to the situation at issue with Lumryz. The first quotation,

125

from the background section of the Depomed decision, simply describes how the definition of 

“same drug” “effectively limits the scope of exclusivity,” but neither Depomed nor Eagle

addressed the scope of the plaintiffs’ exclusivity (i.e., whether approval of another sponsor’s 

drug was blocked by the plaintiffs’ exclusivity).126 Jazz also quotes language in the Depomed 

decision stating, “This Court will not impute to Congress an intention to authorize an exception 

that Congress itself did not think worth enacting.”127 However, the regulatory definition of 

“same drug” does not create an extra-statutory “exception” to ODE. As explained in section II.B 

above, under section 527(a), FDA may not approve another sponsor’s application for the same 

drug for the same use or indication as a drug with ODE.128 Exceptions to ODE describe

situations where FDA can nevertheless approve another sponsor’s application for the same drug 

for the same use or indication during a period of unexpired ODE.129 Instead of creating such an 

exception to ODE where same drugs for the same indications or uses can be approved despite a 

drug’s unexpired ODE, the definition of “same drug” identifies certain drugs that are not the 

same (e.g., clinically superior drugs) and, in this context, helps clarify the scope of ODE once it 

has attached. When a subsequent drug that is otherwise the same drug (i.e., contains the same 

active moiety and is for the same use or indication) as a drug with unexpired ODE and is found 

to be clinically superior to that drug with unexpired ODE, then the subsequent drug is not the 

“same drug,” and the unexpired ODE cannot block approval of that drug under section 527(a) of 

the FD&C Act (because such ODE can only block same drugs for the same uses or 

indications).130 That section 527(b) enumerates two exceptions to ODE does not undermine the 

Certain Products Containing Bendamustine Letter, Docket No. FDA-2018-N-3773 (Feb. 20, 2019) (“FDA has . . . 

determined that the agency will continue to apply its existing ‘same drug’ regulation when determining the scope of 

Bendeka’s exclusivity (i.e., exclusivity prevents the approval of any other drug with the same active moiety (here, 

bendamustine) for the exclusivity-protected indications.”). 125 Sidley Slides, supra note 13, at 14 (quoting Depomed v. HHS, 66 F. Supp. 3d 217 (D.D.C. 2014) (“FDA’s 

‘insertion of the ‘same drug’ concept ... effectively limits the scope of exclusivity protection because under the 

regulations, only if a new drug uses the same [active moiety] to treat the same disease or condition ... and the new 

drug is also not found to be ‘clinically superior’ to the existing orphan drug will the FDA ... forbid its marketing 

within the exclusivity period.’”). 126 Depomed.v. HHS, 66 F. Supp. 3d 217 (D.D.C. 2014); see also Eagle Pharms., Inc. v. Azar, 952 F.3d 323 (D.C. 

Cir. 2020). 127 Sidley Letter, supra note 12, at 6; see also Sidley Slides, supra note 13, at 14. Similarly, the Sidley Letter also 

later quotes from Depomed, “Where Congress explicitly enumerates certain exceptions to a general prohibition, 

additional exceptions are not to be implied.” Sidley Letter, supra note 12, at 8. 128 Section 527(a) of the FD&C Act. 129 The exceptions to 527(a) of the FD&C Act are enumerated in section 527(b). 130 This distinction between an exception to ODE and a definitional exclusion from the term “same drug” is a 

meaningful one. The exceptions to ODE under section 527(b) set forth the circumstances under which FDA may 

approve an application even though it is for the same drug for the same indication or use as the drug that has ODE. 

Meanwhile, a subsequent drug that is clinically superior to the drug with ODE is simply not the same drug as the 

drug that has ODE and is therefore excluded from the scope of subsequent drugs that are blocked by that ODE. A 

standard illustration of this distinction, familiar to most law students, is the evidentiary rule against hearsay. Federal 

Rule of Evidence 802 provides that hearsay is generally inadmissible. Rules 801(c)-(d) exclude certain statements 

from the definition of hearsay: 801(c) limits hearsay to out-of-court statements offered for their truth, while 801(d)

further specifies certain statements that are “not hearsay.” Meanwhile, Rules 803, 804, and 807 provide for certain 

exceptions to the rule against hearsay—statements that meet the definition of hearsay, but that are nevertheless not 

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20 

agency’s conclusion that a clinically superior drug is definitionally not the “same drug,” and 

therefore its approval is not blocked by ODE. 

Jazz also cites quotations from Eagle critiquing “FDA’s imposition of its clinical-superiority 

requirement” and that FDA’s “interpretation reads a limitation into the text that is not there.”131 

Again, Eagle concerned FDA’s imposition of the condition of clinical superiority for a sponsor 

to be eligible for its own period of ODE, which is not at issue here. We have already recognized 

that Xywav is eligible for ODE. Xywav’s ODE, however, only blocks approval of the same drug 

for the same indication or use. 

Second, Jazz argues that the enactment of section 527(c) of the FD&C Act superseded and 

invalidated the regulatory definition of “same drug.” Specifically, Jazz argues that the regulatory 

definition of “same drug” is inconsistent with section 527(c)(1), because the statute does not 

contain what Jazz refers to as the “‘not-the-same’ fiction.”132 However, Jazz ignores crucial 

words in the statute. As explained above, Section 527(c)(1) requires a demonstration of clinical 

superiority when the sponsor of a drug is seeking ODE for “a drug that is designated under 

section 526 and is otherwise the same, as determined by the Secretary, as an already approved or 

licensed drug” for the same use or indication.133 The orphan-drug regulations, which predate 

section 527(c)(1), use this same phrase; see, e.g., 21 CFR § 316.3(b)(3) (stating “that a drug is 

shown to provide a significant therapeutic advantage over and above that provided by an 

approved drug (that is otherwise the same drug)” (emphasis added)); 21 CFR § 316.34(c) (“If a 

drug is otherwise the same drug as a previously approved drug for the same use or indication, 

FDA will not recognize orphan-drug exclusive approval if the sponsor fails to demonstrate upon 

approval that the drug is clinically superior to the previously approved drug.” (emphasis added)); 

Congress legislated against this backdrop. Black’s Law Dictionary defines “otherwise” as: 

otherwise adv. (bef. 12c) 1. In a different way; in another manner <David 

Berkowitz, otherwise known as Son of Sam>. 2. By other causes or means <to 

succeed by hard work and otherwise>. 3. In other conditions or circumstances <to 

know him otherwise than through law practice>. 4. Except for what has just been 

mentioned <page 99 was illegible; otherwise, the records were easy to 

decipher>. 5. Busy doing something else <she was otherwise engaged that 

day>. 6. To the contrary; differently <although the economists say that legal 

markets are soft, many law-firm leaders think otherwise>. • The 

term otherwise tends to be quite broad in scope. 

subject to the rule against hearsay. Exceptions to the rule against hearsay and exclusions from its definition are 

therefore addressed separately. The same is true here. 

131 Sidley Letter, supra note 12, at 6; see also Sidley Slides, supra note 13, at 14. 132 Sidley Slides, supra note 13, at 15-16. Id. at 15 (arguing that “[t]he statute does not rely on any legal fiction and 

does not pretend that a clinically superior product is no longer “the same” as prior drugs that contain the same active 

moiety; that “[i]nstead, the statute created a clinical superiority requirement that embraces ‘sameness;’” that 

“[p]ursuant to section 527(c)(1), a second or further period of ODE is conditioned on a demonstration that the 

proposed drug is ‘clinically superior to any already approved or licensed drug that is the same drug;’” and that “[p]er 

the statute XYWAV remains ‘the same drug’ as other oxybates even though it is clinically superior”). 133 Section 527(c)(1) of the FD&C Act (emphasis added).

FDA-OOPD-May23-POSTING-000020
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These dictionary definitions make clear that “otherwise” connotes difference. By using the 

phrase “otherwise the same” the statute (and regulations) acknowledges that a clinically superior 

drug is not, in fact, considered to be the same as a previously approved drug. The orphan-drug 

regulations defining “same drug” state that “if the subsequent drug can be shown to be clinically 

superior to the first drug, it will not be considered to be the same drug,” which is entirely 

consistent with section 527(c)’s description of a clinical superior drug as one that is “otherwise 

the same” as (i.e., different than) a previously approved drug. FDA has previously considered 

whether the enactment of the FDARA provisions at section 527 conflicted with its regulations 

and concluded that “FDA’s current regulations are consistent with FDARA.”134

Third, Jazz argues that allowing a clinically superior drug to overcome the ODE of an otherwise 

same drug goes against the intent of Congress and renders ODE meaningless.135 FDA disagrees. 

As Jazz itself acknowledges, Congress expressed an interest in incentivizing the development of 

clinically superior products.136 The ODE framework executes that intention in two ways: first, 

clinically superior drugs can be eligible for their own terms of ODE; second, clinically superior 

drugs can be approved during the ODE period for a drug that is otherwise the same as the 

clinically superior drug because they fall outside the scope of that drug’s ODE. Although ODE 

does not block as much as Jazz would prefer in this instance, that does not render ODE 

“meaningless.” Xywav’s ODE blocks FDA approval of all applications from other sponsors for 

the same drug for the same use or indication for seven years (subject to the exceptions in section 

527(b)), a valuable benefit that is not just limited to blocking FDA’s approval of generic drugs 

referencing Xywav. 

ii. MCTPC in Relation to Safety

As explained above, Lumryz may demonstrate clinical superiority to Xywav by showing that it 

provides a significant therapeutic advantage through greater effectiveness, greater safety, or by 

making a MCTPC. Doing so would render Lumryz a different drug than Xywav such that 

Xywav’s ODE would not block Lumryz’s approval. Importantly, as explained above, one drug 

can demonstrate a MCTPC over a previously approved drug even if the drug is not as effective 

or safe in every respect as the previously approved drug. Jazz tries to argue otherwise. Jazz 

claims that “longstanding FDA policy requires the second-in-time drug to achieve at least 

comparable safety as the earlier drug” in order to be clinically superior.137 Additionally, Jazz 

claims that “to be eligible for clinical superiority a drug must also provide safety at least 

comparable to the approved drug” and that “a new drug that is less safe than an already approved 

orphan drug cannot be considered ‘clinically superior’ to the first drug.”138 The same argument 

is also made in the Sidley Letter, which states, “clinical superiority cannot be demonstrated 

through tradeoffs—a later drug is not clinically superior if it sacrifices the safety or efficacy 

134 Dear Applicants for Certain Products Containing Bendamustine Letter, supra note 124. Jazz points to section 

527(d) of the FD&C Act to suggest that the agency cannot apply its definition of “same drug” to interpret the statute 

and its regulations at Subpart D of Part 316. As noted here, FDA has previously considered this issue and concluded 

that FDA’s current regulations are consistent with FDARA.

135 Sidley Letter, supra note 12, at 8; see also Sidley Slides, supra note 13, at 17. 136 Sidley Slides, supra note 13, at 17. 137 Jazz’s September 2021 Letter, supra note 11, at 1. 138 Id. at 2. 

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achieved by its predecessors.”139 In the Sidley Slides, Jazz relies on the words “over and above” 

in section 527(c)(2) to argue that clinical superiority requires “progress” and thus a drug cannot 

be clinically superior to a previously approved drug if it is also less safe than the previously 

approved drug. These assertions are not correct.

First, the words “over and above,” in the context of the statute and regulation at 21 CFR § 

316.3(b)(3), cannot be read to mean a drug must be as safe as a previously approved drug to 

make a MCTPC. As explained in section II.C above, section 527(c)(2) of the FD&C Act defines 

clinically superior to mean that “the drug provides a significant therapeutic advantage over and 

above an already approved or licensed drug in terms of greater efficacy, greater safety, or by 

providing a [MCTPC],” and 21 CFR § 316.3(b)(3) defines clinically superior to mean that “a 

drug is shown to provide a significant therapeutic advantage over and above that provided by an 

approved drug (that is otherwise the same drug) in one or more of the following ways:” greater 

effectiveness, greater safety, or a MCTPC (emphasis added). Jazz conveniently ignores the 

italicized statutory and regulatory language in these definitions. In both definitions, the 

subsequent drug must provide a significant therapeutic advantage “over and above” an already 

approved drug in just one way—greater efficacy, greater safety, or by providing a MCTPC—to 

be considered clinically superior. The plain reading of both the statute and the regulation does

not impose an additional requirement that in order to provide a significant therapeutic advantage 

in one of the three measures, the drug must also be at least comparable in the other two 

measures. The relative effectiveness and safety of the drug may be relevant in assessing whether 

a drug makes a MCTPC, and a drug must meet FDA’s fundamental safety and effectiveness 

thresholds to obtain approval (see section II.D above), but nothing in the statute or regulation 

requires comparable effectiveness and safety in every respect. 

In fact, in the 2011 proposed rule for amending the orphan-drug regulations, FDA proposed 

adding such a requirement to the regulation.140 Specifically, FDA proposed adding that a 

demonstration of MCTPC must also include “a demonstration that the drug provides safety and 

effectiveness comparable to the approved drug.”141 In the 2013 final rule, however, FDA did not 

adopt that proposed change, so as not to create “a new standard” for MCTPC.142 Instead, FDA 

stated that MCTPC “determinations can be complex and encompass consideration of a number 

of factors that potentially implicate safety and effectiveness, which are evaluated on a case-bycase basis for each drug product.”143 

Jazz points to the 2011 proposed rule to argue that a “comparable safety showing” is “consistent 

with longstanding FDA policy.”144 To the contrary, as discussed above, the final rule makes 

clear that requiring a showing of comparable safety and effectiveness for a MCTPC would create

a “new standard.”145 Jazz also claims that it “could find no precedent where FDA has endorsed a 

139 Sidley Letter, supra note 12, at 8-9; see also Sidley Slides, supra note 13, at 29. 140 FDA, Orphan Drug Regulations, Proposed Rule, 76 Fed. Reg. 64868, 64871 (Oct. 19, 2011) [hereinafter 2011 

Proposed Rule]. 141 Id. at 64878. 142 2013 Final Rule, 78 Fed. Reg. at 35124. 143 Id. 144 Jazz’s September 2021 Letter, supra note 11, at 2 footnote 4 (referencing 2011 Proposed Rule, 76 Fed. Reg. at 

64876).

145 2013 Final Rule, 78 Fed. Reg. at 35124.

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comparably effective but less safe product as clinically superior.”146 However, more 

importantly, based on our review, agency precedent is devoid of instances in which we refused to 

find a MCTPC for a drug based on a failure to show comparable safety or efficacy.

147 As 

explained above, safety concerns could inform a MCTPC analysis, but a safety concern present 

in a subsequent drug that was not present in the previous drug would not automatically defeat a 

finding of MCTPC. That determination would be made on a case-by-case basis and depend upon 

the nature of the safety concern weighed against the benefits of the MCTPC. As described in 

detail in section II.C, FDA’s ODE determination regarding Rebif provides at least one instance 

where we found a drug to be clinically superior based on greater efficacy even though the drug 

was less safe in one measure than the previously approved drug with ODE. As noted above, 

Rebif patients experienced skin necrosis at injection sites that patients on a previously approved 

drug (Avonex) did not (i.e., the same adverse event that was present with the previously 

approved drug Betaseron that led to the determination that Avonex was clinically superior to 

Betaseron based on safety).148 While this clinical superiority determination was not based on a 

MCTPC finding, the example nonetheless demonstrates that the agency does not require 

comparable safety and efficacy to be considered clinically superior. 

Jazz claims that FDA’s clinical superiority analyses include an assessment of whether the 

subsequent drug is at least “not less safe than” the previously approved drug to support its 

assertion that “a new drug that is less safe than an already approved orphan drug cannot be 

considered ‘clinically superior’ to the first drug.”149 To support these claims, Jazz cites 

examples where FDA considered whether a previously approved drug is at least not less safe.150 

As discussed below, although these examples discuss the relative safety of two drugs, they do 

not support a conclusion that a drug must be at least “not less safe” than an already approved 

drug to be clinically superior to that drug. FDA has considered whether a subsequent drug has 

comparable safety and efficacy to the previously approved drug as part of an overall assessment 

of whether the subsequent drug makes a MCTPC. For example, to reiterate what we said above, 

where certain adverse events associated with a change in administration raise safety concerns for 

a subsequent drug that are not present for a previous drug, FDA could consider such information 

to determine whether the safety concerns affect the agency’s finding that certain benefits of the 

drug create a MCTPC, but such safety concerns would not automatically lead FDA to deny the 

drug approval or exclusivity based on a finding that the drug was not clinically superior. 

The specific examples provided by Jazz do not counsel otherwise. First, Jazz cites to OOPD’s 

statements, in determining that Revcovi (elapegademase-lvlr) is clinically superior to Adagen 

(pegademase bovine), that “OOPD does not need to determine whether Revcovi is in fact more 

safe than Adagen. Clinical superiority based on effectiveness has been demonstrated, and 

146 Jazz’s September 2021 Letter, supra note 11, at 1. 147 We are aware of certain language in agency documents that could be interpreted as suggesting FDA has such a 

policy. As described further below, despite these statements, none of FDA’s past precedents that OOPD reviewed

manifest application of such a policy upon approval when FDA is determining eligibility for ODE or when it is 

considering whether a drug may be approved in light of another sponsor’s ODE. Given the quantum of information 

suggesting otherwise, it is clear that those statements do not reflect such an agency policy. 148 CBER Rebif memo, supra note 32, at 20. 149 Jazz’s September 2021 Letter, supra note 11, at 2. 150 Id. at 2 footnote 4; see also Sidley Slides, supra note 13, at 30. 

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Revcovi is at least not less safe than Adagen.”151 Revcovi and Adagen are both enzyme 

replacement therapies used to treat adenosine deaminase (“ADA”) deficiency in patients with 

severe combined immunodeficiency. Adagen is derived from a bovine source, while Revcovi is 

recombinant (i.e., made in a laboratory). OOPD determined that Revcovi is clinically superior to 

Adagen based on a consult with expert clinicians in the review division, who found that Revcovi 

is more effective as it provides more stable plasma ADA activity, more consistently above the 

therapeutic threshold associated with clinical benefit associated with long term survival.152 

Because OOPD found Revcovi to be clinically superior based on greater efficacy, it did not need 

to determine if Revcovi also provided greater safety. Efficacy and safety are alternative prongs

for clinical superiority. Nothing in OOPD’s reasoning suggests that the fact that Revcovi was 

“not less safe than Adagen” was a factor in OOPD’s finding of clinical superiority based on 

greater effectiveness or that if Revcovi had been less safe, then Revcovi could not have been 

found to be clinically superior. Nor do OOPD’s statements mean that FDA has a policy that in 

order to be clinically superior based on efficacy, a subsequent drug must also provide safety at 

least comparable to the previously approved drug. 

Second, Jazz cites an ODD memo regarding a potential plausible hypothesis of clinical 

superiority of enteric-coated cysteamine (later named Procysbi (cysteamine bitartrate)) over 

another cysteamine product for the treatment of cystinosis.153 Enteric-coated cysteamine had 

ODD for the treatment of cystinosis based on a plausible hypothesis that enteric-coated 

cysteamine may be clinically superior to the previously approved cysteamine product for the 

same disease based on safety by causing less nausea and vomiting.154 Note that at the time of the 

cited memo, OOPD was not conducting an analysis of whether the sponsor had, in fact,

demonstrated clinical superiority. The memo responded to a June 23, 2008, letter from the 

sponsor asking to update the hypothesis that was the basis of the ODD.155 OOPD reviewed this 

request, and in the memo cited by Jazz, explained that OOPD assesses MCTPC “individually” 

(on a case-by-case basis) and considers factors including “the nature of the orphan indication, 

course of treatment for the indication, and benefits that could be obtained from the new 

product.”156 The memo then states, as cited by Jazz, “Inherent in this analysis is the general 

assumption that changes in drug administration would maintain a similar or improved adverse 

event profile and similar efficacy.”157 As explained below, this statement is consistent with and 

reflects the MCTPC standard we described above. 

At the ODD stage, as is the case in the Procysbi memo, FDA does not have full safety, efficacy, 

and other data for the drug necessary to make a definitive determination about clinical 

151 Jazz’s September 2021 Letter, supra note 11, at 2 footnote 4. 152 FDA, Exclusivity Memorandum, DRU-2014-4675, Revcovi (elapegademase-lvlr) at 3 (Oct. 14, 2020). 153 Jazz’s September 2021 Letter, supra note 11, at 2 footnote 4; see also Sidley Slides, supra note 13, at 30. 154 FDA, Review of Request for ODD for enteric-coated cysteamine, DRU-2006-2310 (Oct. 10, 2006) [hereinafter 

Procysbi Designation Memo]. 155 Letter from Ted Daley to Timothy Cote, Orphan Drug Exclusivity Determination for Delayed-release 

Cysteamine Bitartrate Capsules (i.e., enteric-coated beads) for Treatment of Cystinosis, DRU-2006-2310 (Jun. 23, 

2008). Note that there is no requirement for a sponsor to update the hypothesis of clinical superiority upon which an 

ODD is based. This sponsor seemingly wanted to know if OOPD would accept the hypothesis for clinical 

superiority as it anticipated later submitting a marketing application for which it wanted ODE. 156 FDA, Memorandum, Request for OOPD Opinion, DRU-2006-2310 (Mar. 3, 2009) [hereinafter Procysbi 2009 

memo]. 157 Id. 

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superiority; therefore, for the plausible hypothesis analysis at the ODD stage, unless a safety or 

efficacy concern is readily apparent to the agency absent receipt of safety and efficacy data in the 

sponsor’s application for approval, we generally assume that the drug provides comparable 

safety and efficacy.

158 At the approval stage, once such safety and efficacy data about the drug 

has been submitted in an application for marketing approval, that general assumption may or 

may not still apply, depending on what the submitted data shows. As we stated above, FDA may 

consider whether, for example, any adverse events documented within the drug’s safety data 

submitted in its application for approval diminish the advantages of, for example, a change in 

route or frequency of administration. In that respect, as explained above, safety concerns could 

inform the MCTPC analysis, but a safety concern present in a subsequent drug that was not 

present in the previous drug would not automatically disqualify the drug from obtaining a 

MCTPC finding. As stated above, clinical superiority analyses can “vary depending on many 

factors”159 and MCTPC “implies a more global assessment.”160 

In the case of Procysbi, upon approval, FDA found that Procysbi was clinically superior to the 

previously approved cysteamine product Cystagon based upon a MCTPC finding. The reviewer 

noted that the safety profile for Procysbi and Cystagon were similar “although a higher incidence 

of GI AEs were observed in the pivotal trial with delayed-release cysteamine in comparison to 

Cystagon.”161 If anything, this example shows that FDA has made a MCTPC finding upon 

approval where a drug was potentially less safe in at least one respect than the previously 

approved drug. 

Third, Jazz cites to a memo about the clinical superiority of BeneFix (coagulation factor IX 

(recombinant)) based on safety to previously approved factor IX products for the prevention of 

bleeding in hemophilia B.162 The memo considers whether a demonstration of greater safety 

under 21 CFR § 316.3(b)(3)(ii) requires a demonstration of a single safety advantage without 

regard for other safety considerations, or a demonstration of an overall increase in safety 

considering all aspects of safety.163 The memo does not conclude which standard is applicable, 

but finds that BeneFix provides greater safety under both standards.164 Each of the quotations 

158 Jazz also cites to FDA’s review of a request for ODD for Ravicti as another example of a requirement for 

comparable safety. See Sidley Slides, supra note 13, at 30. This is another example of FDA considering whether 

there is a plausible hypothesis of clinical superiority, not a demonstration of clinical superiority. In this example, 

FDA was concerned that the sponsor did not adequately explain why the new dosage form would represent a 

significant advantage over the previous dosage form, and FDA was concerned that the new dosage form could 

introduce new safety risks that were not accounted for in the sponsor’s hypothesis. See FDA, Review of Request for 

Orphan-Drug Designation, 05-2035, Glyceryl tri(4-phenylbutyrate) at 4 (Sep. 2, 2005) (“[I]t is unclear whether the 

glycerol byproduct of GT4P metabolism would pose its own safety risk in chronic use of the drug.”). Thus, a safety 

concern was readily apparent to the agency at the designation stage absent receipt of safety data in the sponsor’s 

application for approval. Without additional information about the potential safety of the drug and without 

additional information about the advantages of the drug, FDA was unable to determine there was a plausibly 

hypothesis of clinical superiority that would warrant ODE. 159 1992 Final Rule, 57 Fed. Reg. at 62078. 160 OOPD Rebif memo, supra note 36, at 3. 161 FDA, Review of an Amended Request for Orphan Drug Designation, 2006-2310, Procysbi (enteric-coated 

cysteamine) at 6 (May 28, 2013) [hereinafter Procysbi Exclusivity Memo]. 162 Jazz’s September 2021 Letter, supra note 11, at 2 footnote 4. 163 FDA, Memorandum, Orphan Product Status of BeneFix Coagulation Factor IX (Recombinant) (Jan. 21, 1997)

[hereinafter “BeneFix memo”]. 164 Id. 

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that Jazz cites are in the context of considering whether one safety advantage needs to be 

compared to safety concerns in order to make an assessment about greater safety under 21 CFR § 

316.3(b)(3)(ii). This is a different question than whether a drug can be clinically superior overall 

if it is less safe in one respect than the previously approved drug. The first quotation (i.e., “A 

significant risk associated with the new drug, that is not shared by the approved orphan, would 

likely render the new drug unapprovable”) is making the obvious point that significant new 

safety risks inform FDA’s evaluation of the fundamental safety of a drug for marketing approval 

under section 505 of the FD&C Act. The other two quotations (i.e., “it would be unreasonable to 

ignore an apparent risk that may outweigh the purported advantage of a new drug,” and “[s]ince 

there is no established risk to ‘outweigh’ the enhanced viral safety of BeneFix, the significant 

therapeutic advantage of BeneFix has not been outweighed by anything”) describe a situation 

where a safety risk associated with the subsequent drug would need to be considered in an 

overall assessment of safety, but not necessarily prevent a finding of greater safety. These 

quotations do not support Jazz’s position. 

Fourth, Jazz cites FDA’s determination that Signifor LAR (pasireotide)—a “long-acting release” 

formulation—made a MCTPC by providing once-per-month dosing as compared to twice-perday pasireotide to treat Cushing’s disease.165 Specifically, Jazz cites to the statement that 

“[t]here are no notable differences in the safety and efficacy profiles between the immediate 

release and long-acting formulations.”166 Again, stating that there are no notable differences in 

safety is not the same as stating that if Signifor LAR were less safe then it could not make a 

MCTPC. The exclusivity memorandum for Signifor LAR does not state that having comparable 

safety was a requirement to finding a MCTPC.167 

Overall, none of these examples support that FDA will consider a new drug to be clinically 

superior to a previously approved drug only if the new drug is at least as safe as the previously 

approved drug. 

Finally, Jazz tries to argue from a policy perspective that finding clinical superiority based on 

one significant advantage to patients even if the drug is less safe in some other measure would 

undermine the value of the ODE incentive.168 FDA disagrees. FDA interprets the purpose of the 

Orphan Drug Act to incentivize the development of better versions of drugs for the treatment or 

prevention of rare diseases or conditions. FDA believes that a drug may provide a significant 

therapeutic advantage to patients over a previously approved drug even if, for example, it is less 

safe in one measure than the previously approved drug. If new drugs were required to be at least 

as safe as the previously approved drugs, that would prevent a drug that provides a significant 

therapeutic advantage and otherwise meets FDA’s approval standard from coming to the market 

during the duration of the previously approved drug’s ODE. Implementing ODE requires 

balancing the need to incentivize the development of drugs for rare diseases or conditions and 

the need for patients to access better versions of such drugs. Requiring comparable safety on 

165 Sidley Slides, supra note 13, at 30. 166 Id. (quoting clinical superiority findings available at https://www fda.gov/industry/designating-orphan-productdrugs-and-biological-products/clinical-superiority-findings). 167 FDA, Exclusivity Memorandum, 09-2887 Signifor LAR (Apr. 3, 2019) [hereinafter Signifor Exclusivity Memo]. 168 Jazz’s September 2021 Letter, supra note 11, at 20. See also id. at 1 (“Because the concept of clinical superiority 

does not include regression, longstanding FDA policy requires the second-in-time drug to achieve at least

comparable safety as the earlier drug”).

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every measure before a drug can be found to be clinically superior would be an arbitrarily rigid 

requirement that would significantly delay approval of drugs with important therapeutic 

advantages for patients with rare diseases. 

FDA has adopted a more nuanced approach to clinical superiority, where a potential MCTPC is 

considered in the overall context of the safety, efficacy, and other features of the drug to 

determine if there is an overall significant therapeutic advantage of the new drug. As FDA has 

stated, MCTPC “determinations can be complex and encompass consideration of a number of 

factors that potentially implicate safety and effectiveness, which are evaluated on a case-by-case 

basis for each drug product.”169 Improvements to drugs are not necessarily linear, where every 

version of a drug builds off and is better in every respect than the one that came before. An 

improvement in one respect may benefit patients, even if there is a disadvantage in another 

aspect of the drug. As FDA has stated, “there can not [sic] be an infinite number of comparison 

criteria if this provision of the regulation is to be meaningful.”170 That is not to say that a small 

advantage provided by a new drug should overcome a large disadvantage also introduced by the 

drug; however, it would not serve the purpose of the Orphan Drug Act—and public health—if a 

drug were automatically disqualified from being clinically superior if it were less safe in one 

regard, while still meeting FDA’s approval standards for safety. 

B. Lumryz is Clinically Superior to Xyrem and Xywav

Avadel has not contended that Lumryz has greater effectiveness than Xyrem and Xywav, and 

DN1 has concluded that “[t]here is no evidence suggesting that the efficacy of Lumryz is 

different from that of Xyrem or Xywav.”171 Avadel did present arguments why it believes that 

Lumryz provides greater safety than Xyrem and Xywav,172 but OOPD concludes that Avadel has 

not demonstrated that Lumryz provides greater safety than either Xyrem or Xywav.173 DN1 has 

also concluded that Avadel’s arguments do not support a finding of greater safety of Lumryz 

over either Xyrem or Xywav.174 Because Avadel has not demonstrated either greater 

effectiveness or greater safety, Lumryz can be deemed to be clinically superior over Xyrem and 

Xywav only if Lumryz makes a MCTPC over the previously approved drugs.175 As explained

below, FDA concludes that Lumryz makes a MCTPC over Xyrem and Xywav. 

Based on a review of the arguments submitted by Avadel and Jazz, consultation with DN1,

176

and consultation with two board certified sleep experts in FDA,177 OOPD finds that Lumryz 

makes a MCTPC over Xyrem and Xywav by providing a once-nightly dosing regimen that 

169 2013 Final Rule, 78 Fed. Reg. at 35124. 170 See OOPD Rebif memo, supra note 36, at 3 (emphasis added). 171 DN1 Lumryz Consult, supra note 5, at 3. There has been no head-to-head study to directly compare Lumryz to 

Xyrem or Xywav.

172 See Avadel’s Exclusivity Claim, supra note 6; see also Avadel’s Exclusivity Claim Supplement, supra note 7. 173 For the purposes of this analysis, OOPD will not include a response to each of Avadel’s claims of greater safety. 

OOPD ultimately finds Lumryz to be clinically superior to Xyrem and Xywav based on making a MCTPC, and 

Avadel’s arguments about greater safety do not factor into the MCTPC finding.

174 DN1 Lumryz Consult, supra note 5, at 3. 175 21 CFR § 316.3(b)(3)(iii). 176 DN1 Lumryz Consult, supra note 5. 177 See Sleep Expert Consult, supra note 5. 

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avoids a nocturnal arousal to take a second dose. Crucial to this finding is that the three oxybate 

products are for the treatment of symptoms of narcolepsy—a chronic sleep disorder. The 

purpose of oxybate treatment is to consolidate a narcoleptic’s sleep to improve daytime 

symptoms of EDS and cataplexy.178 As explained in more detail below, waking up to take a 

second dose of Xyrem and Xywav is antithetical to the goal of improving sleep. This is 

compounded by the fact that narcolepsy is a chronic condition and patients may need treatment 

for the remainder of their lives.

As explained by FDA’s sleep experts in greater detail in their consult, even with a single 

nocturnal arousal, there can be impairment of alertness and decline in cognitive performance the 

following day.179 It is known that disrupting sleep, even briefly, changes sleep architecture—the 

normal pattern of NREM and REM cycles requisite for daily restoration.180 As explained in 

section III.A of this document and by FDA’s sleep experts, when an arousal occurs (e.g., when 

waking up to take medication during the night after falling asleep), there is a shift in an EEG 

pattern—one that leads to a longer Stage W with alertness or consciousness, even if not 

remembered.181 The duration of time in Stage W necessary to take the second dose and fall back 

asleep is prolonged and will adversely impact WASO.182 In treating sleep disorders, including 

narcolepsy, the goal is to maximize the time in sleep and minimize wake time (i.e., minimize 

WASO).183 Hence, nocturnal arousals should be avoided—especially in those with sleep 

disorders—as the goal of treatment is to restore normal sleep architecture.184 

Xyrem and Xywav are administered in two divided doses, with the first dose taken at bedtime 

and second dose taken 2.5 to 4 hours later. FDA’s sleep experts have concluded that awakening 

to take a second dose of Xyrem or Xywav is not optimally supportive of the continual sleep 

necessary for narcolepsy patients to restore sleep architecture and daytime alertness with more 

normal functioning.185 Such dosing necessitates awakening from sleep, prompting a nocturnal 

arousal.

186 Both Xyrem and Xywav labeling explain that after a dose, it usually takes at least 5 

to 15 minutes to fall asleep, which means it usually takes at least 5 to 15 minutes to fall back 

asleep after taking the second dose.187 Awakening to take a second dose necessarily disrupts 

sleep and causes fragmented sleep.

188 A person with disrupted sleep cannot simply return to 

sleep and resume their normal sleep cycle.189 Disruption of sleep leads to the inability to enter 

Stage N3, or disruption of N3, and such individuals will revert back to Stage W and subsequently 

progress to Stage N1 sleep and so forth.190 So, upon taking a second dose of Xyrem or Xywav, 

178 Scammell, Treatment, supra note 77. 179 See Sleep Expert Consult, supra note 5, at 7-8; see also Cirelli, supra note 46. 180 Sleep Expert Consult, supra note 5, at 8; see also Philip, supra note 61, at 244-245. 181 Kirsch, supra note 48; see also Philip, supra note 61, at 244-245. 182 Sleep Expert Consult, supra note 5, at 5; see also Suni, supra note 62. 183 Sleep Expert Consult, supra note 5, at 5. 184 Id. at 6; see also Scammell, Treatment, supra note 77. 185 See Sleep Expert Consult, supra note 5, at 7. 186 Id. at 7 footnote 45 (“It is self-evident that an arousal occurs upon taking the second dose of Xyrem or Xywav 

because some degree of consciousness or alertness is needed for the voluntary movements involved in taking 

medicine”). 187 Xyrem 2023 Labeling, supra note 86, at section 2.3; Xywav 2023 Labeling, supra note 93, at section 2.4. 188 Sleep Expert Consult, supra note 5, at 5. 189 Sleep Expert Consult, supra note 5, at 8. 190 Id. at 6; see also Berry supra note 64, at 22-33.

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after the minimum 5-15 minutes to return to sleep, such sleep does not resume where the patient 

left off to take their medication.191 If patients do not intentionally awaken to take the second 

dose (e.g., by setting an alarm), the effect of the drug will wear off, and the patients may awaken 

anyway and need the second dosing to return to sleep.192 As explained above, the disruption 

changes sleep architecture and will increase WASO and is something to be avoided in the 

narcoleptic patient, if possible.193 

In contrast to Xyrem and Xywav, Lumryz is an extended-release formulation that is indicated to 

be administered once daily at bedtime. Importantly, patients on Lumryz do not need to wake 

mid-sleep to take a second dose. The dosing regimen of Lumryz “provides an opportunity for 

narcolepsy patients to achieve normal sleep architecture, which is not a possibility for a patient 

on Xyrem or Xywav who must either wake up to take a second dose (disrupting sleep 

architecture) or allow the drug to wear off after 2.5-4 hours (reverting patients back to their 

naturally occurring, disrupted sleep architecture).”194 This is medically relevant because the 

purpose of oxybate therapy is to improve sleep consolidation.195 Additionally, the benefit 

provided by the dosing regimen of Lumryz is germane to several of the factors that FDA may

consider when determining if a drug makes a MCTPC.196 Lumryz’s extended release properties

provide for longer periods between doses, which is significant not only because it reduces the 

nightly number of doses from two to one but also because it eliminates the need to awaken in the 

middle of sleep to take a second dose. FDA considers this to be significantly more convenient 

for patients, an advancement in the ease of drug administration, and a reduction in treatment 

burden. As explained by FDA’s sleep experts, patients taking Xyrem and Xywav typically 

prepare both doses before bed, may need to set an alarm to wake up at the proper time to take the 

second dose, and then may require 5-15 or more minutes to return to sleep. Aside from the 

medical benefits of not having to awaken to take a second dose already explained above, it is 

inherently more convenient, easier, and less burdensome for patients to forgo that process on a 

nightly basis. Importantly, this is in the context of a chronic neurological condition that requires 

potentially lifelong treatment. 

i. MCTPC Finding Consistent with Past Precedent

Our basis for finding a MCTPC for Lumryz is similar to FDA’s MCTPC finding for Procysbi. 

As introduced above, Procysbi is an enteric-coated cysteamine product that has ODD for the 

treatment of cystinosis. The ODD was based in part on a plausible hypothesis that enteric-coated 

cysteamine would be clinically superior to the previously approved cysteamine product, 

Cystagon, for the same disease based on safety by causing less nausea and vomiting.197 Procysbi 

191 Sleep Expert Consult, supra note 5, at 8. 192 Id. at 7. 193 Id. at 6. 194 Id. at 8. 195 Scammell, Treatment, supra note 77. 196 See, e.g., 2013 Final Rule, 78 Fed. Reg. at 35125 (“The following factors, when applicable to severe or lifethreatening diseases, may in appropriate cases be taken into consideration when determining whether a drug makes a 

major contribution to patient care: convenient treatment location; duration of treatment; patient comfort; reduced 

treatment burden; advances in ease and comfort of drug administration; longer periods between doses; and potential 

for self-administration”). 197 Procysbi Designation Memo, supra note 154. 

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was first approved on April 20, 2013, and to be eligible for ODE, FDA required a demonstration 

of clinical superiority over Cystagon. Cystagon was labeled to be dosed every six hours, 

whereas Procysbi was labeled to be dosed every 12 hours (a reduction of 50%).198 By requiring 

dosing every six hours, patients taking Cystagon would be required to awaken from sleep to take 

a dose in order to administer the drug as labeled.199 FDA concluded that many patients taking 

Cystagon were unable to follow the strict six-hour-dosing schedule, and that strict six-hourdosing was required for the drug to be clinically beneficial (by maintaining white blood cell 

cystine levels below 1.0 nmol/1⁄2 cystine/mg protein).200 FDA found that Procysbi made a 

MCTPC over Cystagon, because Procysbi is effective at 12-hour-dosing, and many patients are 

unable to follow Cystagon’s strict six-hour-dosing, especially due to the need to awaken from 

sleep to ensure a timely dose.201 Similar to Procysbi, Lumryz provides for 50% reduction in 

dosing frequency that eliminates the need to awaken to take a dose in order to achieve the 

medication’s intended benefit. 

ii. Consideration of Sodium Differences 

OOPD has also considered whether other relevant factors inform whether Lumryz makes a 

MCTPC over Xyrem and Xywav.202 Specifically, we considered the sodium differences 

between Lumryz and Xywav. At the recommended daily dose of 6 g to 9 g, Lumryz contains 

approximately 1,100 mg to 1,640 mg of sodium whereas Xywav contains 87 mg to 131 mg. 

At the recommended daily dose of 6 g to 9 g, Xyrem and Lumryz both have the same sodium 

content (approximately 1,100 mg to 1,640 mg). The difference in sodium content between 

Xywav and Xyrem was explained in a DN1 consult for OOPD’s Xywav ODE determination: 

Given the differences in sodium content between Xywav and Xyrem, Xywav is safer and 

thus clinically superior to Xyrem in the following: all patients with narcolepsy; the 

substantial proportion of the narcolepsy population that is salt-sensitive (i.e., individuals 

who have greater changes in blood pressure with changes in salt intake than those who 

are not salt sensitive, representing about 50% of the general population); the substantial 

proportion of the narcolepsy population that is hypertensive (about 30% of the general 

population is hypertensive); and the substantial proportion of the narcolepsy population 

(39%) who cannot be prescribed Xyrem due to co-existing medical conditions that can be 

made worse as a result of the high sodium content of Xyrem.203

This division consult also states: 

198 Procysbi Exclusivity Memo, supra note 161, at 9-10. 199 Id at 5. 200 Id. at 9. 201 Id. at 10. The reviewer also observed that the safety profile for Procysbi and Cystagon were similar “although a 

higher incidence of GI AEs were observed in the pivotal trial with delayed-release cysteamine in comparison to 

Cystagon.” Id. at 6. The clinical superiority finding for Procysbi reflects multiple MCTPC factors, such as longer 

period between doses, increased ease of administration, and reduced treatment burden. 202 See OOPD Rebif memo, supra note 36, at 3 (“an assessment of the safety or effectiveness of the new form of the 

subsequent product might be considered in determining whether the drug made a major contribution to patient 

care”).

203 DN1 2020 Xywav Consult, supra note 99, at 6.

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The relationship between daily salt intake and cardiovascular morbidity is widely 

accepted, as is the need for salt intake to be generally restricted and not only in subjects 

with conditions such as hypertension, cardiac failure, and impaired renal function. The 

difference in sodium content between Xywav and Xyrem is both substantial and 

clinically meaningful when daily sodium intake requires restriction in patients who 

concomitantly have conditions such as cardiac failure, hypertension, and renal 

impairment. Xywav rather than Xyrem will be the medication of choice in such patients. 

Such patients, especially those with hypertension, may constitute a significant proportion 

of those with cataplexy and excessive daytime sleepiness in narcolepsy. The difference in 

sodium content between Xywav and Xyrem is also very likely to be clinically meaningful 

in all patients with narcolepsy, including those who are salt sensitive.204

OOPD found Xywav to be clinically superior (within the meaning of the orphan-drug 

regulations) to Xyrem because the reduction of sodium “will be clinically meaningful in 

reducing cardiovascular morbidity in a substantial proportion of patients for whom the drug is 

indicated.”205 

OOPD acknowledges that the sodium content of Lumryz raises the same safety concern that was

present for Xyrem and that is not present with Xywav. The agency stated in the consult response 

quoted above that the difference in sodium content between Xywav and Xyrem is “very likely to 

be clinically meaningful in all patients with narcolepsy”206 and that “[g]iven the differences in 

sodium content between Xywav and Xyrem, Xywav is safer and thus clinically superior to 

Xyrem in [. . .] all patients with narcolepsy.”207 The logic of these statements, if extended here, 

would mean that the difference in sodium content between Xywav and Lumryz is likely to be 

clinically meaningful in all patients with narcolepsy and that Xywav is safer than Lumryz in all 

such patients, albeit based solely on one specific measure, i.e., reduced sodium. Nonetheless, 

FDA has concluded that Lumryz is clinically superior to Xywav as a MCTPC given the benefit 

of Lumryz’s once-nightly dosing despite Xywav’s greater safety due to reduced sodium. First, 

as explained above, there is no requirement for comparable safety when making a MCTPC 

finding, and finding clinical superiority based on one parameter — greater safety, greater 

efficacy, or a MCTPC — is sufficient to meet the clinical superiority standard.

208 Second, for 

the reasons explained below, we believe that the benefit of Lumryz’s once-nightly dosing 

outweighs the safety concern raised by its increased sodium content for a substantial number of 

narcolepsy patients. Neither the statute nor regulations require a MCTPC to benefit the entire 

patient population for which a drug is intended. 

Although it is widely accepted that individuals should limit sodium intake generally, the warning 

in Lumryz’s labeling regarding sodium is directed only at “patients sensitive to sodium intake” 

204 Id. at 9-10. 205 FDA, Clinical Superiority Findings, available at https://www fda.gov/industry/designating-orphan-product-drugsand-biological-products/clinical-superiority-findings. 206 DN1 2020 Xywav Consult, supra note 99, at 10. 207 Id. at 6. 208 As OOPD stated in the Rebif example above, for one drug to be clinically superior in one parameter, it does not 

also need to be at least equal in all others. See OOPD Rebif memo, supra note 36, at 3.

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such as “those with heart failure, hypertension, or renal impairment.”209 For narcolepsy patients

who are not sensitive to sodium intake, OOPD concludes that a once-nightly dosed oxybate drug 

will provide a significant therapeutic advantage. It is true that patients who are not sensitive to 

sodium could also benefit from a reduction in sodium, but we consider the benefit offered by 

once-nightly dosing to outweigh the risk of increased sodium intake in such patients because

having to wake up to take a second dose is antithetical to oxybate’s goal of improving sleep; 

disrupting sleep contributes to chronic sleep loss, which is well known to cause reduced 

performance, increased risk for accidents and death, and detrimental effects on both 

psychological and physical health; and there are other ways such patients may reduce sodium in 

their diet.

210 For narcolepsy patients who are sensitive to sodium, healthcare practitioners would 

need to weigh the benefits of once-nightly dosing against the severity of the patient’s sodium 

sensitivity and the nature of their comorbidities to determine whether, in the practitioners’

judgment, use of Lumryz or Xywav was appropriate. For certain sodium-sensitive patients with 

narcolepsy, the benefit offered by once-nightly dosing would outweigh the risk of increased 

sodium intake for the same reasons (e.g., having to wake up to take a second dose is antithetical 

to oxybate’s goal of improving sleep; disrupting sleep contributes to chronic sleep loss, which is 

well known to cause reduced performance, increased risk for accidents and death, and 

detrimental effects on both psychological and physical health; and there are other ways such 

patients may reduce sodium in their diet).211 

For a drug to make a MCTPC, the drug should provide adequate safety to meet the approval 

standard (not necessarily the same or greater safety as a previously approved drug). FDA has 

weighed the benefits and the risks of Lumryz and determined that the safety profile is adequate 

to meet the requirements for marketing approval.212 Thus, although Lumryz has an increased 

sodium burden compared to Xywav, the safety risk from such an increase is not significant 

enough to preclude Lumryz from meeting the requirements for marketing approval. The safety 

risk associated with sodium for Lumryz is mitigated by labeling with an appropriate warning and 

precaution for patients sensitive to high sodium intake,213 as has been done for Xyrem.214 

In summary, OOPD concludes that the benefits of Lumryz’s once-nightly dosing rise to the level 

of making a MCTPC because Lumryz’s dosing provides for oxybate therapy that does not 

involve disrupting or fragmenting sleep, whereas Xyrem and Xywav necessitate a nocturnal 

awakening to take a second dose, which disrupts sleep architecture in patients with known sleep 

209 Lumryz labeling, supra note 105, at section 5.8. 210 Sleep Expert Consult, supra note 5, at 2. Jazz argues that approving Lumryz would undermine FDA’s policy 

regarding the benefits of reducing daily sodium intake. Jazz’s September 2021 Letter, supra note 11, at 20. FDA 

acknowledges the importance of reducing sodium intake generally, and this determination does not erode that stance

merely because we have concluded that sodium can be reduced by other means for patients who would benefit from 

taking this drug. 211 We note that the DN1 Lumryz Consult explains that “the available safety data for Lumryz do not indicate that the 

higher sodium content of each dose of that drug is reflected in a greater incidence of adverse events than is observed 

with equivalent doses of Xywav.” DN1 Lumryz Consult, supra note 5, at 3. 212 DN1 Lumryz Consult, supra note 5, at 3 (“the safety profile of Lumryz meets the Agency’s standards for 

approval.”). See also OOPD Rebif memo, supra note 36, at 3 (“A more meaningful standard is a significant 

therapeutic benefit in terms of increased effectiveness and adequate safety, or increased safety and adequate 

effectiveness.”).

213 See Lumryz Labeling, supra note 105, at section 5.8. 214 See Xyrem 2023 Labeling, supra note 86, at section 5.8.

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disorder. This decision is based on consultations with DN1 and FDA sleep experts and relies on 

the scientific understanding about treating narcolepsy by minimizing nocturnal arousals and 

consolidating sleep. OOPD believes that the science supports a finding that the MCTPC 

provided by Lumryz over Xyrem and Xywav has been demonstrated.

V. Jazz’s Arguments Are Not Persuasive

A. Safety

Jazz argues that Lumryz does not provide greater safety than Xyrem and Xywav and is less safe 

than Xyrem and Xywav in several ways.215 As explained above, OOPD’s determination that 

Lumryz is clinically superior to Xyrem and Xywav is not based on Lumryz providing greater 

safety than Xyrem and Xywav. Therefore, OOPD has not responded to each safety argument 

from Jazz.

216 In addition, OOPD has acknowledged above that Lumryz has a higher sodium 

content than Xywav and addressed why Lumryz is still clinically superior to Xywav. Finally, as 

explained below, OOPD is not convinced by Jazz’s remaining arguments that there are additional 

ways that Lumryz is less safe than Xyrem and Xywav. 

First, Jazz argues that the risk of falls may be greater with Lumryz than with Xyrem and 

Xywav.217 Jazz characterizes its argument as speculation (“one can equally speculate about 

alternate scenarios in which nocturnal awakenings and falls increase due to [Lumryz’s] 

extended-release formulation”) and hypothesis (“[Lumryz] introduces its own hypothetical fall 

risks”).218 Jazz speculates that because Lumryz is an extended release formulation, if a patient 

were to awaken and get out of bed, the patient using Lumryz would have more active drug in 

their blood compared to Xyrem and Xywav and could be at a higher risk for falls.219 Jazz also 

states that Lumryz has “apparently higher rates of enuresis” (i.e., bedwetting), which may lead to 

more falls.220 Jazz’s claim is based on a cross-study comparison showing a higher rate of 

enuresis with Lumryz compared to Xyrem and Xywav. Cross-study comparisons refers to drug 

studies in which a given drug is independently investigated from a second drug and does not 

allow direct comparison of results from one study to the other. Inferences cannot be reliably 

drawn as the two study populations and conditions of each study may not be the same. OOPD 

consistently has rejected use of such comparisons to conclude one drug has a higher rate of an 

adverse event than another drug. Nevertheless, even if Lumryz were to have a higher rate of 

enuresis than Xyrem and Xywav, Jazz’s argument is based on speculation that enuresis may lead 

to falls, because the patient may wake up, get out of bed, and change their sheets.221 DN1 agrees 

215 Jazz’s September 2021 Letter, supra note 11, at 6-15. 216 See Jazz’s September 2021 Letter, supra note 11, at 6-15. These arguments include that the pivotal REST-ON 

study was not designed to detect superiority (at 7-8), that findings of greater safety for other drugs were based on 

more data than is available for Lumryz (at 8-9), that there is insufficient evidence to support that the risk of falls is 

reduced with Lumryz compared to Xyrem and Xywav (at 10-13), that there is insufficient evidence to support that 

Lumryz will have better rates of adherence than Xyrem and Xywav (at 13-15), and that there is insufficient evidence 

to support that Lumryz will have lower rates of diversion (i.e., illegally transferring the drug to another person) than 

Xyrem and Xywav (at 15).

217 Jazz’s September 2021 Letter, supra note 11, at 12-13. 218 Id. 219 Id. at 12. 220 Id. 221 Id. 

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that Jazz’s arguments are speculative and is not aware of any data to support their arguments.222 

Ultimately, as Jazz admits, its arguments are based on speculation and hypotheses, and there are 

no scientific data to support a conclusion that there is a higher risk for falls with Lumryz 

compared to Xyrem and Xywav. 

Second, Jazz argues that Lumryz may have worse adherence rates than Xyrem and Xywav.223 

Jazz states that patients taking Lumryz may decide to skip taking their medication on nights 

when they do not expect to get 8-10 hours of sleep before they need to awaken the next day, or 

on nights where they do not limit fluid intake or consume alcohol.224 Jazz contrasts this with 

patients taking Xyrem or Xywav who, according to Jazz, in similar situations may choose to 

forgo the second dose on a given night instead of forgoing oxybate treatment entirely on such a 

night.225 These assertions that Lumryz will have lower rates of adherence than Xyrem and 

Xywav appear to be based upon speculation,226 and we are unaware of any scientifically valid 

evidence to suggest that adherence should be different between the two drugs.227 

Third, Jazz speculates that Lumryz may have higher rates of diversion (i.e., illegally transferring 

the drug to another person) than Xyrem and Xywav.228 Jazz suggests without evidence that 

Lumryz has “greater concealability and ease of transport” compared to Xyrem and Xywav, 

which would make Lumryz easier to divert.229 Jazz also suggests without evidence that multiple 

doses of Lumryz can more easily be combined into a single, more powerful dose than Xyrem and 

Xywav.230 Jazz presents no evidence that Lumryz would be easier to conceal, transport, and 

combine into a large dose than Xyrem and Xywav, and FDA is not aware of any such data.231

Fourth and finally, Jazz argues that Lumryz is less safe than Xyrem and Xywav because the dose 

of Lumryz cannot be adjusted, whereas the dose of Xyrem and Xywav can be adjusted. 

Specifically, Lumryz comes in four dosage strengths: 4.5 g, 6 g, 7.5 g, and 9 g,232 and thus the 

dose of Lumryz can be adjusted to those four strengths. Xyrem and Xywav are oral solutions, in 

concentrations of 0.5 g per mL,233 and administered using a dosing syringe that measures dosing 

222 DN1 Lumryz Consult, supra note 5 at 6. 223 Jazz’s September 2021 Letter, supra note 11, at 14-15. 224 Id. at 14. 225 Id. 226 We also note that alcohol ingestion is contraindicated for all three medicines. 227 Jazz also argues: “FT218 patients who do take their medication in these scenarios may also be non-adherent and 

at greater risk. Patients who take their FT218 with less than 8-10 hours to spend in bed before arising the next 

morning will be at greater risk of next-day impairment. And patients who do not follow Avadel’s recommendation 

to limit fluid intake for ‘several hours before dosing,’ or who ingest alcohol, will be at greater risk of enuresis, bed 

exits, falls, serious respiratory depression, and death.” Jazz’s September 2021 Letter, supra note 11, at 14. The 

DN1 consult states, and OOPD agrees that: “This is again a speculative argument. There should not be a significant 

difference in the risks cited between Lumryz and Xywav/Xyrem, if those drugs are used as recommended in 

labeling.” DN1 Lumryz Consult, supra note 5, at 6. 228 Jazz’s September 2021 Letter, supra note 11, at 15. 229 Id. 230 Id. 231 DN1 Lumryz Consult, supra note 5, at 7. 232 Lumryz labeling, supra note 105, at section 3. 233 Xyrem 2023 Labeling, supra note 86, at section 3; Xywav 2023 Labeling, supra note 93, at section 3.

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35 

increments of 0.25 g.234 Jazz argues that the limited ability to dose adjust Lumryz makes it less 

safe than Xyrem and Xywav for patients who would need to adjust the dose, including patients 

taking the anti-epileptic medication divalproex, patients taking other central nervous system 

(“CNS”) depressants, and patients who are hepatically impaired.235 

Regarding patients taking divalproex sodium, no significant pharmacokinetic interaction between 

Lumryz and divalproex sodium was observed in a drug-drug interaction study conducted by 

Avadel, so Lumryz’s labeling does not include a specific dose reduction recommendation when 

Lumryz is co-administered with divalproex sodium.236 Therefore, a specific dose reduction 

recommendation, such as that present in Xyrem and Xywav’s labeling related to Xyrem and 

Xywav patients taking divalproex sodium, is not necessary for Lumryz patients also taking 

divalproex sodium. Although FDA concluded that a pharmacodynamic interaction between 

Lumryz and divalproex sodium cannot be ruled out given that both Lumryz and divalproex 

sodium are CNS depressants, it has determined that the description of the general risks 

associated with use of CNS depressants in section 5.1 of Lumryz’s labeling is sufficient to 

inform healthcare prescribers of the risks associated with using Lumryz with other CNS 

depressants, including divalproex sodium.237 

Regarding patients taking CNS depressants, the labeling for Xyrem, Xywav, and Lumryz have a 

contraindication for the use of some CNS depressants (i.e., alcohol and sedative hypnotics) with 

each of those drugs. The labeling for all three drugs contains the same warning that “Use of 

other CNS depressants may potentiate the CNS-depressant effects of” Xyrem/Xywav/and 

Lumryz,238 and a recommendation that “[i]f use of these CNS depressants in combination with” 

Xyrem/Xywav/Lumryz “is required, dose reduction or discontinuation of one or more CNS 

depressants” (including Xyrem/Xywav/Lumryz) “should be considered.”239 Therefore, a patient 

taking Xyrem or Xywav and another CNS depressant has the option to reduce the dose of 

Xyrem/Xywav or the other CNS depressant (along with the option to discontinue Xyrem/Xywav 

or the other CNS depressant). A patient taking Lumryz and another CNS depressant has the 

option to reduce the dose of Lumryz to one of the set doses below the maximum of 9 g (4.5 g, 6 

g, 7.5 g) or reduce the dose of the other CNS depressant (along with the option to discontinue 

Lumryz or the other CNS depressant). A patient taking Xyrem or Xywav and another CNS 

depressant may have more options for dose adjustment than a patient taking Lumryz and another 

CNS depressant, but this does not mean that Lumryz is less safe than Xywav and Xyrem in 

patients taking another CNS depressant. Lumryz’s labeling mitigates the risk posed by 

concurrent use of another CNS depressant by providing the same warning in section 5.1 as 

provided by Xyrem and Xywav. Lumryz patients have the option to reduce the dose of Lumryz 

to one of the set doses or reduce the dose of the other CNS depressant. Patients who cannot 

234 Xyrem 2023 Labeling, supra note 86, at Instructions for Use; Xywav 2023 Labeling, supra note 93, at 

Instructions for use.

235 Jazz’s September 2021 Letter, supra note 11, at 19-20. 236 DN1 Lumryz Consult, supra note 5, at 7. 237 See Clinical Pharmacology Review, NDA 214755 (October 14, 2021); see Addendum to Clinical

Pharmacology Review, NDA 214755 (May 24, 2022).

238 Xyrem 2023 Labeling, supra note 86, at section 7.1; Xywav 2023 Labeling, supra note 93, at section 7.1; and 

Lumryz Labeling, supra note 105, at section 7.1. 239 Xyrem 2023 Labeling, supra note 86, at section 5.1; Xywav 2023 Labeling, supra note 93, at section 5.1; and 

Lumryz Labeling, supra note 105, at section 5.1. 

FDA-OOPD-May23-POSTING-000035
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reduce the dose of the other CNS depressant and need to reduce the dose of oxybate below 4.5 g 

or at more precise increments than 1.5 g might not be able to use Lumryz but may be able to use 

Xyrem and Xywav. This in theory could be a disadvantage of Lumryz for this very particular set 

of patients (i.e., patients taking oxybate and another CNS depressant who cannot reduce the dose 

of the other CNS depressant and need to reduce the dose of oxybate below 4.5 g or at more 

precise increments than 1.5 g), but Jazz has provided no evidence to support and FDA is not 

aware of any such evidence that this population even exists.

240 

Finally, regarding patients who are hepatically impaired, Jazz’s September 2021 Letter states that 

“1.8% of U.S. adults have been diagnosed with liver disease,” and that “it is reported that 

diseases of the digestive system (including liver disease) are more frequently reported in patients 

with narcolepsy compared to the general population.”241 This statistic does not provide an

estimate of the number of narcolepsy patients with hepatic impairment, but according to DN1, 

patients with narcolepsy have not been reported to have coexisting hepatic impairment.242 

Nevertheless, for patients with hepatic impairment, the labeling for Xyrem and Xywav 

recommends that the starting dose should be reduced by half,243 whereas the labeling for Lumryz 

states that Lumryz “should not be initiated in patients with hepatic impairment because 

appropriate dosage adjustments for initiation of LUMRYZ cannot be made with the available 

dosage strengths.”244 However, the labeling also states that “[p]atients with hepatic impairment 

who have been titrated to a maintenance dosage of another oxybate product can be switched to 

LUMRYZ if the appropriate dosage strength is available.”245 Therefore, Lumryz is labeled for 

use by some patients with hepatic impairment, but not all such patients. This does not mean that 

Lumryz is less safe than Xyrem and Xywav in patients with hepatic impairment because when 

used as labeled, Lumryz should not be used in patients with hepatic impairment who cannot be 

switched to Lumryz. 

In summary, the limited ability to adjust Lumryz’s dosage compared to Xyrem and Xywav does 

not make Lumryz less safe than Xyrem or Xywav. At most, the increased ability to adjust the 

dose of Xyrem and Xywav compared to Lumryz provides a minor convenience. For the 

potential limited number of patients who require a lower or more adjustable dose (i.e., (1) 

patients taking oxybate and another CNS depressant who cannot reduce the dose of the other 

CNS depressant and need to reduce the dose of oxybate below 4.5 g or at more precise 

increments than 1.5 g, and (2) patients with hepatic impairment that cannot be switched to 

Lumryz), Lumryz may not be the right product for them. Nevertheless, given the paucity of 

evidence supporting the existence of such population, we still conclude that Lumryz makes a 

MCTPC over Xyrem and Xywav by providing a once-nightly dosing regimen. As discussed 

above, MCTPC requires a “global assessment” and there “can not [sic] be an infinite number of 

240 Jazz’s September 2021 Letter, supra note 11, at 19 footnote 104 states, “in the latest Xywav and Xyrem REMS 

Assessment Report, e.g., 6.2% of patients reported use of benzodiazepines, 4.6% reported use of muscle relaxants, 

and 4.3% reported use of opioid analgesics and subsequently received a shipment of Xyrem or Xywav.” This does 

not reflect a percentage of patients who cannot reduce the dose of the other CNS depressant and need to reduce the 

dose of oxybate below 4.5 g or at more precise increments than 1.5 g. 241 Jazz’s September 2021 Letter, supra note 11, at 19 footnote 104. 242 DN1 Lumryz Consult, supra note 5, at 8. 243 Xyrem 2023 Labeling, supra note 86, at section 8.6; Xywav 2023 Labeling, supra note 93, at section 8.6. 244 Lumryz Labeling, supra note 105, at section 8.6. 245 Id. 

FDA-OOPD-May23-POSTING-000036
37 

comparison criteria.”246 The advantage of Lumryz’s once-nightly dosing is a significant 

advantage for patients who can take Lumryz and rises to the level of a MCTPC. What is more, 

Jazz has not demonstrated any safety concerns regarding Lumryz compared to Xyrem and 

Xywav, aside from the previously discussed lower sodium of Xywav compared to Lumryz. 

OOPD has already factored in the safety risk associated with the differences in the content of 

sodium between Lumryz and Xywav, as discussed above, and concluded that Lumryz makes a 

MCTPC.

B. MCTPC

Jazz also raised several arguments why Avadel has not met the standard to demonstrate that 

Lumryz makes a MCTPC over Xyrem and Xywav. 

First, Jazz suggests that head-to-head comparative trials should be required for FDA to find that 

Lumryz makes a MCTPC.

247 We do not agree; comparative trials are not required for a 

demonstration of MCTPC. The definition of “clinically superior” in the regulation states that

demonstrating greater effectiveness requires direct comparative clinical trials “in most cases,” 

and that demonstrating greater safety requires direct comparative clinical trials “in some 

cases,”248 but similar or comparable language for a MCTPC is absent.

249 Consistent with the 

regulation, FDA does not require direct comparative clinical trials to demonstrate that a drug 

makes a MCTPC.250 Additionally, the types of factors that FDA considers when determining 

MCTPC (e.g., convenient treatment location; duration of treatment; patient comfort; reduced 

treatment burden; advances in ease and comfort of drug administration; longer periods between 

doses; and potential for self-administration)251 are not typically studied in a clinical trial for 

marketing approval. 

246 OOPD Rebif memo, supra note 36, at 3. 247 Jazz’s September 2021 Letter, supra note 11, at 15; see also Sidley Letter, supra note 12, at 9; see also Sidley 

Slides, supra note 13, at 31. 248 The clinical superiority findings for BeneFix and Xywav are two examples where FDA found greater safety 

without direct comparative trials. For BeneFix, FDA concluded that even without direct comparative trials, there 

was an established epidemiological understanding that certain viruses can be transmitted by plasma-derived 

coagulation factor IX preparations, and that because those viruses do not exist in the source material for BeneFix, it 

was reasonable to conclude that the risk of transmitting these viruses is removed for treatment with BeneFix 

compared to the previously approved drugs. See BeneFix memo, supra note 163, at 2. Similarly for Xywav, FDA 

concluded that even without comparative trials, Xywav was clinically superior to Xyrem based on the established

scientific knowledge that Xywav’s reduced sodium would be clinically meaningful in reducing cardiovascular 

morbidity as compared to Xyrem. See Xywav Exclusivity Memo, supra note 99. 249 21 CFR § 316.3(b)(3). 250 See, e.g., FDA, Exclusivity Memorandum DRU-2012-3825, Valtoco (diazepam nasal spray) (Jan. 10, 2020) 

(finding an intranasal spray formulation makes a MCTPC over a rectal gel formulation without head-to-head 

comparative trials, because rectal administration is inherently invasive for the patient and difficult to administer, 

whereas intranasal administration is inherently more comfortable); Signifor Exclusivity Memo, supra note 167

(finding an intramuscular injection dosed once monthly makes a MCTPC over a subcutaneous injection dosed twice 

daily without head-to-head comparative trials, because of the greatly reduced injections per month); FDA, 

Exclusivity Memorandum DRU-2015-5130, Ultomiris (ravulizumab-cwvz) (Sep. 4, 2020) (finding dosing every eight 

weeks makes a MCTPC over dosing every two weeks without head-to-head comparative trials, because of the heavy 

burden associated with each dose); Procysbi Exclusivity Memo, supra note 161 (finding dosing every 12 hours 

makes a MCTPC over dosing every six hours without head-to-head comparative trials, because many patients were 

unable to follow a strict six-hour-dosing, especially due to the need to awaken from sleep to ensure a timely dose). 251 2013 Final Rule, 78 Fed. Reg. at 35125. 

FDA-OOPD-May23-POSTING-000037
38 

Jazz points to quotations from the regulation preambles to suggest that head-to-head comparative 

trials should be required for FDA to find that Lumryz makes a MCTPC. Specifically, Jazz cites 

the 1992 Final Rule, where it states, “While comparative trials are, of course, preferred and will 

usually be required, it is possible that, in some circumstances, a demonstration of a major 

contribution to patient care can be made without such trials.”252 Although this comment in the 

preamble could suggest that findings of MCTPC will usually be supported by comparative trials, 

the statement makes clear that a demonstration of MCTPC does not require such trials.253 More 

importantly, in practice, FDA has not required comparative trials to support findings of 

MCTPC.254 Jazz also points to the 1992 Final Rule, where it states, “As stated, the kinds of data 

needed to demonstrate clinical superiority for purposes of the Orphan Drug Act will be the same 

as the kinds of data required to allow label claims of superiority.”255 In context, this quotation is 

discussing the final rule, and the words “[a]s stated” mean “as stated in the final rule.”256 As 

explained above, the final rule requires clinical trials “in most cases” to demonstrate greater 

efficacy, and “in some cases” to demonstrate greater safety, but does not require clinical trials for 

a MCTPC.257 Because the quotation is referring to what is stated in the final rule, it cannot be 

read to superimpose a requirement that there be clinical trials to demonstrate a MCTPC

particularly in light of text in the final rule that suggests otherwise.258 Additionally, in context, 

the quotation is responding to a comment on the proposed rule that suggested FDA require 

rigorous double-blind, head-to-head comparative clinical trials such as those required to support 

other comparative safety and efficacy claims.259 The comment only addressed types of studies 

for safety and efficacy claims. Thus, FDA’s response to the comment only addresses clinical 

superiority based on greater safety and efficacy. As stated above, in practice, FDA has not 

required comparative trials to support findings of MCTPC.260 Finally, if comparative trials were 

required to demonstrate a MCTPC, that would be inconsistent with FDA’s statements that 

MCTPC is judged on a case-by-case basis and that FDA may take into consideration factors, 

such as convenient treatment location and patient comfort. Comparative trials are not required to 

find that Lumryz makes a MCTPC. 

Second, Jazz argues that the standard for finding a demonstration of clinical superiority is higher 

than the standard for finding a plausible hypothesis of clinical superiority and that Avadel has 

not met that standard for Lumryz. Jazz states that a “mere hypothesis is not enough to support a 

252 Jazz’s September 2021 Letter, supra note 11, at 15 (quoting 1992 Final Rule, 57 Fed. Reg. at 62079); see also 

Sidley Slides, supra note 13, at 31. 253 To the extent the statement could also be read to be discussing clinical superiority generally, it is simply restating 

the commonly accepted preference for demonstrating clinical superiority through greater efficacy or greater safety 

using comparative clinical trials, yet a sponsor can also demonstrate clinical superiority through a MCTPC without 

such trials.

254 See supra note 250. 255 Sidley Letter, supra note 12, at 9 (quoting 1992 Final Rule, 57 Fed. Reg. at 62078). 256 See 1992 Final Rule, 57 Fed. Reg. at 62078. 257 21 CFR § 316.3(b)(3). 258 Jazz also cites to 21 CFR § 202.1(e)(6)(ii) regarding the level of evidence required for advertising claims. See 

Sidley Letter, supra note 12, at 9. The level of evidence required to make advertising claims comes from a different 

part of the regulation and is not connected to the level of evidence required to demonstrate clinical superiority for 

the purposes of the orphan-drug regulations. 259 See 1992 Final Rule, 57 Fed. Reg. at 62078. 260 See supra note 250.

FDA-OOPD-May23-POSTING-000038
39 

finding of clinical superiority,”261 because the standard for being eligible for ODE is higher than 

the “plausible hypothesis” standard and the sponsor bears the burden to demonstrate that its drug 

is in fact clinically superior to the previously approved drug.262 

As a threshold matter, FDA agrees that the standard for clinical superiority for approval and 

ODE eligibility is higher than the “plausible hypothesis standard” for ODD.263 Specifically, the 

condition of clinical superiority for ODE eligibility requires that a sponsor “demonstrate” clinical 

superiority,264 and “different drug” status for a drug that is otherwise same drug as one with 

ODE also requires a demonstration of clinical superiority.265 FDA has explained that the 

difference in standards is meant to meet the intent of the Orphan Drug Act by encouraging “the 

development of improved versions of existing drugs” by having a lower standard for designation, 

“while protecting any applicable orphan-drug exclusivity” by requiring an actual demonstration 

of clinical superiority to overcome such ODE.266

Jazz argues that Avadel’s evidence for clinical superiority is hypothetical and does not meet the 

demonstration standard.267 Jazz appears to base this argument on an assumption as to what 

evidence and arguments Avadel has submitted to FDA and what FDA has found compelling in 

demonstrating clinical superiority. Specifically, Jazz cites public statements from Avadel about 

market research concerning patient preference for a once-nightly formulation and prescriber 

surveys that dosing-related challenges are to blame for oxybate-eligible patients not taking 

oxybate.268 OOPD, however, is not relying on the cited market research and prescriber surveys 

in its determination that Lumryz makes a MCTPC, and therefore Jazz’s arguments about these 

sources are moot. 

The clinical superiority of Lumryz is not merely hypothetical. As explained above, the science

underlying sleep hygiene supports the finding that in the context of oxybate drugs for the 

treatment of narcolepsy, where the purpose of therapy is to promote sleep consolidation, a drug 

with once-nightly dosing that avoids disrupting sleep consolidation by avoiding a nocturnal 

awakening to take a second dose makes a MCTPC over the previously approved drugs for which 

the patient awakens and disrupts sleep consolidation to take a second dose. Awakening to take a 

second dose of Xyrem or Xywav fragments sleep and disrupts sleep architecture. If possible, 

this should be avoided in a narcoleptic patient. Sleep consolidation is the intended purpose of 

oxybate therapy. Lumryz provides a treatment option that avoids the need to awaken to take a 

second dose. Thus, based on its scientific expertise and consultation of the literature, FDA has 

determined that the clinical superiority of Lumryz has been demonstrated. 

261 Jazz’s September 2021 Letter, supra note 11, at 2; see also Sidley Slides, supra note 13, at 21. 262 Jazz’s September 2021 Letter, supra note 11, at 3. 263 21 CFR § 316.20(a). 264 Section 527(c)(1) of the FD&C Act. 265 2013 Final Rule, 78 Fed. Reg. at 35122 (“allowing the subsequent drug to be approved during the pendency of 

the already approved drug's exclusivity period (if any) . . . provided that clinical superiority is demonstrated upon 

approval”). 266 Id. 267 Jazz’s September 2021 Letter, supra note 11, at 16-18. 268 Id. at 16; see also Sidley Slides, supra note 13, at 31. 

FDA-OOPD-May23-POSTING-000039
40 

The type of evidence on which FDA is basing its finding of Lumryz’s demonstration of clinical 

superiority over Xywav and Xyrem is quite similar to the type of evidence on which FDA based 

its finding of Xywav’s demonstration of clinical superiority over Xyrem. FDA found Xywav 

clinically superior to Xyrem based on greater safety because Xywav provided less sodium than 

Xyrem, and scientific literature exists that shows reduced dietary sodium generally would be 

clinically meaningful in reducing cardiovascular morbidity in the general population.269 Jazz did 

not conduct a head-to-head trial to compare the safety of Xywav and Xyrem.270 Nevertheless, 

the underlying science supported that “[t]he relationship between daily salt intake and 

cardiovascular morbidity is widely accepted, as is the need for salt intake to be generally 

restricted.”271 That was sufficient for OOPD to conclude that Xywav was clinically superior to 

Xyrem, because, as OOPD explained, “although it has never been specifically and adequately 

investigated whether the sodium content of Xyrem increases cardiovascular risks in patients with 

narcolepsy, the general base of knowledge about the effects of sodium support that the amount of 

sodium in Xyrem would increase cardiovascular risks in patients with narcolepsy.”272 By similar 

logic, for Lumryz, FDA has found that the scientific knowledge of sleep hygiene and the 

importance of consolidating sleep to treat narcolepsy supports its finding that a drug that avoids a 

nocturnal awakening to take a second dose provides a significant therapeutic advantage over and 

above that provided by a drug that necessitates a nocturnal awakening to take a complete nightly 

dosage. 

Third, Jazz argues that Lumryz does not meet the standard for clinical superiority because the 

change from Xyrem and Xywav’s twice-nightly dosing to Lumryz’s once-nightly dosing does 

not meet the “high bar” to be considered a MCTPC.273 Jazz argues that because MCTPC 

represents a “narrow category”274 of “unusual cases,”275 FDA’s prior MCTPC findings have 

been based on “much more substantial quantitative and qualitative improvements” than 

Lumryz’s “50% decrease in dosing frequency relative to Xyrem and Xywav.”276 Jazz cites to 

two examples where FDA found a MCTPC for a drug going from twice-a-day dosing to oncemonthly dosing and a drug going from administration that took one hour to taking one minute.277 

FDA does not agree with Jazz’s arguments and finds that Lumryz’s benefit meets the narrow 

category of MCTPC. All MCTPC determinations are made on a case-by-case basis, and the 

nature and severity of the disease or condition is a relevant factor.278 More goes into a MCTPC 

determination than merely a quantitative assessment of the percentage reduction in dosing 

frequency. For Lumryz, the reduction in the number of doses makes a MCTPC because the 

dosing eliminates the need to awaken in the middle of sleep to take the second dose. This is 

relevant in the context of treating narcolepsy with oxybate because the goal of narcolepsy 

therapy is to enhance sleep consolidation; awakening to take a second dose works directly 

269 Xywav Exclusivity Memo, supra note 99, at 3. 270 Id. 271 Id. (quoting DN1 2020 Xywav Consult). 272 Xywav Exclusivity Memo, supra note 99, at 5. 273 Jazz’s September 2021 Letter, supra note 11, at 15-16. 274 Id., at 15 (quoting 1991 Proposed Rule, 56 Fed. Reg. at 3343). 275 Id. (quoting 21 CFR § 316.3(b)(3)). 276 Id. at 16. 277 Id. 278 1992 Final Rule, 57 Fed. Reg. at 62078. 

FDA-OOPD-May23-POSTING-000040
41 

against this goal. Furthermore, as noted above, our basis for finding a MCTPC for Lumryz is 

similar to our basis for FDA’s MCTPC finding for Procysbi. 

Fourth, and finally, Jazz argues that FDA should not consider Lumryz to make a MCTPC 

because FDA did not grant priority review for Lumryz’s marketing application.279 Jazz notes 

that the standard for priority review is similar to the standard for clinical superiority.280 A 

review designation type (standard or priority review) for a marketing application is determined 

on a case-by-case basis at the time that an application is filed based on the information and data 

available at the time the application is submitted.281 As described in the guidance for industry, 

Expedited Programs for Serious Conditions – Drug and Biologics (May 2014), “[a]n application 

will receive priority review designation if it is for a drug that treats a serious condition and, if 

approved, would provide a significant improvement in safety or effectiveness.”282 “Significant 

improvement” may be illustrated by the following examples: (1) evidence of increased 

effectiveness in treatment, prevention, or diagnosis of a serious or life-threatening condition; (2) 

elimination or substantial reduction of a treatment-limiting adverse reaction; (3) documented 

enhancement of patient compliance that is expected to lead to an improvement in serious 

outcomes; or (4) evidence of safety and effectiveness in a new subpopulation.283 

The clinical superiority standard, as described throughout this analysis, includes that “the drug 

provides a significant therapeutic advantage over and above an already approved or licensed 

drug in terms of greater efficacy, greater safety, or by providing a major contribution to patient 

care.”284 FDA makes clinical superiority determinations for the purposes of approval and ODE 

eligibility after the agency has conducted a full and substantive review of the relevant marketing 

application and determined if the drug meets the safety and efficacy requirements for approval; 

whereas, the priority review designation is made at the time of submission of the marketing 

application, based upon a “[p]reliminary review.”285 Although the concepts of “clinical 

superiority” in the orphan-drug context and “significant improvement” in the priority review 

context may have some practical overlap, the standard for demonstrating clinical superiority

differs from the standard for priority review designation; the analyses are conducted at different 

times in the review of a marketing application and involve different levels of data scrutiny. 

Given these differences, there are many reasons why FDA could deny priority review for a 

marketing application for a drug and find clinical superiority for that drug.286 FDA’s decision 

not to grant priority review for the Lumryz application is not inconsistent with its determination 

that Lumryz makes a MCTPC over Xyrem and Xywav. 

279 Jazz’s September 2021 Letter, supra note 11, at 16; see also Sidley Slides, supra note 13, at 34. 280 Sidley Slides, supra note 13, at 34. 281 See CDER’s Manual of Policies and Procedures 6020.3 Rev. 2, Review Designation Policy: Priority (P) and 

Standard (S) at 3-4, June 2013, https://www.fda.gov/media/72723/download. 282 Expedited Programs for Serious Conditions – Drug and Biologics (May 2014) at 2-3 (accessed at 

https://www.fda.gov/media/86377/download). 283 Id. 284 Section 527(c)(2) of the FD&C Act; see also 21 CFR § 316.3(b)(3). 285 MAPP 6020.3 Rev. 2, supra note 281, at 6. 286 The drug Valtoco (diazepam nasal spray) is another recent example where FDA granted standard review 

designation for an application but found clinical superiority over a previously approved otherwise same drug for the 

same indication or use upon approval. 

FDA-OOPD-May23-POSTING-000041
42 

In sum, FDA finds Jazz’s arguments about why Lumryz does not make a MCTPC over Xyrem 

and Xywav unpersuasive. 

VI. Conclusion 

For the reasons explained above, we have determined that Lumryz, which is dosed once nightly, 

is clinically superior to Xyrem and Xywav, which are dosed twice nightly. See 21 CFR § 

316.3(b)(3). Because Lumryz is clinically superior to Xywav and, therefore, not the “same drug” 

as Xywav under 21 CFR § 316.3(b)(14) and section 527(a) of the FD&C Act, Xywav’s 

unexpired ODE does not block marketing approval of Lumryz. Additionally, because of its 

clinical superiority to Xyrem and Xywav, Lumryz has met the condition set forth at section 

527(c) of the FD&C Act, and Lumryz is eligible for its own term of ODE for the treatment of 

cataplexy or EDS in adults with narcolepsy under section 527(a) of the FD&C Act. 

_________________________________ 

Sandra S. Retzky, D.O., J.D., M.P.H. 

Director 

Office of Orphan Products Development 

cc: 

Jazz Pharmaceuticals, Inc. 

Attn: Arthur Merlin d’Estreux 

Arthur.MerlindEstreux@jazzpharma.com 

ProPharma Group 

U.S. Agent for Flamel Ireland Ltd. dba Avadel Ireland 

Attn: Marla Scarola 

marla.scarola@propharmagroup.com 

Sandra 

Retzky -S

Digitally signed by 

Sandra Retzky -S 

Date: 2023.05.01 

09:58:53 -04'00'
MEMORANDUM 

 

 DEPARTMENT OF HEALTH AND HUMAN SERVICES 

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

Division of Neurology 1 (DN1)

Office of Neuroscience (ON)

Center for Drug Evaluation and Research

Date: May 1, 2023

From: Ranjit Mani, MD

Clinical Reviewer, DN1

Teresa Buracchio, MD

Deputy Director, ON1

Subject: Office of Orphan Products Development Consult Request #16-5302

NDA 214755 

Lumryz (Sodium Oxybate Extended-Release for Oral Suspension [FT218]) 

 Request for Orphan Drug Exclusivity 

 

To: Director

 Office of Orphan Products Development

 

 

Document Type: Consult 

Enclosed is the Division’s response to your request 

1 This consult memo was substantially reviewed and prepared by Teresa Buracchio in her former 

capacity as Director of the Division of Neurology 1. In her current capacity as Deputy Director of 

the Office of Neuroscience, she continues to be involved in the review and preparation of this 

consult and is authorized to sign this consult, among other things, for Lumryz.

FDA-OOPD-May23-POSTING-000043
Ranjit B. Mani, MD, HFD-120 Medical Review Page 2 of 9 

NDA 214755, Lumryz*, Avadel 

Review and Evaluation of Clinical Data

NDA (Serial Number) 214755

Sponsor: Avadel

Product: Lumryz*

Proposed Indication: Narcolepsy

Reviewer: Ranjit B. Mani, M.D.

*Sodium Oxybate Extended-Release for Oral Suspension (FT218)

1. Background

Avadel submitted an original New Drug Application (NDA), #214755, for Sodium 

Oxybate Extended-Release for Oral Suspension (FT218), which carries the 

proprietary name “Lumryz,” on December 15, 2020. This NDA seeks approval of 

Lumryz for the treatment of cataplexy and excessive daytime sleepiness in 

narcolepsy. The issue currently before the agency is whether Lumryz is clinically 

superior (as defined in the orphan-drug regulations) to Jazz’s approved oxybatecontaining product, Xywav, as well as Jazz’s other oxybate-containing product,

Xyrem. The answer to this question will inform whether Lumyrz can be approved 

and whether Lumryz is eligible for its own term of orphan-drug exclusivity (ODE). 

Jazz, Avadel, and their counsel have made multiple submissions to the agency 

regarding ODE and Lumryz’s approvability. This memorandum memorializes 

responses to questions posed by the Office of Orphan Products Development 

(OOPD) to the Division since NDA 214755 was submitted on December 15, 

2020, regarding Lumryz and responses to those questions. 

Whether Lumryz is clinically superior to Xywav and Xyrem was previously 

addressed by this Division in a consultation memorandum completed on August 

31, 2021 (appended to this memorandum). This current memorandum updates 

and supersedes that August 31, 2021 response after further refinement of OOPD 

and the Division’s thinking based on careful consideration of the legal, regulatory, 

and scientific issues raised by this question; information submitted by the 

sponsors of Lumryz and Xywav/Xyrem; and the agency’s own scientific expertise

and precedent. 

The following provides additional background information: 

• Currently, two products are approved for the treatment of cataplexy or 

excessive daytime sleepiness in patients 7 years and older with 

narcolepsy. These are Xyrem (sodium oxybate oral solution) and Xywav 

(a low-sodium oxybate oral solution formulation containing a mixture of 

calcium, magnesium, potassium, and sodium oxybates); the manufacturer 

of both formulations is Jazz Pharmaceuticals, Inc. Generic formulations of 

sodium oxybate oral solution have also been approved for the treatment of 

cataplexy or excessive daytime sleepiness in narcolepsy.

FDA-OOPD-May23-POSTING-000044
Ranjit B. Mani, MD, HFD-120 Medical Review Page 3 of 9 

NDA 214755, Lumryz*, Avadel 

• Lumryz was granted a tentative approval on July 18, 2022, for the 

treatment of cataplexy or excessive daytime sleepiness in adults with 

narcolepsy.

• While the currently-approved formulations of sodium oxybate, Xyrem and 

Xywav, are liquids, Sodium Oxybate for Extended-Release Oral 

Suspension (FT218; Lumryz) is a powder for oral suspension. Whereas 

the approved formulation Xyrem is administered in two separate doses 

nightly, separated by an interval of 2.5 to 4.0 hours, Sodium Oxybate for 

Extended-Release Oral Suspension (FT218) is administered once nightly.

• The maximum recommended doses of Xyrem and Xywav are each 9 

grams per night, as is the maximum recommended dose of Lumryz. The 

sodium content of the 9-gram doses of Xyrem, Xywav, and Lumryz is 

1640 mg, 131 mg, and 1640 mg, respectively.

2. OOPD Questions and DN1 Responses

1. Is there any evidence to suggest that the efficacy of Lumryz may be 

different from Xyrem or Xywav? If so, please elaborate.

DN1 Response

There is no evidence suggesting that the efficacy of Lumryz is different from that 

of Xyrem or Xywav.

2. Is there any evidence, including in Avadel’s submissions, to support

that Lumryz provides greater safety in a substantial portion of the 

target population when compared to Xyrem or Xywav?

DN1 Response

The available data do not indicate that Lumryz provides greater safety in a 

substantial proportion of patients in the target population (i.e., patients who have 

narcolepsy with cataplexy and/or excessive daytime sleepiness) than Xyrem or 

Xywav, despite the arguments provided by the applicant. In broad terms, the 

safety profiles of all 3 products (Lumryz, Xyrem, and Xywav) are not substantially 

different, but the sodium content of Lumryz is higher than that of an equivalent 

dose of Xywav and the same as that of an equivalent dose of Xyrem. To address 

this safety concern, Lumryz’s labeling includes a warning (similar to Xyrem’s 

labeling), which states: “LUMRYZ has a high sodium content. In patients 

sensitive to sodium intake (e.g., those with heart failure, hypertension, or renal 

impairment), consider the amount of daily sodium intake in each dose of 

LUMRYZ.” We note that available safety data for Lumryz do not indicate that the 

higher sodium content of each dose of that drug is reflected in a greater 

incidence of adverse events than is observed with equivalent doses of Xywav, 

which has a lower sodium content. The safety profile of Lumryz meets the

Agency’s standards for approval. 

FDA-OOPD-May23-POSTING-000045
Ranjit B. Mani, MD, HFD-120 Medical Review Page 4 of 9 

NDA 214755, Lumryz*, Avadel 

3. Does the review division consider Lumryz to be clinically superior 

based on a major contribution to patient care (MCTPC)? 

DN1 Response

In a prior consultation dated August 31, 2021, DN1 stated: “While the oncenightly regimen of Lumryz will be more convenient for patients than a twicenightly regimen, that attribute cannot be considered a [MCTPC].” Following that 

consultation, DN1 has reconsidered its conclusion in light of several factors, 

including scientific, legal, and regulatory considerations raised by OOPD and the

expert opinion of FDA’s sleep team, which is also memorialized in a separate 

consult response.

2 OOPD has clarified that MCTPC determinations include 

consideration of factors such as reduced treatment burden, advances in ease of 

drug administration, and longer periods between doses; that the orphan-drug 

regulations do not require a drug to be clinically superior for all patients for whom 

the drug is indicated; and that a drug does not need to have comparable safety to 

another drug to make a MCTPC over the other drug. OOPD has also made the 

Division aware of a previous MCTPC determination with delayed release 

cysteamine (Procysbi) for the treatment of cystinosis. In that case, FDA 

determined that Procysbi met the MCTPC standard based on dosing every 12 

hours compared to dosing every 6 hours for immediate release cysteamine. The 

need to awaken the patient to maintain an every 6-hour dosing regimen with 

cysteamine and the chronic nature of the disease were important considerations 

in that MCTPC determination. 

Previously, in its August 31, 2021 response, the Division did not fully consider the 

issues raised in the paragraph above. The Division has since carefully 

reconsidered whether Lumryz’s once-nightly dosing may rise to the level of a 

MCTPC in the setting of a chronic disease such as narcolepsy and now 

concludes that awakening to take medication on a nightly basis for a long 

duration of treatment (e.g., every night for the remainder of the patient’s life, 

because narcolepsy is a chronic condition) would have a significant negative 

impact on patient care and counteract the purpose of oxybate therapy. In 

particular, we note that FDA’s sleep team, based on a robust scientific review of

the literature and their own scientific expertise, have explained that Lumryz 

provides an opportunity for narcolepsy patients to achieve normal sleep 

architecture, which is not a possibility for a patient on Xyrem or Xywav who must 

either wake up to take a second dose (disrupting sleep architecture) or allow the 

drug to wear off after 2.5-4 hours (reverting patients back to their naturally 

occurring, disrupted sleep architecture). We agree with this conclusion. The 

delayed release cysteamine exclusivity memo also informs our reassessment of 

MCTPC. For that decision FDA considered that less frequent dosing eliminated 

the need to awaken to take a dose in a situation where the timing of the dose 

was critical to achieving the drug’s intended benefit. 

2 See generally Mahadevappa Hunasikatti MD FCCP and Nargues Weir MD FCCP FAASM 

ATSF, Consult request on Lumryz (Apr. 29, 2023) (“Sleep Expert Consult”).

FDA-OOPD-May23-POSTING-000046
Ranjit B. Mani, MD, HFD-120 Medical Review Page 5 of 9 

NDA 214755, Lumryz*, Avadel 

The Division also acknowledges the sodium content of Lumryz raises the same 

safety concern that was present for Xyrem and that is not present for Xywav. 

However, it is our opinion that the benefit of Lumryz’s once-nightly dosing 

outweighs the safety concern raised by its increased sodium content for a 

substantial number of narcolepsy patients. Although it is widely accepted that 

individuals generally should limit sodium intake, the warning in Lumryz’s labeling 

regarding sodium is directed only at patients sensitive to sodium intake such as 

those with heart failure, hypertension, or renal impairment. For narcolepsy 

patients who are not sensitive to sodium intake, it is our opinion that a oncenightly dosed oxybate drug will provide a significant therapeutic advantage. It is 

true that patients who are not sensitive to sodium could also benefit from a 

reduction in sodium, but it is our opinion that the benefit offered by once-nightly 

dosing outweighs the risk of increased sodium intake in such patients because, 

for example, having to wake up to take a second dose is antithetical to oxybate’s 

goal of improving sleep, and there are other ways such patients may reduce 

sodium in their diet.

3 For narcolepsy patients who are sensitive to sodium, 

healthcare practitioners would need to weigh the benefits of once-nightly dosing 

against the severity of the patient’s sodium sensitivity and the nature of their 

comorbidities to determine whether, in the practitioners’ judgment, use of Lumryz 

or Xywav was appropriate. For certain sodium-sensitive patients with 

narcolepsy, the benefit offered by once-nightly dosing would outweigh the risk of 

increased sodium intake for the same reasons (e.g., having to wake up to take a 

second dose is antithetical to oxybate’s goal of improving sleep, and there are 

other ways such patients may reduce sodium in their diet). 

 

Taking all of these factors into consideration and for the reasons explained 

above, DN1 has reconsidered its prior assessment dated August 31, 2021, and 

now concludes that Lumryz provides a MCTPC over Xywav and Xyrem. 

4. Risk of Falls. Can you address the arguments Jazz raised in its letter 

dated September 16, 2021 (“Jazz’s September 2021 Letter”) on pages 

12-13 that Lumryz may increase the risk of falls over Xywav? 

Specifically, is there any basis for thinking, as Jazz speculates, that 

“nocturnal awakenings and falls increase due to FT218’s extendedrelease formulation”? Is there any basis for thinking that “FT218 

patients who get out of bed will have sustained therapeutic blood 

levels of oxybate throughout the night, potentially putting them at 

higher risk of falls than with...Xywav’s immediate release 

formulations” or that “FT218’s apparently higher rates of enuresis 

may lead to more falls”?

3 We note that the sleep expert consult explains that disrupting sleep contributes to chronic sleep 

loss, which is well known to cause reduced performance, increased risk for accidents and death, 

and detrimental effects on both psychological and physical health. 

FDA-OOPD-May23-POSTING-000047
Ranjit B. Mani, MD, HFD-120 Medical Review Page 6 of 9 

NDA 214755, Lumryz*, Avadel 

DN1 Response

This is entirely speculative. We are unaware of data to support these statements. 

We note that our clinical superiority recommendation is not based on a claim of 

superior safety for Lumryz.

5. Adherence. Can you address the arguments on pages 13-15 of Jazz’s 

September 2021 Letter that “one can equally speculate that FT218’s 

extended-release formulation will result in reduced adherence 

compared to...Xywav”?

 

a. Is there any basis for thinking that Lumryz will result in 

reduced adherence compared to Xywav? Is there any basis 

for thinking that patients will be more likely to forgo taking 

Lumryz compared to Xywav in situations where they do not 

expect to be able to sleep for 8-10 hours, or if they had not 

been limiting fluid intake or had been ingesting alcohol? 

DN1 Response

This is also a speculative argument. We have no scientifically valid 

evidence to suggest that adherence should be different between 

the two drugs. Additionally, use of alcohol with oxybate is 

contraindicated in the PI. 

We also note that adherence did not factor into the Division’s 

clinical superiority determination described above. 

b. Is there any basis for thinking that “[p]atients who take their 

FT218 with less than 8-10 hours to spend in bed before arising 

the next morning will be at greater risk of next-day impairment 

[over Xywav]”? And is there any basis for thinking that 

“patients who do not follow Avadel’s recommendation to limit 

fluid intake for ‘several hours before dosing,’ or who ingest 

alcohol, will be at greater risk of enuresis, bed exits, falls, 

serious respiratory depression, and death”?

DN1 Response

This is again a speculative argument. There should not be a 

significant difference in the risks cited between Lumryz and 

Xywav/Xyrem, if those drugs are used as recommended in labeling.

6. Diversion. Can you address the arguments on page 15 of Jazz’s 

September 2021 Letter that there is an increased risk of diversion 

and abuse with Lumryz compared to Xywav? Is there any basis for 

thinking that it is easier to conceal and transport Lumryz sachets 

and that it would lead to more diversion compared to Xywav? Is 

there any basis for thinking that combining multiple Lumryz 

FDA-OOPD-May23-POSTING-000048
Ranjit B. Mani, MD, HFD-120 Medical Review Page 7 of 9 

NDA 214755, Lumryz*, Avadel 

sachets is easier than creating an equivalent dose of Xywav and that 

will lead to a greater risk of diversion and abuse?

DN1 Response

This is also a speculative argument. The Division is not making a clinical 

superiority recommendation for Lumryz based on superiority with regard to 

diversion. There is no evidence to suggest that Lumryz would be any different 

from Xywav in that regard. There is no reason to think that a sachet would be any 

easier to divert than a solution. Vials can be as easily transported as sachets, 

and a powder poured into a drink may dissolve less rapidly and be more 

noticeable than a solution.

7. Dose Adjustment. Can you address the arguments on pages 19-20 of 

Jazz’s September 2021 Letter that Lumryz is less safe than Xyrem 

and Xywav because patients cannot dose adjust Lumryz? 

DN1 Response

Lumryz comes in four dosage strengths: 4.5 g, 6 g, 7.5 g, and 9 g, and thus the 

dose of Lumryz can be adjusted to those four strengths. Xyrem and Xywav are 

oral solutions, in concentrations of 0.5 g per mL, and administered using a dosing 

syringe that measures dosing increments of 0.25 g. Jazz argues that the limited 

ability to dose adjust Lumryz makes it less safe than Xyrem and Xywav for 

patients who would need to adjust the dose, including patients taking the antiepileptic medication divalproex, patients taking other central nervous system 

(“CNS”) depressants, and patients who are hepatically impaired. We do not 

agree with these arguments.

Regarding patients taking divalproex sodium, no significant pharmacokinetic 

interaction between Lumryz and divalproex sodium was observed in a drug-drug 

interaction study conducted by Avadel, so Lumryz’s labeling does not include a 

specific dose reduction recommendation when Lumryz is co-administered with 

divalproex sodium. Therefore, a specific dose reduction recommendation, such 

as that present in Xyrem and Xywav’s labeling related to Xyrem and Xywav 

patients taking divalproex sodium, is not necessary for Lumryz patients also 

taking divalproex sodium. Although FDA concluded that a pharmacodynamic 

interaction between Lumryz and divalproex sodium cannot be ruled out given that 

both Lumryz and divalproex sodium are CNS depressants, it has determined that 

the description of the general risks associated with use of CNS depressants in 

section 5.1 of Lumryz’s labeling is sufficient to inform healthcare prescribers of 

the risks associated with using Lumryz with other CNS depressants, including 

divalproex sodium.4 

We note that the labeling for Xyrem, Xywav, and Lumryz have a contraindication 

for the use of some central nervous system (CNS) depressants (i.e., alcohol and 

4 See Clinical Pharmacology Review, NDA 214755 (October 14, 2021); see Addendum to Clinical

Pharmacology Review, NDA 214755 (May 24, 2022).

FDA-OOPD-May23-POSTING-000049
Ranjit B. Mani, MD, HFD-120 Medical Review Page 8 of 9 

NDA 214755, Lumryz*, Avadel 

sedative hypnotics) with each of those drugs. Aside from those CNS 

depressants contraindicated, Section 7.1 describes a potential pharmacodynamic 

effect where other CNS depressants may potentiate the CNS-depressant effects

of Xyrem, Xywav, or Lumryz. Section 5.1 in the labeling for Xyrem, Xywav, and 

Lumryz state that “[i]f use of these CNS depressants in combination with” Xyrem. 

Xywav, or Lumryz “is required, dose reduction or discontinuation of one or more 

CNS depressants” including Xyrem, Xywav, or Lumryz “should be considered.” 

Therefore, a patient taking Xyrem or Xywav and another CNS depressant has 

the option to reduce the dose of Xyrem/Xywav or the other CNS depressant 

(along with the option to discontinue Xyrem/Xywav or the other CNS 

depressant). A patient taking Lumryz and another CNS depressant has the 

option to reduce the dose of Lumryz to one of the set doses below the maximum 

of 9 g (4.5 g, 6 g, 7.5 g) or reduce the dose of the other CNS depressant (along 

with the option to discontinue Lumryz or the other CNS depressant). A patient 

taking Xyrem or Xywav and another CNS depressant may have more options for 

dose adjustment than a patient taking Lumryz and another CNS depressant, but 

this does not mean that Lumryz is less safe than Xywav and Xyrem in patients 

taking another CNS depressant. Lumryz’s labeling mitigates the risk posed by 

concurrent use of another CNS depressant by providing the same warning in 

section 5.1 as provided by Xyrem and Xywav. Lumryz patients have the option 

to reduce the dose of Lumryz to one of the set doses or reduce the dose of the 

other CNS depressant. Patients who cannot reduce the dose of the other CNS 

depressant and need to reduce the dose of oxybate below 4.5 g or at more 

precise increments than 1.5 g might not be able to use Lumryz but may be able 

to use Xyrem and Xywav. This in theory could be a disadvantage of Lumryz for 

this very particular set of patients (i.e., patients taking oxybate and another CNS 

depressant who cannot reduce the dose of the other CNS depressant and need 

to reduce the dose of oxybate below 4.5 g or at more precise increments than 1.5 

g), but Jazz has provided no evidence to support and FDA is not aware of any 

such evidence that this population even exists. 

The safety of these oxybate products in patients with hepatic impairment is 

addressed in Section 8.6 of their respective labeling. The labeling for Xyrem and 

Xywav recommends that the starting dose should be reduced by half, whereas 

the labeling for Lumryz states that Lumryz should not be initiated in patients with 

hepatic impairment because appropriate dosage adjustments for initiation of 

Lumryz cannot be made with the available dosage strengths. The labeling for 

Lumryz also states that patients with hepatic impairment who have been titrated 

to a maintenance dosage of another oxybate product can be switched to Lumryz

if the appropriate dosage strength is available. Therefore, Lumryz is labeled for 

use by some patients with hepatic impairment but not all such patients. Patients 

with narcolepsy have not been reported to have coexisting hepatic impairment, 

and Lumryz should not be less safe than Xyrem or Xywav in patients with hepatic 

impairment because when used as labeled, Lumryz should not be used in 

patients with hepatic impairment who cannot be switched to Lumryz.

FDA-OOPD-May23-POSTING-000050
Ranjit B. Mani, MD, HFD-120 Medical Review Page 9 of 9 

NDA 214755, Lumryz*, Avadel 

For the reasons described above, Lumryz is not less safe than Xywav for 

reasons related to dose adjustment. 

3. Summary Comments 

Our conclusion is that Lumryz provides a major contribution to patient care over 

Xywav. The basis for that opinion is explained above. 

 Ranjit B. Mani, M.D. 

 Medical Reviewer, DN1 

 Teresa Buracchio, M.D. 

 Deputy Director, ON 

 

rbm 

cc: 

HFD-120 

NDA 214755 

Ranjit B. Mani -

S

Digitally signed by Ranjit B. 

Mani -S 

Date: 2023.05.01 09:35:48 

-04'00'

Teresa 

Buracchio -S

Digitally signed by 

Teresa Buracchio -S 

Date: 2023.05.01 

09:48:41 -04'00'
MEMORANDUM 

 

 DEPARTMENT OF HEALTH AND HUMAN SERVICES 

 PUBLIC HEALTH SERVICE

 FOOD AND DRUG ADMINISTRATION

Division of Neurology 1

Office of Neuroscience 

Center for Drug Evaluation and Research

Date: August 30, 2021

From: Eric Bastings, MD

 Division Director (Acting)

Subject: Office of Orphan Products Development Consult Request #16-5302

NDA 214755: 

Lumryz (Sodium Oxybate Extended-Release for Oral Suspension [FT218])

 Request for Orphan Drug Exclusivity

 

To: Director

 Office of Orphan Products Development

 

 

Document Type: Consult 

Enclosed is the Division’s response to your request
Ranjit B. Mani, MD, HFD-120 Medical Review Page 2 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

Review and Evaluation of Clinical Data

NDA: 214755

Sponsor: Avadel

Product: Lumryz*

Proposed Indication: Narcolepsy

Material Submitted: Consultation Request

Date Of Request: 7/6/21

Date Request Received By Reviewer: 7/6/21

Date Review Completed: 8/30/21

Reviewer: Ranjit B. Mani, M.D.

*Sodium Oxybate Extended-Release for Oral Suspension (FT218)

1. Background

This consultation request has been received from the Office of Orphan Products 

Development (OOPD), and pertains to a request from the sponsor for orphan 

drug exclusivity for Sodium Oxybate Extended-Release for Oral Suspension 

(FT218), which carries the proprietary name “LumryzTM.” This request for orphan 

drug exclusivity for LumryzTM was submitted on December 15, 2020. 

An original New Drug Application (NDA), #214755, seeking the approval of 

LumryzTM for the treatment of cataplexy and excessive daytime sleepiness in 

narcolepsy is currently under review by the Agency. That application was also 

submitted on December 15, 2020, and included a copy of the request for orphan 

drug exclusivity that was submitted on the same date.

A supplement to the main request (dated December 15, 2020) for orphan drug 

exclusivity for LumryzTM was submitted on July 14, 2021, and is also currently 

under review by OOPD. That supplement was also submitted to NDA 214755 

and its contents will also be addressed in this consultative review. That

supplement is entitled “Exclusivity Claim – Supplemental Information in 

Demonstration of Clinical Superiority of FT218.”

Currently, two products are approved for the treatment of cataplexy or excessive 

daytime sleepiness, (both products) in patients 7 years and older with 

narcolepsy. These are Xyrem® (sodium oxybate oral solution) and XywavTM (a

low-sodium oxybate oral solution formulation containing a mixture of calcium, 

magnesium, potassium, and sodium oxybates); the manufacturer of both 

formulations is Jazz Pharmaceuticals, Inc. Generic formulations of sodium 

oxybate oral solution have also been approved for the treatment of cataplexy and 

excessive daytime sleepiness in narcolepsy.

While the currently-approved formulations of sodium oxybate, Xyrem® and

XywavTM, are liquids, Sodium Oxybate for Extended-Release Oral 

Suspension (FT218) is a powder for oral suspension. Whereas the 
Ranjit B. Mani, MD, HFD-120 Medical Review Page 3 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

approved formulation Xyrem® is administered in two separate doses 

nightly, separated by an interval of 2.5 to 4.0 hours, the sponsor anticipates 

that Sodium Oxybate for Extended-Release Oral Suspension (FT218) will be 

administered once nightly.

In this review, the names “LumryzTM,” “Sodium Oxybate Extended-Release for 

Oral Suspension,” and “FT218,” will be used interchangeably. The term 

“applicant” has also been interchangeably with sponsor.

2. Text Of Main Consultation Request

The full text of this consultation request, dated July 6, 2021, is copied verbatim 

below in purple font. That text is both comprehensive and self-explanatory.

Background: 

The Office of Orphan Products Development (OOPD) granted orphan drug designation 

to sodium oxybate extended-release oral suspension on 1/08/2018 for the treatment of 

narcolepsy. With input from the review division (consult dated 11/24/17), this 

designation was granted based on a plausible hypothesis that the drug may be clinically 

superior to the same drug that was already approved for the same indication because it 

“may be more safe due to the ramifications associated with the dosing regimen for the 

previously approved sodium oxybate in treating patients with narcolepsy.” On 

12/15/2020, the sponsor, Avadel, submitted a marketing application for sodium oxybate 

extended-release oral suspension, with the proposed trade name Lumryz, for the 

treatment of cataplexy and excessive daytime sleepiness in adults with narcolepsy (NDA 

214755). 

 

Another sponsor, Jazz, has received marketing approval for the same active moiety, 

oxybate, for use in the treatment of narcolepsy. Specifically, Xywav (calcium, 

magnesium, potassium, and sodium oxybates) was approved on 7/21/2020 and has 

orphan-drug exclusivity (ODE) until 7/21/2027 for the treatment of cataplexy or 

excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. 

In addition, Xyrem (sodium oxybate) was previously approved for the treatment of 

cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with 

narcolepsy. Xyrem has ODE only for the portion of the indication pertaining to pediatric 

patients until 10/26/2025. 

In order for Lumryz to receive marketing approval for the treatment of cataplexy and 

EDS in adults with narcolepsy, it must be clinically superior, as defined in the orphan 

drug regulations, to the previously approved same drugs, Xywav and Xyrem, for the 

same indication. If Lumryz is clinically superior to Xywav and Xyrem, it may also be 

eligible for its own 7-year period of ODE. For the purpose of orphan drug exclusivity, 

clinical superiority can be based on greater effectiveness, greater safety in a substantial 

portion of the target population, or a major contribution to patient care (MCTPC), with 
Ranjit B. Mani, MD, HFD-120 Medical Review Page 4 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

all else being equal (see definition below). Please note that for orphan drug exclusivity 

purposes we apply the definition of clinical superiority from the regulations below and 

do not apply the substantial evidence standard as is required for a labeling claim. 

Avadel submitted a request to the OOPD on 12/15/20 for orphan drug exclusivity for 

Lumryz based on clinical superiority over Xyrem and Xywav. The same request was also 

submitted to the NDA on the same date (see NDA 214755 eCTD Sequence Number 

0001). In this document, the sponsor contends that Lumryz is clinically superior to 

Xyrem and Xywav with respect to safety and it also provides a major contribution to 

patient care (MCTPC). Appendix 2 of Avadel’s submission contains several letters from 

Key Opinion Leaders in the field of narcolepsy and patient advocacy groups which 

support Avadel’s arguments. 

Safety: 

Avadel notes that both Xyrem and Xywav require a twice-nightly dosing regimen, once 

at bedtime and once again 2.5-4 hours later. In contrast, Lumryz is an extended-release 

formulation of sodium oxybate that is given once nightly and therefore obviates the 

need for awakening to take a second dose. Avadel argues that this provides a safety 

advantage for Lumryz because it reduces the risk of nighttime falls. This is due to the 

fact that patients that forcibly wake after receiving one dose of Xyrem may get out of 

bed, ambulate, and fall because of a drug-induced groggy or stuporous state. Also, 

because of the rapid onset of effects, patients are at risk of falls or other accidental 

injuries if the second dose of Xyrem is not consumed while they are in bed. To support 

their argument, Avadel has provided an analysis of cases of falls in patients receiving 

Xyrem that were reported to the FDA Adverse Event Reporting System (FAERS) 

database. Avadel indicates that for the time period from 1/01/03 to 6/30/20, there 

were 2,056 cases that reported a reaction of fall in patients receiving Xyrem, and they 

have reviewed 120 of these cases. Of these, there were 14 (11.67%) in which a patient 

experienced a fall after the second dose of Xyrem. Injuries reported include lacerations 

and various broken bones. In some cases following these injuries, Xyrem was 

discontinued or the dose was reduced. 

In addition, Avadel indicates that PK differences between these drugs result in Lumryz 

having lower rates of well-known adverse events compared to Xyrem. They have 

provided a summary of reported rates of nausea, vomiting, dizziness, somnolence, and 

tremor for Lumryz and Xyrem. Although it does not appear that these two drugs were 

compared in a head-to-head manner, and the orphan drug regulations do not 

necessarily require head-to-head studies to support clinical superiority based on safety, 

generally, the rates of nausea, vomiting, and dizziness provided appear to be lower with 

Lumryz versus Xyrem. 

Avadel also indicates that there is a risk of misuse associated with the second dose of 

Xyrem because patients are supposed to measure out both nightly doses prior to 
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NDA 214755, LumryzTM, Consultation 8/30/21

bedtime and place the second dose near the bed. They note that a child could consume 

the second dose if the child-resistant container is not used, the second dose could be 

stolen, or patients could accidently consume both doses. 

Another argument presented by Avadel related to safety concerns, illicit use and 

diversion. They note that Lumryz will be formulated as white granules while Xyrem is a 

clear to slightly opalescent oral solution. Avadel states that Lumryz will be cloudy in 

solution and both its appearance and gritty consistency should alert individuals if it has 

been added to their drink. They also note that Lumryz tastes salty and bitter; however, 

they do not describe the taste of Xyrem or Xywav, and they do not describe the 

appearance of Xywav. 

Avadel’s last argument regarding safety concerns sodium content in Lumryz, Xyrem, and 

Xywav. Lumryz contains a similar amount of sodium as Xyrem. Avadel argues that the 

reduced sodium in Xywav does not render Xywav clinically superior to Xyrem. These 

arguments have already been evaluated in DN1 consult responses to OOPD dated 

11/27/20 and 3/08/21 regarding Xywav. Avadel concludes that overall, the safety, 

efficacy, and quality of life issues related to the second dose of twice-nightly sodium 

oxybate present a greater risk to patients than sodium content, and each of these 

greater risks is significantly improved and addressed with the once-nightly formulation 

of Lumryz. 

Major Contribution to Patient Care: 

Avadel provides other arguments that appear to be aimed at making a case for Lumryz 

providing a MCTPC. The OOPD notes that a MCTPC can only be considered in cases 

where greater effectiveness or greater safety have not been demonstrated. To support 

their argument, Avadel references a survey of 1,350 individuals impacted by narcolepsy, 

the results of which were distributed at the September 24, 2013 FDA Meeting on Drug 

Development for Narcolepsy. This survey found that patients’ ideal therapy was “a drug 

that would provide consistent and adequate control of the daytime sleepiness without 

the hard crash and one that would require one dose taken at bedtime resulting in 8 

hours of restorative sleep.” Avadel also conducted a study using publicly available 

digital Xyrem and narcoleptic-related data from 9/01/17 to 10/15/19. Sources included 

things such as blogs, forums, message boards, social media outlets, and OpenFDA. Data 

are provided from this study regarding the volume and type of quality of life issues that 

are associated with the need for a second nightly dose of Xyrem, such as trouble waking 

up to take the second dose. 

Avadel also indicates that there is a food effect which appears to be more pronounced 

with Xyrem and Xywav compared to Lumryz. They note that both the Xyrem and Xywav 

labels instruct patients to take the first nightly dose at least two hours after eating. 

Examples are mentioned of patients reporting reduced effectiveness after taking Xyrem 

too close to a meal. Avadel states that Lumryz’s reduced food effect and subsequent 

impact on blood levels, could result in greater efficacy and improved quality of life. 
Ranjit B. Mani, MD, HFD-120 Medical Review Page 6 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

In addition, Avadel conducted a Discrete Choice Experiment (DCE) to quantitatively 

characterize the preferred treatment attributes of narcolepsy patients. This consisted of 

a 30-minute web-based survey of 75 narcolepsy patients that were past or current 

Xyrem users. This survey found that dosing frequency (once nightly vs. twice nightly) 

was the single most important attribute when selecting a narcolepsy treatment, and the 

most common reasons for overall product preference were lack of need to wake up in 

the middle of the night to take a second dose (48%), fewer side effects (46%), and ease 

of taking/handling (32%). 

The OOPD notes that most of the arguments provided regarding a MCTPC, suggest that 

Lumryz would provide greater convenience than Xyrem and Xywav, and that patients 

may prefer it over these other oxybate products. Improved convenience and patient 

preference alone may not rise to the level to support a claim of clinical superiority for 

the purpose of orphan drug exclusivity. However, given that narcolepsy is a chronic 

sleep disorder and requires long-term therapy, the impact that Lumryz’s once-nightly 

dosing may have on patient quality of life may be substantial enough to constitute a 

MCTPC. In addition, the fact that there is no second nightly dose for patients to 

potentially miss and effect the efficacy of the drug may also render Lumryz as a MCTPC 

compared to Xyrem and Xywav. 

In summary, one of the definitions of clinical superiority that is stated in the orphan 

drug regulations is greater safety in a substantial portion of the target populations. 

“Substantial” is not defined in the regulations. Thus, it is not necessary for a drug to 

provide greater safety in all of the indicated population in order for it to be considered 

clinically superior. This definition also recently served as the basis for finding Xywav 

clinically superior to Xyrem since the differences in the sodium content of these two 

products at the recommended doses will be clinically meaningful in reducing 

cardiovascular morbidity in a substantial proportion of patients for whom the drug is 

indicated. Among the arguments provided by Avadel, the OOPD finds most persuasive 

the argument for greater safety due to reduced fall potential with Lumryz compared to 

Xyrem and Xywav. It appears that there may be a substantial portion of the indicated 

population of adult patients with narcolepsy that may achieve greater safety with 

Lumryz due to its once nightly dosing compared to the twice nightly dosing required for 

Xyrem and Xywav. 

Consult Questions: 

1. Is there any evidence to suggest that the efficacy of Lumryz may be substantially 

different from Xyrem or Xywav? If so, please elaborate. 

2. Does the review division agree that Lumryz provides greater safety in a substantial 

portion of the target population when compared to Xyrem and Xywav? If so, what 

safety advantage does Lumryz provide? Please elaborate. (As a reminder, the orphan 

drug regulations do not require head-to-head studies for safety.) 
Ranjit B. Mani, MD, HFD-120 Medical Review Page 7 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

3. Does the review division agree with the sponsor that Lumryz has less potential for 

illicit use and diversion compared to Xyrem and Xywav? Please explain. 

4. Does the review division consider Lumryz to provide a major contribution to patient 

care (MCTPC) compared to Xyrem and Xywav? If so, on what basis? 

5. Are there any other issues not addressed above that the review division would like 

the OOPD to consider in its determination of eligibility for orphan-drug exclusivity for 

Lumryz? 

Regulations: 

21 CFR 316.3(b)(3) defines clinical superiority as follows: 

(3) Clinically superior means that a drug is shown to provide a significant 

therapeutic advantage over and above that provided by an approved drug (that 

is otherwise the same drug) in one or more of the following ways: 

(i) Greater effectiveness than an approved drug (as assessed by effect on a 

clinically meaningful endpoint in adequate and well controlled clinical trials). 

Generally, this would represent the same kind of evidence needed to support a 

comparative effectiveness claim for two different drugs; in most cases, direct 

comparative clinical trials would be necessary; or 

(ii) Greater safety in a substantial portion of the target populations, for example, 

by the elimination of an ingredient or contaminant that is associated with 

relatively frequent adverse effects. In some cases, direct comparative clinical 

trials will be necessary; or 

(iii) In unusual cases, where neither greater safety nor greater effectiveness has 

been shown, a demonstration that the drug otherwise makes a major 

contribution to patient care. 

3. Contents Of Review

The contents of this consultative review will be in the same consecutive order as 

below.

x Request for priority review designation for LumryzTM.

x Response to questions in original OOPD consultation request of July 6, 

2021.

x Supplement to request for orphan exclusivity: July 14, 2021.

x Summary comments.
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NDA 214755, LumryzTM, Consultation 8/30/21

4. Request For Priority Review Designation For LumryzTM

A request for priority review designation accompanied the original submission of 

NDA 214755. That request was denied by the Agency after full review of its 

contents. As many components of that request are pertinent to the current 

consultation, the Agency’s criteria for priority review designation, the contents of 

that request, and the Agency’s action in response to that request are further 

summarized below.

The full text of the applicant’s priority review request is available at the following 

link

\\CDSESUB1\evsprod\nda214755\0001\m1\us\12-cov-let\priority-reviewrequest.pdf

4.1 Criteria For Granting Priority Review Designation

The core criteria for granting priority review designation to a marketing 

application for a drug or biologic are as follows:

1. The product is intended to treat a serious condition.

2. The product if approved would provide a significant improvement in safety 

or effectiveness 

These criteria are discussed in more detail in an Agency Guidance for Industry 

publication entitled “Expedited Programs for Serious Conditions – Drugs and 

Biologics” (May 2014) available at:

https://www.fda.gov/media/86377/download

4.2 Summary Basis For Applicant’s Request For Priority Review 

Designation

The applicant’s request for priority review designation for LumryzTM was based 

on the following overall conclusion: the once-nightly dosing regimen for that 

product would provide a significant improvement in safety and effectiveness in 

the treatment of cataplexy and excessive daytime sleepiness in narcolepsy 

compared to currently available therapies, including Xyrem® and XywavTM.

The above overall conclusion was based in turn on the following summary 

assertions (for which additional data was provided in the request).

x A once-nightly dosing regimen, as with LumryzTM would remove the 

anxiety and sleep disruption resulting from the need to awaken to take a 

second dose (as is the case with Xyrem® and XywavTM).
Ranjit B. Mani, MD, HFD-120 Medical Review Page 9 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

x A once-nightly dosing regimen would be less likely to result in missed 

doses, and would thus improve effectiveness and quality of life, as 

compared with a twice-nightly regimen.

x The need to awaken at night to take a second dose (as with Xyrem® and

XywavTM) increases the risk of adverse events, such as falls. Since the 

Cmax of oxybate products may correlate with other adverse events such as 

nausea and vomiting, a second Cmax as occurs the twice-nightly 

formulations make increase the risk of those adverse events, too.

x Data from the key efficacy study of LumryzTM (Study CLFT218-1501; 

REST-ON) indicate that the better known adverse events associated with 

sodium oxybate are less frequent with LumryzTM than with Xyrem®.

x Data from a patient survey indicate a preference for a once-nightly dosing 

regimen (i.e., with LumryzTM) than for the twice-nightly regimen used for 

Xyrem® and XywavTM.

It is readily apparent that the arguments used by the applicant in support of the 

priority review designation request for LumryzTM were very similar to those used 

in support of the current request for orphan exclusivity currently under review.

4.3 Agency Action In Response To Request For Priority Review 

Designation

The Agency was not persuaded by the arguments used in support of the 

applicant’s request for priority review designation and in a letter dated February 

26, 2021, assigned this application a standard review.

5. Response To Questions In Original OOPD Consultation 

Request Of July 6, 2021

Please note that our responses to the question are based in part on our 

preliminary review of data submitted with NDA 214755, the review of which is 

ongoing, and of the available data for Xyrem® and XywavTM.

Question 1. Is there any evidence to suggest that the efficacy of Lumryz 

may be substantially different from Xyrem or Xywav? If so, please 

elaborate.

Division of Neurology 1 Response to Question 1

There is no evidence suggesting that the efficacy of LumryzTM is substantially 

different from that of Xyrem® or XywavTM.
Ranjit B. Mani, MD, HFD-120 Medical Review Page 10 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

Question 2. Does the review division agree that Lumryz provides greater 

safety in a substantial portion of the target population when compared to 

Xyrem and Xywav? If so, what safety advantage does Lumryz provide? 

Please elaborate. (As a reminder, the orphan drug regulations do not 

require head-to-head studies for safety.)

Division of Neurology 1 Response to Question 2.

The available data do not indicate that LumryzTM provides greater safety in a 

substantial proportion of patients in the target population (i.e., patients who have 

narcolepsy with cataplexy and/or excessive daytime sleepiness) than Xyrem® or 

XywavTM, despite the arguments provided by the applicant. Very limited 

conclusions, if any, can be drawn from the comparison of the frequency of 

specific individual adverse events seen with LumryzTM with those seen with 

Xyrem® that has been presented by the sponsor. That comparison is flawed for a

number of readily-evident reasons. In broad terms, the safety profiles of all 3 

products (LumryzTM, Xyrem®, and XywavTM) are not substantially different.

Question 3. Does the review division agree with the sponsor that Lumryz 

has less potential for illicit use and diversion compared to Xyrem and 

Xywav? Please explain. 

Division of Neurology 1 Response to Question 3

We are not persuaded by the applicant’s arguments that LumryzTM has 

meaningfully less potential for illicit use and diversion compared with Xyrem® and

XywavTM, based either on the appearance and taste of each these products, or 

on the administration of a once-nightly dose of LumryzTM versus two nightly 

doses of Xyrem® and XywavTM.

Question 4. Does the review division consider Lumryz to provide a major 

contribution to patient care (MCTPC) compared to Xyrem and Xywav? If 

so, on what basis?

Division of Neurology 1 Response to Question 4

While the once-nightly regimen of LumryzTM will be more convenient for patients 

than a twice-nightly regimen, that attribute cannot be considered a major 

contribution to patient care.

Question 5. Are there any other issues not addressed above that the review 

division would like the OOPD to consider in its determination of eligibility 

for orphan-drug exclusivity for Lumryz?

Division of Neurology 1 Response to Question 5
Ranjit B. Mani, MD, HFD-120 Medical Review Page 11 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

From the perspective of this Division, there are no other issues that appear to 

warrant further consideration by OOPD when determining the eligibility of 

LumryzTM for the grant of orphan drug exclusivity,

6. Supplement To Request For Orphan Exclusivity: July 14, 2021

As noted earlier, this supplement to the original request for orphan exclusivity for

LumryzTM is being primarily reviewed by OOPD. However, this Division has been 

asked to review and comment on this supplement in conjunction with the 

response to the original consultation request of July 6, 2021.

6.1 Summary Of Supplement To Original Request For Orphan Exclusivity

As already noted, this supplement is entitled “Exclusivity Claim – Supplemental 

Information in Demonstration of Clinical Superiority of FT218.”

A full link to the contents of this supplement is available at the link below:

\\CDSESUB1\evsprod\nda214755\0022\m1\us\13-admin-info\exclusivity-ode.pdf

The key observations and assertions made by the applicant in this supplement

are as follows.

x A proportion of the 67 patients who transitioned from twice-nightly Xyrem®

or XywavTM to once-nightly LumryzTM in an interim analysis of an ongoing

open-label uncontrolled study CLFT218-1901 reported the following while 

receiving the twice-nightly regimen: falls while taking the second nightly 

dose (6%), nausea and/or vomiting after taking the second nightly dose 

(23%), missing the second nightly dose at least once over a 3-month

(85%), and “anxiety related to the second nightly dose” (21%). 28 out of 

30 patients who had completed 3 months of stable dosing with FT218 

preferred the once-nightly regimen of LumryzTM to the twice nightly 

regimen of either Xyrem® or XywavTM.

x A market analysis of physicians experienced in prescribing Xyrem® and

XywavTM may have suggested that a once-nightly regimen may be 

preferred to a twice-nightly regimen by patients.

x Poor sleep quality, sleep interruption, short sleep duration, and other sleep 

disturbances may all be associated in themselves with an increased 

cardiovascular risk based on a review of the medical literature (further 

details are provided in this submission). A once-nightly dosing regimen, as 

with LumryzTM, is less likely to interrupt sleep than a twice-nightly regimen,

as with Xyrem® and XywavTM, which cannot result a normal sleep pattern.

Data from the efficacy study CLFT218-1501 included in NDA 214755 

indicate that patients receiving LumryzTM have an improvement in several 
Ranjit B. Mani, MD, HFD-120 Medical Review Page 12 of 12

NDA 214755, LumryzTM, Consultation 8/30/21

parameters that measure nocturnal sleep. Thus LumryzTM has the

potential to provide a cardiovascular safety benefit, unlike Xyrem® and

XywavTM which may be associated with an increased cardiovascular risk 

on account of the interruption in nighttime sleep associated with the need 

to taking a second dose.

6.2 Division Of Neurology 1 Comments 

The contents of this supplement suggest, not unexpectedly, that patients may 

prefer a once-nightly dosing regimen (as with LumryzTM) to a twice-nightly dosing 

regimen (as with Xyrem® and XywavTM).

Any conclusions that LumryzTM may have the potential for being associated with 

a lower cardiovascular risk than Xyrem® or XywavTM on account of being 

administered only once-nightly are at best highly speculative.

7. Summary Comments

In this Division’s opinion, no evidence has been provided by the applicant that 

LumryzTM is clinically superior to Xyrem® or XywavTM as defined in the orphan 

drug regulations [21 CFR 316.3(b)(3)].

Ranjit B. Mani, M.D.

Medical Reviewer

Eric Bastings, M.D.

Division Director (Acting)

cc:

HFD-120

IND 

Ranjit B. Mani -S

Digitally signed by Ranjit B. Mani -S 

DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 

ou=People, cn=Ranjit B. Mani -S, 

0.9.2342.19200300.100.1.1=1300122852 

Date: 2021.08.31 12:13:34 -04'00'

Eric P. 

Bastings -S

Digitally signed by Eric P. 

Bastings -S 

DN: c=US, o=U.S. Government, 

ou=HHS, ou=FDA, ou=People, 

0.9.2342.19200300.100.1.1=1300

158815, cn=Eric P. Bastings -S 

Date: 2021.08.31 14:01:43 -04'00'
1

Date: April 29, 2023

From: Mahadevappa Hunasikatti, MD FCCP

Nargues Weir, MD FCCP FAASM ATSF

Sleep Team/DSRA/OHT1/CDRH

Through: Rachana Visaria Ph.D.

Assistant Director/Sleep Team/DSRA/OHT1/CDRH

To: Sandra Retzky DO, JD, MPH

Director, Office of Orphan Product Development

OPCR: DRU 16-5302

Subject: Consult request on Lumryz (extended-release sodium oxybate) administered as 

an oral solution once at bedtime for treatment of cataplexy or excessive daytime 

sleepiness associated with narcolepsy. 

OOPD (“you”) have consulted the Sleep Team/DSRA/OHT1/CDRH for input on whether 

Lumryz (extended-release sodium oxybate), with once nightly administration, is “clinically 

superior” to Xywav and Xyrem based on being a “major contribution to patient care” or 

MCTPC. Specifically, you seek our opinion, as board certified sleep specialists, on whether 

Lumryz, with once nightly dosing, makes a MCTPC over Xywav and Xyrem, both with twice 

nightly dosing, and if so, why. We understand that other factors may also inform the agency’s 

MCTPC determination, and this memo considers solely Lumryz’s once nightly dosing. 

Summary Response

It is our opinion that Lumryz is clinically superior because it provides a significant therapeutic 

advantage over and above that of Xywav and Xyrem. The underpinning of our rationale is that

patients with narcolepsy, a sleep disorder, will not need to awaken from sleep to take a second 

dose of Lumryz—which is dosed only once at bedtime—unlike Xywav and Xyrem, which are 

both labeled for twice nightly dosing.1 From a therapeutic perspective, it is highly desirable to 

eliminate, or at least minimize, nocturnal arousals from sleep—especially for patients who have 

1 See Section 2.1, Adult Dosing Information, Xyrem labeling, (accessed at 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=926eb076-a4a8-45e4-91ef-411f0aa4f3ca); See Section 

2.1 Dosing Information in Adult Patients with Narcolepsy, Xywav labeling (accessed at 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e0ae43a-037f-42af-8e23-a0e51d75abe8).

Nargues A. 

Weir -S

Digitally signed by 

Nargues A. Weir -S 

Date: 2023.04.29 06:53:17 

-04'00'

Mahadevappa 

Hunasikatti -S

Digitally signed by 

Mahadevappa Hunasikatti -S 

Date: 2023.04.29 08:46:03 

-04'00'

Rachana 

Visaria -S

Digitally signed by 

Rachana Visaria -S 

Date: 2023.04.29 

10:44:41 -04'00'
2 

a sleep disorder and seek treatment.2 A nocturnal arousal from sleep to take a second dose of 

sleep medication will fragment sleep and disrupt sleep architecture.3, 4, 5

The goal of treatment for all sleep disorders—including narcolepsy—is to restore a normal sleep

pattern. To that end, not awakening the patient to take a second dose of sleep medication is 

highly preferable from a clinical standpoint. Therefore, a once nightly dose of oxybate, makes a 

MCTPC because Lumryz, as compared to Xywav and Xyrem, avoids an arousal from sleep and 

will help to minimize sleep disruption. 

Normal sleep

Adequate sleep is essential for humans as it physically and psychologically restores bodily 

functions.6 Without adequate sleep, humans function poorly and may die prematurely.

7

 Chronic 

sleep loss, sometimes called sleep debt, is well known to cause reduced performance, increased 

risk for accidents and death, and detrimental effects on both psychological and physical health.8

 

2 The American Academy of Sleep Medicine (AASM) defines “arousal” as a finding on a sleep study using an 

electroencephalogram (EEG) to view brain wave patterns. An arousal leads to wakefulness and is a type of sleep 

disturbance in which the person awakens, or shifts to lighter sleep, preventing progression to deeper more restorative 

sleep. Richard Berry, et. al, The AASM Manual for the Scoring of Sleep and Associated Events (ver 2.6) American 

Academy of Sleep Medicine (Jan 2020) at 46 (describing rules in adults that define arousals by certain EEG wave 

patterns and behavioral cues, e.g., eyes open, chin movement, etc. Arousals shift sleep stages, N2, N3, and R, back 

to stage N1 or stage Wake, and this fragments and disrupts sleep.). Awakening to take a second dose of oxybate, and 

having to set an alarm to do so (see fn 5 on AASM terminology defining arousal by Berry; see fn 27 on Xyrem and 

Xywav labeling) will cause sleep disruption and negatively impact sleep consolidation which is important for 

restorative sleep. 3 Douglas Kirsch, Stages and architecture of normal sleep, UpToDate (Sep 12, 2022) (explaining that “[s]coring of 

sleep stages occurs in 30-second epochs based on current American Academy of Sleep Medicine (AASM) scoring 

rules.”). See Richard Berry, et. al, Arousal rule, The AASM Manual for the Scoring of Sleep and Associated Events, 

Rules, Terminology and Technical Specifications, American Academy of Sleep Medicine (2020), version 2.6 at 46. 4 Richard Berry, et. al, Arousal rule, The AASM Manual for the Scoring of Sleep and Associated Events, Rules, 

Terminology and Technical Specifications, American Academy of Sleep Medicine (AASM) (2020), version 2.6 at 

46 (explaining that arousals are defined with EEG criteria during stages N1, N2, N3, or R and are based on “an 

abrupt shift of EEG frequency . . . that lasts at least 3 seconds, with at least 10 seconds of stable sleep preceding this 

stage.”). When an individual awakens to take a second dose of medicine an “arousal” occurs because “behavioral

cues, including open eyes [and] movement . . . demonstrates alertness”—a change in consciousness. See Douglas 

Kirsch, Stages and architecture of normal sleep, UpToDate (Sep 12 , 2022). These behavioral cues inevitably occur 

in order to take a second dose of medicine, and even if the awakening is not remembered, nonetheless, it will 

fragment or disrupt sleep and is counterproductive to the treatment of narcolepsy. 5 Douglas Kirsch, Stages and architecture of normal sleep, UpToDate (Sep 12, 2022) (stating that: “[s]leep is a 

rapidly reversible state of reduced responsiveness, motor activity, and metabolism. It is a phenomenon observed in 

all animals in some form; this universality suggests that the act of sleeping likely has some evolutionary relevance.

Humans spend approximately one-third of their life, or about eight hours per night, sleeping. The purpose of 

sleeping is poorly understood, however, and multiple theories exist. These theories include restoration, energy 

conservation, and memory consolidation.”) (internal citation omitted). 6 Kiran Maski, Insufficient sleep: evaluation and management, UpToDate (May 23, 2022) at 

https://www.uptodate.com/contents/insufficient-sleep-evaluation-andmanagement?search=sleep&source=search result&selectedTitle=1~150&usage type=default&display rank=1). 7 Chiara Cirelli, Insufficient sleep: Definition, epidemiology, and adverse outcomes, UpToDate (Oct 10, 2022) at 

https://www.uptodate.com/contents/insufficient-sleep-definition-epidemiology-and-adverse-outcomes). 

(explaining that “individuals may experience reduced performance, increased risk for accidents and death, and 

detrimental effects on both psychological and physical health.”). 8 Id. 

FDA-OOPD-May23-POSTING-000053
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Normal sleep architecture is characterized in adults as a progression of 90 to 120 minute sleep 

cycles starting with non-REM Stage 1 sleep (NREM or N1 sleep), then non-REM Stage 2 

(NREM or N2) sleep, then non-REM Stage 3 (NREM or N3) sleep, and ending in Rapid Eye 

Movement (REM or stage R) sleep.9

 “Stage R is characterized by the presence of rapid eye 

movements and . . . is a unique time of the night in that dreaming occurs during Stage R sleep.”10

After Stage R, the normal adult has a very brief return to stage Wake (stage W), in the transition

of going from cycle to cycle, though this awakening is not typically remembered, is normal and 

does not contribute to sleep fragmentation, sleep loss, or daytime sleepiness.11, 12 It is part of the 

normal structure of sleep.13 The normal sleep cyclical pattern repeats 4-5 times per night 

allowing sufficient time for all the purposes of sleep to be met.14 Cycling progression through 

these stages is the basic structural organization of normal sleep and is called “sleep 

architecture.”15

Each sleep stage has unique features. Stage N1 sleep is light sleep (easily arousable), Stage N2 

sleep is intermediate in depth (less light sleep), and Stage N3 is deep sleep, otherwise known as 

restorative sleep, slow-wave sleep (SWS), or delta sleep.16 Brain activity is low during Stage N3 

sleep, and importantly, many recovery functions in the body occur only in this stage of 

sleep.17 “For an average individual in their second decade, Stage N1 is 2–5% of the total sleep 

9 Douglas Kirsch, Stages and architecture of normal sleep, UpToDate (Sep 12, 2022) (accessed at 

https://www.uptodate.com/contents/stages-and-architecture-of-normal-sleep?source=history widget) (stating that 

“[s]coring of sleep stages occurs in 30-second epochs based on current American Academy of Sleep Medicine 

(AASM) scoring rules.” Figure 10 portrays a hypnogram [sleep study] of a 36-year-old man in a sleep laboratory 

and it “represents the movement of a patient through various sleep cycles over the course of a single night . . . .”). 10 James A. Rowley & M. Safwan Badr, Normal Sleep at 3-5 in Chapter 1, Essentials of Sleep Medicine a Practical 

Approach to Patients with Sleep Complaints, (Meir Kryger et al. eds., 6th ed. 2017) 11 See Figure 1.2, James A. Rowley & M. Safwan Badr, Normal Sleep at 5 in Chapter 1, Essentials of Sleep 

Medicine a Practical Approach to Patients with Sleep Complaints, (Meir Kryger et al. eds., 6th ed. 2017) (depicting 

normal sleep architecture which includes 4-5 sleep cycles per night with five progressive stages, beginning at stage 

W and ending in stage R before the cycle begins anew). 12 Douglas Kirsch, Stages and architecture of normal sleep, UpToDate (Sep 12, 2022) (explaining that: “[t]he 

polysomnogram is the primary tool for assessing sleep in the laboratory for both clinical and research purposes. 

During a polysomnogram, electroencephalography (EEG) and other sensors are used to categorize sleep in discrete 

stages.”).

13 M. A. Carskadon & W. C. Dement. Monitoring and staging human sleep, Chapter 2, in Principles and practice of 

sleep medicine, (Meir Kryger, et. al eds., 5th ed. 2011) at 12 (accessed at 

http://apsychoserver.psych.arizona.edu/jjbareprints/psyc501a/readings/Carskadon%20Dement%202011.pdf)

(explaining that “[b]rief episodes of wakefulness tend to intrude later in the night, usually near REM sleep 

transitions, and they usually do not last long enough to be remembered in the morning”.) 

14 C. S. Nayak, et. al, EEG Normal Sleep. (accessed at https://www.ncbi.nlm.nih.gov/books/NBK537023/) 

(explaining that “[i]n normal adults, each cycle lasts for about 90 to 120 minutes, and there are about 4 to 5 such 

cycles that occur during a normal 8 hour night sleep.”). 15 James A. Rowley and M. Safwan Badr, Normal Sleep, Chapter 1 at 3-5 in Essentials of Sleep Medicine

A Practical Approach to Patients with Sleep Complaints, 2e (M. Safwan Badr ed., 2022) (describing sleep 

architecture as “the organization of the sleep stages over the course of the night.”). 16 M. A. Carskadon & W. C. Dement. Monitoring and staging human sleep, Chapter 2, in Principles and practice of 

sleep medicine, (Meir Kryger, et. al eds., 5th ed. 2011) (accessed at 

http://apsychoserver.psych.arizona.edu/jjbareprints/psyc501a/readings/Carskadon%20Dement%202011.pdf) at 11

(explaining that “[i]nvestigators often refer to the combined stages 3 and 4 sleep as slow-wave sleep [SWS], delta 

sleep, or deep sleep.”). In the most current sleep terminology, Stage 4 is now part of Stage 3 and is no longer 

considered an independent sleep stage. 17 D-J Dijk, et. al, Regulation and functional correlates of slow wave sleep, Journal of Clinical Sleep Medicine 

(2009) (accessed at https://pubmed ncbi nlm nih.gov/19998869/ at 1 (stating that “[d]eep nonrapid eye movement 

FDA-OOPD-May23-POSTING-000054
4 

time, Stage N2 is 45–55%, Stage N3 13–23%, and Stage R is 20–25%.”18 Normally, the sleep 

cycles progress through the night with increasing time in Stage N3 during initial sleep cycles and 

increasing REM sleep in each later sleep cycle during the night.19 

Stage N3 sleep has a unique and important role in restoring the mind and body.20 With sleep loss 

or deprivation or interruption, one enters Stage N3 sleep earlier and with increased quantity 

during the night.21 Thus, the body attempts to achieve sleep equilibrium by rapidly restoring this 

critical stage of sleep. On polysomnography (PSG)—a diagnostic full sleep study with an 

electroencephalogram (EEG)—REM sleep is a time of active brain EEG waves and 

physiological instability characterized by somewhat irregular heart rate and breathing patterns.22, 

23 REM is associated with paralysis of all muscles except the essential respiratory muscles (the 

diaphragm).24

(NREM) sleep, also known as slow wave sleep (SWS), is considered to be the most restorative sleep stage and to be 

associated with sleep quality and maintenance of sleep.”). 18 James A. Rowley and M. Safwan Badr, Normal Sleep, Chapter 1 at 3-5 in Essentials of Sleep Medicine

A Practical Approach to Patients with Sleep Complaints (M. Safwan Badr, ed., 2nd ed. 2022). The second decade of 

life is often used as a standard or heuristic in sleep medicine literature. The percent of time spent in each sleep stage 

declines with age when adulthood is reached. See, also, Kirsch (explaining how “[s]leep architecture also varies 

across the lifespan.”); Figure 11: graphic representation of the changes of sleep as humans age. The graph portrays 

“age-related trends for stage 1 sleep, stage 2 sleep, slow wave sleep, rapid eye movement sleep, wake after sleep 

onset, and sleep latency (in minutes).” 19 See fn 13, Figure 2-7 at 11 (picturing a sleep histogram with the progression of sleep stages across a single night 

in a normal young adult). The text describes the ideal or average pattern of time spent per stage. 20 Lixia Chen, et. al, The association between sleep architecture, quality of life, and hypertension in patients 

with obstructive sleep apnea, Sleep and Breathing (2023) (accessed at https://doi.org/10.1007/s11325-022-02589-z

at 192 (explaining that “N3 or SWS sleep is considered the most ‘restorative’ type of sleep . . . .”). 21 Douglas Kirsch, Stages and architecture of normal sleep UpToDate (Sep 12, 2022) (accessed at

https://www.uptodate.com/contents/stages-and-architecture-of-normalsleep?search=stage%20N3%20sleep%20and%20sleep%20loss&source=search result&selectedTitle=1~150&usage

type=default&display rank=1 (explaining “[p]rior acute or chronic sleep deprivation may cause increases in stage 

N3 sleep and REM sleep."). See also M.A Carskadon and W. C. Dement Monitoring and staging human sleep, 

Chapter 2, in Principles and Practice of Sleep Medicine, (Meir Kryger, et. al eds., 5th ed. 2011) accessed at 

http://apsychoserver.psych.arizona.edu/jjbareprints/psyc501a/readings/Carskadon%20Dement%202011.pdf) at 12, 

15 (stating that “[t]he SWS pattern reflects the homeostatic sleep system, highest at sleep onset and diminishing 

across the night as sleep pressure wanes. . . . Therefore, with total sleep loss, SWS tends to be preferentially 

recovered compared with REM sleep, which tends to recover only after the recuperation of SWS”.). 22 Ye Zhang, Polysomnographic nighttime features of narcolepsy: A systematic review and meta-analysis, Sleep 

Medicine Reviews (Aug 2021) at 1 (stating that: [p]olysomnography . . . is the gold standard for objectively 

assessing sleep quantity and sleep quality.”). See also Carley, et. al Physiology of Sleep at 6 (explaining that: 

“[p]hysiologically, the gold standard for assessment of sleep and wake states is the laboratory polysomnogram 

(PSG)” and further describing the numerous noninvasive sensors are attached to a subject). 23 Douglas Kirsch, Stages and architecture of normal sleep, UpToDate UpToDate (Sep 12, 2022) (accessed at 

https://www.uptodate.com/contents/stages-and-architecture-of-normalsleep?search=stage%20N3%20sleep%20and%20sleep%20loss&source=search result&selectedTitle=1~150&usage

type=default&display rank=10; M. A. Carskadon & W. C. Dement. Monitoring and staging human sleep, Chapter 

2, in Principles and practice of sleep medicine, (Meir Kryger, et. al eds., 5e. 2011) (accessed at 

http://apsychoserver.psych.arizona.edu/jjbareprints/psyc501a/readings/Carskadon%20Dement%202011.pdf) at 3-4 

(explaining that REM sleep is characterized by bursts of rapid eye movements, muscle twitches and 

cardiorespiratory irregularities. “The mental activity of human REM sleep is associated with dreaming, based on 

vivid dream recall reported after approximately 80% of arousals from this state of sleep. . . . A shorthand definition 

of REM sleep, therefore, is an activated brain in a paralyzed body.”). 24 See James A. Rowley & M. Safwan Badr, Normal Sleep, Chapter 1 in Essentials of Sleep Medicine

A Practical Approach to Patients with Sleep Complaints, (ed. M. Safwan Badr, 2nd ed. 2022) at 5. 

FDA-OOPD-May23-POSTING-000055
5 

Arousals 

When an arousal occurs, e.g., to take medication during the night after falling asleep, there is a 

shift in an EEG pattern—one that leads to a longer stage W with alertness or consciousness, even 

if not remembered.

25 Both Xyrem and Xywav labeling explain that after a dose, it usually takes 

at least 5 to 15 minutes to fall asleep, which means it usually takes at least 5 to 15 minutes to fall 

back asleep after taking the second dose.26 Awakening to take a second dose necessarily disrupts 

sleep and causes fragmented sleep.

27, 28 That duration of time in stage W is prolonged and will 

adversely impact a clinical measure called Wake After Sleep Onset (WASO)—a metric of how 

much wakefulness happens in a night of sleep.29 In treating sleep disorders, including 

25 Douglas Kirsch, Stages and architecture of normal sleep, UpToDate UpToDate (Sep 12, 2022) (accessed at 

https://www.uptodate.com/contents/stages-and-architecture-of-normalsleep?search=stage%20N3%20sleep%20and%20sleep%20loss&source=search result&selectedTitle=1~150&usage

type=default&display rank=10 (explaining that arousals “bring[] the individual from deeper to lighter sleep or to 

wakefulness.” See also Pierre Philip, et. al, Sleep Fragmentation in Normals: A Model for Sleepiness Associated 

with Upper Airway Resistance Syndrome. Sleep (Apr 1994) at 244-245 (explaining that in an experiment simulating 

arousals in healthy young volunteers, “the mean duration of an EEG arousal was 11 seconds. Sleep architecture was 

significantly modified after sleep fragmentation [using the external stimulation]. There was a significant increase in 

stage 1 NREM sleep from a mean of 10.4 ± 8% to 23 ± 6%. . . . [D]espite prolongation of sleep to avoid sleep 

deprivation and a protocol set up to obtain sleep fragmentation with transient arousals only, the sleep architecture 

was significantly altered compared to the baseline night.”). This study demonstrates that even short arousals will 

significantly increase wakefulness and disrupt sleep leading to sleep fragmentation resulting with new daytime 

complaints of sleepiness. The authors state: “[t]his investigation thus indicates a progressive increase

in daytime sleepiness from morning to evening after 1 night of sleep fragmentation.” 26 Section 2.3 Important Administration Instructions for All Patients, Xyrem, (accessed at 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=926eb076-a4a8-45e4-91ef-411f0aa4f3ca) (the product 

labeling stating that “[p]atients will often fall asleep within 5 minutes of taking Xyrem, and will usually fall asleep 

within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. 

Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall 

asleep.) (emphasis added); Section 2.4 Important Administration Instructions for All Patients, Xywav, (accessed at 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e0ae43a-037f-42af-8e23-a0e51d75abe8) (explaining 

that “[p]atients will often fall asleep within 5 minutes of taking XYWAV, and will usually fall asleep within 15 

minutes, though the time it takes any individual patient to fall asleep may vary from night to night.” (emphasis 

added). 27 The term “arousal” is based on PSG—a test used to diagnose sleep disorders—which is performed at night and 

“nocturnal arousals” are those arousals that occur at night. The definition of “arousal” is derived from the AASM 

Scoring Manual v 2.6, page 19 and fn 3 supra, defines wakefulness as Stage Wake. Arousals will lead to 

wakefulness or lighter stage sleep. Wakefulness also refers to a clinical term of the state of not being asleep with 

varying degrees of consciousness. See Jonathan R.L. Schwartz & Thomas Roth, Neurophysiology of Sleep and 

Wakefulness: Basic Science and Clinical Implications, Current Neuropharmacology (2008) at 367, 370 (accessed at 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701283) (describing the states of sleep and wake as an “on-off 

switch” between these behaviors, called a “sleep-wake switch.” Per Schwartz and Roth: “[t]hese findings suggest 

that when the self-reinforcing properties of the circuitry are weakened, individuals shift back and forth between 

sleep and wakefulness more frequently as well.” See, also Figure 3 at 370—a schematic diagram of the “flip-flop 

switch model.” This scientific explanation means that sleep and wake are two distinct states, when one is “on” the 

other must be “off.” Arousals, like that for taking a second dose of oxybate, flips the switch from “off” to “on” and 

this undoubtedly will disrupt sleep, cause fragmented sleep, and sleep loss. 28 See fn 2 for the American Academy of Sleep Medicine’s definition of “arousal.” 29 What Is Wakefulness After Sleep Onset (WASO)? Sleep Foundation (accessed at 

https://www.sleepfoundation.org/sleep-studies/wakefulness-after-sleeponset#:~:text=Wakefulness%20after%20sleep%20onset%20is,their%20WASO%20is%2025%20minutes) 

(explaining that “[w]akefulness after sleep onset [WASO] is a measurement used to assess a person's sleep. It is the 

total number of minutes that a person is awake after having initially fallen asleep. For example, if someone wakes up 

once during the night and is awake for 25 minutes, their WASO is 25 minutes.”).

FDA-OOPD-May23-POSTING-000056
6 

narcolepsy, the goal is to maximize the time in sleep and minimize wake time. i.e., minimize 

WASO. 

Disruption of sleep leads to the inability to enter Stage N3, or disruption of N3, and such

individuals will revert back to Stage W and subsequently progress to Stage N1 sleep and so 

forth.

30 The disruption changes sleep architecture and will increase WASO. This disruption is 

something to be avoided in the narcoleptic patient, if possible. 

Narcolepsy

Narcolepsy is a disorder of REM intrusion into wakefulness.31 Sudden REM sleep onset during 

wakefulness causes loss of motor tone (sleep paralysis) along with a dream like state called 

cataplexy.

32 REM intrusion can also occur during sleep, disrupting the normal sleep architecture 

described above.33 Individuals with narcolepsy “generally fall asleep rapidly but can 

spontaneously awaken several times during the night and have difficulty returning to sleep. This 

sleep maintenance insomnia seems paradoxical in a disorder characterized by daytime sleepiness, 

and it may reflect a low threshold to transition from sleep to wakefulness.”34 REM intrusion 

shifts sleep stages and prevents sleep continuity (also called sleep consolidation), fragments 

normal sleep architecture, and prevents sufficient deep sleep (prevents N3 restorative sleep from 

occurring because the sleep stages keep shifting to lighter sleep).35 Often Stage N1 increases at 

the debt of Stage N3 sleep given the increased number of shifts between sleep stages.36 This is 

seen in many sleep disorders, including narcolepsy.37 This results in daytime sleepiness with the 

30 Richard Berry, et. al, Arousal rule, The AASM Manual for the Scoring of Sleep and Associated Events, Rules, 

Terminology and Technical Specifications, American Academy of Sleep Medicine (AASM) (2020), version 2.6 at 

22-32. 31 Thomas E. Scammell, Clinical features and diagnosis of narcolepsy in adults, UpToDate (Jul 12, 2022) (accessed 

at https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-narcolepsy-inadults?search=narcolepsy%20&source=search result&selectedTitle=1~120&usage type=default&display rank=1). 32 Thomas E. Scammell, Clinical features and diagnosis of narcolepsy in adults, UpToDate (Jul 12, 2022). 33 Imran Ahmed & Michael Thorpy, Narcolepsy and Idiopathic Hypersomnia, at 328 in Chapter 15 in Essentials of 

Sleep Medicine (M. Safwan Badr et. al, eds., 2nd ed. 2022) (explaining that “[t]he effects of narcolepsy can be 

considered a manifestation of REM sleep dissociation, with features of REM sleep that intrude into [the NREM 

stages of] sleep and wakefulness” , instead of progressing normally). 34 Thomas E. Scammell, Clinical features and diagnosis of narcolepsy in adults, UpToDate (Jul 12, 2022). 35 Michelle T. Cao, et. al, Narcolepsy: Diagnosis and Management (explaining that “[n]arcolepsy disrupts the 

maintenance and orderly occurrence of wake and sleep stages.”); Ye Zhang, Polysomnographic nighttime features of 

narcolepsy: A systematic review and meta-analysis, Sleep Medicine Reviews (Aug 2021) (accessed at 

https://pubmed.ncbi nlm nih.gov/33934047/) at 11 (stating that: “nighttime PSG changes . . . demonstrate[] poor 

sleep continuity and altered sleep architecture in narcolepsy. It has been suggested that some PSG changes in 

narcolepsy such as frequent SS [stage shifts] and short bouts of wakefulness occur primarily in the second NREM 

sleep episode which hinders slow wave activity and provides inadequate NREM intensity.”). Slow wave sleep only 

occurs in N3 and when SWS does not occur with enough intensity, an individual does not get restorative sleep. See

fn 18 (explaining that: “[d]eep nonrapid eye movement (NREM) sleep, also known as slow wave sleep (SWS), is 

considered to be the most restorative sleep stage and to be associated with sleep quality and maintenance of sleep.”). 36 Ye Zhang, Polysomnographic nighttime features of narcolepsy: A systematic review and meta-analysis. Sleep 

Med Reviews. (Aug 2021) (accessed at https://pubmed ncbi nlm nih.gov/33934047/) at 1 (stating “[m]eta-analyses

revealed significant reductions in sleep latency, sleep efficiency, slow wave sleep percentage, rapid eye movement 

sleep (REM) latency, cyclic alternating pattern rate, and increases in total sleep time, wake time after sleep onset 

(WASO), awakening numbers (AWN) per hour, stage shift (SS) per hour, N1 percentage, apnea hypopnea index, and 

periodic limb movement index in narcolepsy patients compared with [healthy controls]”) (emphasis added). 37 Zhang at 4 (explaining that a “meta-analysis revealed significantly decreased . . . SWS% . . . and increased . . . N1 

percentage” in narcolepsy compared with healthy controls.”). 

FDA-OOPD-May23-POSTING-000057
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consequences of sleep fragmentation or sleep deprivation, i.e., altered sleep architecture which 

may affect daytime performance.

38 

EDS is the most common and chronic symptom of narcolepsy.39 Per Scammell: “[t]he 

sleepiness may be so severe that patients with narcolepsy can rapidly doze off with little 

warning; these episodes are commonly referred to as ‘sleep attacks.’”40 Another symptom of 

narcolepsy, cataplexy, is an “emotionally-triggered transient muscle weakness” that can cause a 

patient to collapse.41 

Xyrem, Xywav, and Lumryz 

The FDA-approved labeling for Xyrem and Xywav instructs patients to awaken to take a second 

dose approximately 2.5 to 4 hours after initial administration and falling asleep.

42 If patients do 

not intentionally awaken to take the second dose (e.g., by setting an alarm), the effects of the 

drug will wear off, and the patients may awaken anyway and need the second dosing to return to 

sleep. It is our opinion that awakening to take a second dose of sleep medication, such as Xywav 

or Xyrem, is not optimally supportive of the continual sleep necessary to restore sleep 

architecture and daytime alertness with more normal functioning. 

Lumryz combines both short-acting and long-acting salts of sodium oxybate allowing once 

nightly dosing.43 Lumryz provides “a proprietary drug delivery technology . . . [and this] 

technology provides an early single peak, following a gradual decline in [oxybate] concentration

. . . The premeasured dosing packets contain a mix of immediate-release and controlled-release 

microparticles of [oxybate].”44 This formulation of oxybate provides a novel dosing 

characteristic of once nightly dosing, which in our expert opinion provides a MCTPC over the 

immediate-release formulations alone, i.e., Xyrem and Xywav. 

As stated above, Xyrem and Xywav are both dosed twice nightly, which means patients 

experience a nocturnal arousal to take the medication.45 Such arousals lead to awakening, i.e., 

consciousness, and this awakening disrupts sleep with the detrimental and harmful consequences 

that are known to occur with sleep loss.46 Even with a single nocturnal arousal, there can be 

38 Id. at 1 (stating “[n]arcolepsy . . . is one of the most common causes of excessive daytime sleepiness (EDS) and is 

associated with an increased risk of car accidents, occupational problems, and injuries.”). 39 Thomas E. Scammell, Clinical features and diagnosis of narcolepsy in adults, UpToDate (Jul 12, 2022). 40 Id. 41 Id. 42 Section 2.1, Dosage and administration, Xyrem labeling, (accessed at 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=926eb076-a4a8-45e4-91ef-411f0aa4f3ca); Section 2.1, 

Dosage and administration, Xywav labeling (accessed at 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e0ae43a-037f-42af-8e23-a0e51d75abe8). 43 Clete A. Kushida, et. al, Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a 

phase 3 randomized clinical trial in patients with narcolepsy, Sleep (Jun 2022) at 2 (accessed at 

https://pubmed.ncbi nlm nih.gov/34358324/). 44 Clete A. Kushida, et. al, Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a 

phase 3 randomized clinical trial in patients with narcolepsy. Sleep (Jun 2022) at 2 (accessed at 

https://pubmed.ncbi nlm nih.gov/34358324/). 45 It is self-evident that an arousal occurs upon taking the second dose of Xyrem or Xywav because some degree of 

consciousness or alertness is needed for the voluntary movements involved in taking medicine. 46 See fn 3, 5 supra. 

FDA-OOPD-May23-POSTING-000058
8 

impairment of alertness and decline in cognitive performance the following day.47 It is known 

that disrupting sleep, even briefly, changes sleep architecture—the normal pattern of NREM and 

REM cycles requisite for daily restoration.48 Nocturnal arousals should be avoided—especially 

in those with sleep disorders—as the goal of treatment is to restore normal sleep architecture.49 

It is incorrect to assume that a person with disrupted sleep can simply return to sleep and resume 

their normal sleep cycle. Rather, upon taking a second dose of Xyrem or Xywav, it may take at 

least 5-15 minutes to return to sleep—and such sleep does not resume where the patient left off 

to take their medication. Rather a new cycle of sleep must begin anew.50 Thus, this disruption to 

take a second dose of Xyrem or Xywav should be avoided, if possible. An oxybate product that 

is dosed once nightly provides an opportunity for narcolepsy patients to achieve normal sleep 

architecture, which is not a possibility for a patient on Xyrem or Xywav who must either wake 

up to take a second dose (disrupting sleep architecture) or allow the drug to wear off after 2.5-4 

hours (reverting patients back to their naturally occurring, disrupted sleep architecture).”51

Conclusion 

In summary, in our opinion, Lumryz provides a MCTPC over Xyrem and Xywav due to its once 

nightly dosing because, in treating a sleep disorder, it is best to eliminate or minimize nocturnal 

arousals to improve sleep quality and sleep architecture. This is a significant therapeutic 

advantage over the short-acting oxybate products. We defer to OOPD and the DN1 to determine

47 Chiara Cirelli, Insufficient sleep: Definition, epidemiology, and adverse outcomes, UpToDate (Oct 10, 2022) at 

https://www.uptodate.com/contents/insufficient-sleep-definition-epidemiology-and-adverse-outcomes) (stating that: 

“[s]leep has two dimensions: duration (quantity) and depth (quality). When individuals fail to obtain adequate 

duration or quality of sleep, daytime alertness and function suffer. In response to sleep deprivation, sleep is often 

both longer and deeper. In many cases, however, sleep intensity can change without major changes in sleep duration. 

Sleep duration alone is therefore not a good indicator of how much sleep is needed to feel refreshed in the morning 

and function properly. . . . Sleep insufficiency exists when sleep is insufficient to support adequate alertness, 

performance, and health, either because of reduced total sleep time (decreased quantity) or fragmentation of sleep by 

brief arousals (decreased quality)”) (emphasis added). 48 See fn 26 supra. Once an arousal occurs, falling back to sleep begins at N1, not where the person left off in their 

sleep cycle prior to the arousal, and therefore, arousals will change sleep architecture. 49 Thomas E. Scammell, Treatment of narcolepsy in adults, UpToDate (Nov 14, 2022) accessed at 

https://www.uptodate.com/contents/treatment-of-narcolepsy-in-adults?source=history widget (explaining that 

“[m]anagement of narcolepsy is symptomatic, and there are no disease-modifying therapies yet available. . . . Sleep 

deprivation [including nocturnal arousals] may worsen narcolepsy symptoms, and therefore patients should be 

counseled to maintain a regular and adequate sleep schedule.”). 50 This is because once arousal occurs, falling back to sleep begins at N1, not where the person left off in their sleep 

cycle prior to the arousal—a missed opportunity to get into deep sleep (N3) which is restorative sleep. 51 See Figure 1, Emmanuel Mignot, et. al, Sleep problems in narcolepsy and the role of hypocretin/orexin deficiency

in Steiner MA, (eds): The Orexin System. Basic Science and Role in Sleep Pathology, Frontiers in

Neurol Neuroscience (2021) at 105 (depicting a 24-hour hypnogram (a sleep study which is read from left to right). 

Panels 1(a) and 1(b) are hypnograms from the same patient suffering from narcolepsy. In Figure (a), the patient is 

close to onset of disease; Figure (b) is the same patient 6 months after diagnosis. Figure c is a control (person with 

no sleep disease). Figures 1(a) and 1(b) represent the natural state of narcolepsy. During the day, the patient is 

falling asleep and has periods of daytime REM sleep (blue bars). The fine needle like projections during nighttime 

sleep (after 8pm) shows cycling between N1 and wake representing fragmented sleep. This is not restorative sleep 

because rapid cycling to wake and N1 prevent stable progression to deeper stages of restorative sleep. The patient 

will be impacted the following day because their sleep has been disrupted—even if they do not awaken during the 

night—and this is what occurs when oxybate wears off.). 

FDA-OOPD-May23-POSTING-000059
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whether and how considerations other than those considered in this consult may factor into the 

agency’s MCTPC analysis. 

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FDA-OOPD-May23-POSTING-000077
FDA-OOPD-May23-POSTING-000078
16640 Chesterfield Grove Road, Suite 200 • Chesterfield, MO 63005 • USA www.avadel.com

July 21, 2021 

Nicole Wolanski

Acting Director, Office of Orphan Products Development 

Food and Drug Administration 

WO32-5295 

10903 New Hampshire Ave. 

Silver Spring, MD 20993-0002 

Mark Raza

Acting Chief Counsel 

Office of the Chief Counsel

Food and Drug Administration 

WO31-4538 

10903 New Hampshire Ave. 

Silver Spring, MD 20993-0002 

Re: Approval and Orphan Drug Exclusivity for FT218 (sodium oxybate for 

extended-release oral suspension) 

Dear Dr. Wolanski and Mr. Raza: 

Avadel CNS Pharmaceuticals, LLC (“Avadel”) submits this correspondence to the Food 

and Drug Administration (“FDA”) Office of Orphan Products Development (“OOPD”) and Office 

of the Chief Counsel regarding approval and orphan drug exclusivity for Avadel’s proprietary drug 

product, FT218 (sodium oxybate for extended-release oral suspension). Specifically, this 

correspondence provides the legal and regulatory basis for FDA approval of FT218 

notwithstanding the recent grant of orphan drug exclusivity to Jazz Pharmaceuticals, Inc.’s 

(“Jazz’s”) Xywav® (calcium, magnesium, potassium, and sodium oxybates oral solution) for the 

treatment of cataplexy and excessive daytime sleepiness (“EDS”) in narcolepsy.

On December 8, 2020, Avadel submitted correspondence to OOPD requesting that OOPD 

refrain from granting orphan drug exclusivity to Xywav. As discussed in this correspondence, by 

way of background, Jazz obtained approval and orphan drug exclusivity for Xyrem® (sodium 

oxybate oral solution) for the treatment of cataplexy and EDS in adult patients with narcolepsy in 

2002 and 2005, respectively. These exclusivities expired in 2009 and 2012. In 2018, Jazz obtained 

approval and orphan drug exclusivity for Xyrem for the same indications in pediatric patients 7-

18 years of age, and these exclusivities are set to expire in 2025. On July 21, 2020, Jazz received 

approval for Xywav, a mixed salts oxybate product, for treatment of cataplexy and EDS in patients 

7 years of age and older with narcolepsy. However, Xywav did not receive orphan drug exclusivity 

at the time of approval. In our prior correspondence, we stated that although Xywav may serve as 

an alternative for the relatively small portion of sodium oxybate-eligible patients with heart failure, 

hypertension, or impaired renal function, significant research indicates that there is no clinically 

supported benefit to the vast majority of narcolepsy patients associated with reducing the sodium 

content of sodium oxybate treatment. Accordingly, we requested an FDA finding that Xywav did 

FDA-OOPD-May23-POSTING-000079
Page 2 of 5

not meet the clinical superiority standard of providing greater effectiveness, greater safety, or a 

major contribution to patient care. 

On June 24, 2021, OOPD nonetheless issued a determination that Jazz had demonstrated 

clinical superiority of Xywav over Xyrem and awarded Xywav its own period of orphan drug 

exclusivity expiring seven years from the Xywav approval on July 21, 2027. On the same day, 

OOPD issued a response to Avadel’s December 8, 2020 letter stating that the Agency determined 

Xywav is clinically superior to Xyrem “by means of greater safety, because Xywav provides a 

greatly reduced chronic sodium burden compared to Xyrem,” and “[t]he differences in the sodium 

content of the two products at the recommended doses will be clinically meaningful in reducing 

cardiovascular morbidity in a substantial portion of patients for whom the drug is indicated.” 

OOPD made clear, however, that “FDA has not yet evaluated the impact of Xywav’s orphan-drug 

exclusivity on the new drug application (NDA) [Avadel] submitted for [its] sodium oxybate 

product.” 

 Avadel’s FT218 is a novel sodium oxybate product formulated in a proprietary, extendedrelease powder for oral suspension that enables once-nightly dosing. With just a single dose before 

bedtime, FT218 provides comparable systemic drug exposure to Xyrem and Xywav oral solution 

products, which are both twice-nightly products—both Xyrem and Xywav require patients to take 

the first dose at bedtime and then set an alarm to wake up 2.5 to 4 hours later to take the required 

second dose. Avadel received orphan drug designation for FT218 in January 2018 based on a 

plausible hypothesis of clinical superiority over twice-nightly sodium oxybate, and Avadel 

submitted its demonstration of clinical superiority in its NDA for FT218, which has a PDUFA date 

of October 15, 2021. As discussed in Avadel’s demonstration of clinical superiority (which was 

provided to OOPD in a courtesy copy at the time of NDA submission), FT218 provides both 

greater safety and a major contribution to patient care over the existing sodium oxybate 

formulations due to its once-nightly dosing, which has been shown to significantly mitigate safety 

risks, compliance issues, potential misuse, and other challenges associated with middle-of-thenight dosing. 

Whether Avadel has satisfactorily demonstrated clinical superiority will determine 

FT218’s eligibility for its own seven-year orphan exclusivity period. However, even if OOPD 

determines that Avadel has not demonstrated clinical superiority for FT218, FDA may still 

approve the NDA. Stated another way, OOPD’s recent finding of clinical superiority for Xywav 

should not block FT218 from approval. In particular, as acknowledged in FDA’s June 24, 2021 

response letter to Avadel, “[u]nder this exclusivity, with limited exceptions, FDA may not approve 

an application from another sponsor for the same drug for the same use or indication for seven 

years from the date of approval of Xywav” (emphasis added). Pursuant to the Orphan Drug Act 

and FDA’s implementing regulations, as a result of FDA’s determination that Xywav is clinically 

superior to Xyrem, FT218 is not the “same drug” as Xywav and is therefore not blocked from 

approval by the Xywav orphan drug exclusivity. 

FDA May Approve FT218 Notwithstanding the Xywav Orphan Drug Exclusivity 

Under the Orphan Drug Act, as amended, the effect of orphan drug exclusivity is that FDA 

may not approve another marketing application “for the same drug for the same disease or 

condition” for seven years from the date of approval of the orphan drug, except in limited 

FDA-OOPD-May23-POSTING-000080
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circumstances.1 In addition, if a sponsor seeks approval of a designated orphan drug that is 

“otherwise the same, as determined by the Secretary, as an already approved or licensed drug,” 

then “the Secretary shall require such sponsor, as a condition of such exclusive approval or 

licensure, to demonstrate that such drug is clinically superior to any already approved or licensed 

drug that is the same drug.”2 

Use of the term “same drug” in the statute was codified in 2017, when Congress sought to 

better align the text of the Orphan Drug Act with FDA’s orphan drug regulations at part 316 of 

title 21 in the Code of Federal Regulations.3 Under these regulations, again, the effect of orphandrug exclusive approval is that “FDA will not approve another sponsor’s marketing application 

for the same drug for the same use or indication before the expiration of 7 years from the date of 

such approval as stated in the approval letter from FDA,” except in certain limited circumstances.4

 

In the case of a drug that is “otherwise the same drug as a previously approved drug for the same 

use or indication, FDA will not recognize orphan-drug exclusive approval if the sponsor fails to 

demonstrate upon approval that the drug is clinically superior to the previously approved drug.”5

 

Within this framework, for small-molecule drugs, “same drug” is defined as “a drug that contains 

the same active moiety as a previously approved drug and is intended for the same use as the 

previously approved drug..., except that if the subsequent drug can be shown to be clinically 

superior to the first drug, it will not be considered to be the same drug.”6

 Thus, as FDA explained 

in its rulemaking proceeding, “even a drug considered the ‘same’ drug structurally could become 

a ‘different’ drug by showing clinical superiority.”7

FDA has advanced this “same drug” interpretation in employing its regulations over the 

years. For example, in litigation where the government sought to explain its clinical superiority 

framework, attorneys for FDA made clear that “[a] clinically superior drug, under this framework, 

is therefore considered to be different from the previously approved drug, even if they share the 

same chemical structure.”8 Thus, “[u]nder FDA’s regulations, ... [in] a situation in which a 

subsequently approved sponsor obtained exclusivity by demonstrating clinical superiority, ... it 

1 21 U.S.C. § 360cc(a) (emphasis added). 

2 Id. § 360cc(c)(1) (emphasis added). 

3 FDA Reauthorization Act of 2017, Pub. L. 115–52 § 607, 131 Stat. 1005, 1049 (Aug. 18, 2017).

4 21 C.F.R. § 316.31(a) (emphasis added). 

5 Id. § 316.34(c) (emphasis added). 

6 Id. § 316.3(b)(14)(i) (emphasis added). 

7 Orphan Drug Regulations, Proposed Rule, 76 Fed. Reg. 64868, 64870 (Oct. 19, 2011) (quoting Orphan Drug 

Regulations, Proposed Rule, 56 Fed. Reg. 3338, 3342 (Jan. 29, 1991)) (internal punctuation omitted).

8 Defendants’ Response to Plaintiff’s Motion for Summary Judgment and Cross-Motion, Eagle Pharms., Inc. v. 

Burwell, No. 16-0790 (D.D.C. Aug. 19, 2016), at 6.

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would no longer be the same drug as the previously approved drug”; rather, the subsequently 

approved drug would be a “clinically superior (and different) drug.”9

In applying this framework, then, FDA is free to approve the pending FT218 NDA without 

regard to any outstanding orphan drug exclusivity for Xywav. When Avadel submitted the FT218 

NDA on December 15, 2020, Xyrem, Xywav, and FT218 could all be considered the “same drug” 

for orphan drug purposes—all contained the sodium oxybate active moiety, all were intended to 

treat cataplexy and EDS in narcolepsy, and none had yet been subject to a finding of clinical 

superiority by FDA. Since then, FDA has determined that Xywav is clinically superior to Xyrem. 

As a result, pursuant to the statute, regulations, and applicable precedent, Xywav is no longer the 

“same drug” as Xyrem. Rather, Xywav is now a “different drug” that must be defined by the 

product characteristics that resulted in its clinical superiority—low sodium. Although FT218 

contains the same sodium oxybate active moiety as both Xyrem and Xywav and is intended for 

the same narcolepsy indications, FT218 is not the “same drug” as Xywav because it is not and 

does not purport to be a low-sodium product. Indeed, FT218 provides the same amount of sodium 

as Xyrem. FT218 is, therefore, the “same drug” as Xyrem, not Xywav. It could not be any other 

way—given that Xyrem and Xywav are themselves “different drugs” under this framework, FT218 

cannot simultaneously be the “same drug” as both of them. In sum, because Xywav is now a 

“different drug,” FDA is not precluded from approving the FT218 NDA during the seven-year 

Xywav orphan drug exclusivity, regardless of whether Avadel makes its own demonstration of 

clinical superiority.10 

FDA Should Grant Orphan Drug Exclusivity to FT218 Upon Approval 

As noted above, at the time Avadel requested and received orphan drug designation for 

FT218, and at the time Avadel submitted its NDA, FT218 would have been considered the “same 

drug” as both Xyrem and Xywav for orphan drug purposes. Accordingly, in the FT218 NDA, 

Avadel provided a demonstration of clinical superiority over both previously approved drugs. 

Namely, regardless of the fact that Xywav provides lower sodium than Xyrem, both products must 

still be dosed on a twice-nightly basis, making FT218’s once-nightly formulation clinically 

superior. Now that Xywav is a “different drug” than Xyrem, Avadel need only demonstrate 

clinical superiority over Xyrem in order for FT218 to obtain its own seven-year orphan drug 

exclusivity. Regardless, Avadel has still demonstrated clinical superiority over both Xyrem and 

Xywav in its NDA. Indeed, Avadel just recently submitted a supplement to its already compelling 

9 FDA Response Regarding Certain Products Containing Bendamustine, Docket No. FDA-2018-N-3773 (Feb. 20, 

2019), at 8.

10 We note that, if FDA were to require Avadel to demonstrate clinical superiority in order for FT218 to receive 

effective approval, Avadel could satisfy that requirement by demonstrating superiority over Xyrem. Namely, in 

seeking approval of a designated orphan drug that is otherwise the “same drug” as an already approved drug, FDA 

must require the sponsor, as a condition of orphan-drug exclusive approval, “to demonstrate that such drug is 

clinically superior to any already approved or licensed drug that is the same drug.” 21 U.S.C. § 360cc(c)(1) 

(emphasis added). Thus, under the statute’s plain terms, the requirement of demonstrating clinical superiority is met 

when clinical superiority is shown as to any one of multiple previously approved “same drugs”—Avadel could 

therefore show clinical superiority of FT218 over Xyrem, rather than Xywav. 

FDA-OOPD-May23-POSTING-000082
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demonstration of clinical superiority with additional literature and data showing that disrupted 

sleep and disordered sleep architecture (as required for effective dosing of Xywav and Xyrem) is 

associated with an increased risk of cardiovascular disease; by eliminating the necessity of a forced 

awakening for patients to take a second dose in the middle of the night, FT218 offers greater sleep 

consolidation and improved sleep architecture for narcolepsy patients, providing both greater 

safety and a major contribution to patient care. In short, Avadel has provided FDA more than 

enough data and clinical support not only to approve FT218, but also to find it clinically superior 

in order to recognize orphan drug exclusivity for FT218 upon approval. 

* * * * 

We thank you for your attention to this issue of great importance to Avadel. We 

respectfully request that OOPD and OCC ensure that the Agency may approve the FT218 NDA 

notwithstanding the recent grant of orphan drug exclusivity to Xywav and facilitate availability of 

a superior once-nightly dosing option to the orphan narcolepsy patient population. 

Please do not hesitate to contact the me at 636-730-1420 or jseurer@avadel.com with any 

questions. 

Sincerely,

Jerad G. Seurer

Vice President, Legal Affairs

Cc: Henry Startzman, M.D.

Director, Orphan Drug Designation Program 

Office of Orphan Products Development 

Food and Drug Administration 

WO32-5280 

10903 New Hampshire Ave. 

Silver Spring, MD 20993-0002 

Amanda Edmonds 

Deputy Chief Counsel for Program Review for Biologics and Drugs 

Office of the Chief Counsel

Food and Drug Administration 

WO31-4508 

10903 New Hampshire Ave.

Silver Spring, MD 20993-0002 

FDA-OOPD-May23-POSTING-000083
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Food and Drug Administration

10903 New Hampshire Avenue

Building 32, Room 2346

Silver Spring, MD 20993

Dear FDA, 

My name is Maria Picone, and I am the Chief Executive Officer of TREND Community, a digital health 

analytics company that works to give a voice to underserved rare and chronic disease communities. We

have been engaging with the narcolepsy community in this capacity since 2017.

TREND Community learns through listening, and we spark progress through insight. This communitycentric approach fills an important gap between patient-reported outcomes in a clinical setting and the

real-world experiences that are often underreported because of stigma, fear of losing access to 

treatments, and other communication barriers.

Following the FDA’s decision to grant tentative approval to LUMRYZ, also known as FT218, earlier this 

year, we began documenting patient experiences with sodium oxybate by surveying and interviewing 

community members and analyzing shared stories and experiences on social media. Through this work, 

we have realized the urgent need for a once-at-bedtime sodium oxybate therapy. This work was 

funded by Avadel Pharmaceuticals as part of their ongoing effort to quantify the need for a once-nightly 

sodium oxybate therapy; however, Avadel Pharmaceuticals did not influence the analysis or output in 

any way. We thank PWN4PWN, a patient-led narcolepsy advocacy organization, for supporting this 

initiative. The perspectives shared within this letter are those of TREND Community and the narcolepsy 

community members who participated. 

Our first step was to listen to the community. What were people saying—unprompted—on social media

on the topic of sodium oxybate? We analyzed more than 25,000 posts and comments contributed by 

more than 15,000 participants over a span of approximately 11 years. The results show that the need to

take a second dose of sodium oxybate creates disruptions and various other issues for the patients and

their caregivers. These issues range from challenges with waking up to take the second dose to 

struggling with getting back to sleep in some cases or dealing with daytime sleepiness in other

instances. The community also spoke of the physical side effects and their impact on their mental

health. The full report, Data Exploration: Social Listening and Sodium Oxybate, is provided as an

appendix.

Next, we fielded a survey prompting the community for input, and 87 qualified patients and caregivers 

responded. Fifty of 85 survey respondents (59%) reported taking the second dose of oxybate therapy

more than 4 hours after the first dose, with 74% reporting that this occurs once per month or more

often. Eighteen respondents reported taking the second dose less than 2.5 hours after the first dose

once a month or more often. When asked about accidentally missing a second dose of oxybate therapy,

three-quarters (75%) reported this type of experience. The full report, Understanding Patient Experience

With Oxybate Therapy, is provided as an appendix. Notable impacts reported include the following:
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• 32% have experienced injuries after waking to take the second dose

• Other impacts and issues reported with missing the second dose include poor sleep quality, 

brain fog, increased daytime sleepiness, decreased awareness, migraines, and worsening 

symptoms

• For some, taking the second dose more than 4 hours after the first dose has resulted in 

missing/being late to school or work, including disciplinary action or termination

Finally, keeping in mind that these data represent real people navigating life with a narcolepsy diagnosis, 

we interviewed 4 community members and asked them to share their experiences (in their own words) 

with sodium oxybate therapy and the challenges they face while taking the medication. I close this letter 

with their messages to the FDA. You can read more about , and at the end of 

this report.

is a 53-year-old husband and father who was diagnosed with narcolepsy at age 22, following a 

12-year journey to diagnosis:

“I passionately urge the FDA to consider an immediate approval of Avadel Pharmaceuticals’ 

investigational formulation of sodium oxybate, LUMRYZTM. Greater predictability and consistency in [a] 

medication regimen is vital to the successful management of this lifelong chronic condition, especially 

during the night when people with narcolepsy need restful sleep the most.”

is a 36-year-old woman who was diagnosed with narcolepsy at age 33, following a 7-year 

journey to diagnosis:

“Sodium oxybate is invaluable to the quality of lives of people with narcolepsy. Providing more options 

can help with compliance and help people have a better structured nighttime sleep. The decision to 

delay treatment is unfair to the patient community.”

is a 24-year-old man who was diagnosed with narcolepsy at age 15, following a 2-year journey to 

diagnosis:

“The benefits of sodium oxybate are so profound and have made my life possible. While I’m incredibly 

grateful to have this support and access to the medication, I think more formulations and options are 

needed.”

is a 33-year-old woman who was diagnosed with narcolepsy at age 23, following a 10-year 

journey to diagnosis:

“Inaction is not harmless! Why is it taking so long to bring this medication to market? Not approving this 

medication is causing real-world consequences. The safety and effectiveness of the medication are 

established. With the current twice-nightly option, many people can’t maximize the benefits of oxybate 

therapy. These delays are resulting in familial and employment consequences. We deserve to have 

options.”

The narcolepsy community is asking for your leadership in addressing their unmet medical needs and 

approving LUMRYZTM without further delay. With the promise of a once-nightly sodium oxybate therapy

(b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6)
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on the horizon, we expect a reduction in the number of injuries that result from missing the second dose 

and improved quality of life for many living with narcolepsy. I appreciate you taking the time to read the 

letter. 

Best,

Maria Picone, CEO

TREND Community

Maria Picone

Digitally signed 

by Maria Picone 

Date: 2022.11.29 

15:12:23 -05'00'
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is a 53-year-old husband and father who was diagnosed with narcolepsy at age 22, following a 

12-year journey to diagnosis:

“I don’t remember much beforehand, but excessive daytime sleepiness was a ‘normal’ part of my life in 

middle school. It was a daily struggle for me to stay awake on the school bus and in my classes. Even 

though I wasn’t very good in athletics, I looked forward to Phys Ed because it was the one class I was not 

sitting and falling asleep.”

Sodium oxybate has been a part of treatment protocol for narcolepsy; however, it is not easy to 

manage taking it:

“It’s been difficult for me to maintain routine usage with Xyrem. It is not uncommon for me to believe I 

woke to take my second dosage only to realize in the morning that this, too, was just part of my dream 

and it’s still sitting on the nightstand.”

For , the challenge of taking Xyrem goes beyond missed second doses; he also battles increased 

sleep inertia and brain fog from doses after 4 hours:

“I was unable to take the second dose of Xyrem the same time every night, and sometimes not at all. 

While staying awake during the day is difficult, waking up is the hardest thing I do all day. Sometimes, the 

brain fog during oxybate therapy lasted longer than anticipated, and a few times, this resulted in my 

driving impaired and damaging my vehicle.”

 has experienced more losses than just an automobile accident. His inability to work through the 

grogginess from late doses impacted his employment and family relationships:

“After initially being understanding, 

because I could not consistently arrive on time for early morning meetings. 

 the stigmas associated with a person with narcolepsy (lazy, 

rude, etc.) makes it even harder. This left me .”

Narcolepsy has had a profound effect on daily life. The related impact on his family weighs heavy 

on him as a husband and father:

“After more than 25 years of living with narcolepsy, it has broken and continues to ravage what remains 

of my marriage, my family, my jobs, my body, my mind, and my life.”

 message to the FDA:

“I passionately urge the FDA to consider an immediate approval of Avadel Pharmaceuticals’ 

investigational formulation of sodium oxybate, LUMRYZTM. Greater predictability and consistency in [a] 

medication regimen is vital to the successful management of this lifelong chronic condition, especially 

during the night when people with narcolepsy need restful sleep the most.”

(b) (6) (b) (6) (b) (6) (b) (6)

(b) (6) (b) (6)

(b) (6) (b) (6) (b) (6)
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is a 36-year-old woman who was diagnosed with narcolepsy at age 33, following a 7-year 

journey to diagnosis:

“I believe that my narcolepsy gene was triggered in when I had a long hospital stay with 

.”

Narcolepsy has had a profound impact on and her family’s life:

“Narcolepsy affects my life daily and is always on my mind. I need to remember my daytime meds, 

monitor my water intake, [and] watch for mood shifts, which are often the first indicator that I need a nap 

or an afternoon medication to get through the day. I rely heavily on my mom/family to help me remember 

appointments and get there, as many are too far for me to safely drive.”

Confusion and even injuries have occurred as a result of awakening for the second dose of 

Xyrem:

“I have gotten confused while preparing my nighttime meds because I am tired, and that automatic

behavior kicks in for all of us when we are doing our routine, but especially for a person with narcolepsy, 

as we might actually be microsleeping.”

“On multiple occasions, I have fallen asleep while on the toilet in between doses. I already touched on 

how brain fog can hinder and be dangerous when mixing and preparing nighttime doses of medication, 

but I have also experienced injuries and extreme confusion. A few examples are stumbling through 

doorways and hallways while trying to get up to take my second dose. I have also been so completely 

sure that I heard my alarm (an auditory hallucination) and gotten up to take my second dose when I 

already had. On a few occasions, I awoke the next day to see the full bottle was on the floor—realizing I 

had missed my dose.”

 also shared the impact of missing or mis-timing doses:

“Missing doses makes people feel sick. Mis-timing doses leaves you ‘seasick’.... My world seems 

wobbly, and my head is cloudy afterwards.”

For , the benefit of a once-nightly formulation is apparent:

“Avoiding a midnight alarm clock will allow my sleep cycle to be less disruptive. People with narcolepsy 

experience disrupted sleep already, and adding another nighttime awakening is unnecessary and more 

disruptive.”

 message to the FDA:

“Sodium oxybate is invaluable to the quality of lives of people with narcolepsy. Providing more options 

can help with compliance and help people have a better structured nighttime sleep. The decision to 

delay treatment is unfair to the patient community.”

(b) (6) (b) (6)

(b) (6)

(b) (6) (b) (6) (b) (6) (b) (6) (b) (6)
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is a 24-year-old man who was diagnosed with narcolepsy at age 15, following a 2-year journey to 

diagnosis:

“I consider myself fortunate to have been diagnosed after only 2 years. Most of my friends living with 

narcolepsy had to look for answers for 5 to 10 years before getting a diagnosis.”

Narcolepsy has had a profound impact on daily life:

“One of my greatest passions is the overseas mission work I did in 

between graduating high school and returning to college. While it was a joy and an honor to help others 

as an English tutor, I couldn’t fully engage because of being undermedicated. I’m currently pursuing a 

 to help others find answers.”

has struggled with awakening for the second dose and spilling doses in the process:

“There are times when I don’t wake up to take the second [dose], and there are other times when I spill 

the vial or only take part of a dose.”

 also shared the impact of missing or mis-timing doses:

“When I miss doses or miss the timing, I must weigh the benefit of taking the full amount or only part of 

it. If I don’t take the second, then I might not be able to make it to school or work. If I do take the second 

dose later than 4 hours, then I might be late or have really bad brain fog.”

The impact of brain fog resulting from missed or mis-timed doses is overwhelming for

“I don’t drink anymore, but from what I remember, the impact of late doses is worse than a hangover. A 

cloud of confusion sets in, and I feel disoriented, dehydrated, and nauseous. Normally my sleep schedule 

is fairly consistent; however, when sleep time is variable, the missed doses are increased. This makes 

enjoying time off even more of a challenge.”

For the benefit of a once-nightly formulation is about compliance and convenience:

“The convenience of taking a once-nightly sodium oxybate formulation means it will be easier to stay 

compliant on my doses. Measuring out 1 prepackaged dose takes the guesswork out of dosing and 

possibly missing a dose. Another advantage of prepackaged packets is not having to carry liquids around 

during travel. During a trip to , I had the bottle top become slightly loose and ended up having 

some of the liquid medication leak out into my luggage.”

s message to the FDA:

“The benefits of sodium oxybate are so profound and have made my life possible. While I’m incredibly 

grateful to have this support and access to the medication, I think more formulations and options are 

needed.” 

(b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6)
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is a 33-year-old woman, who was diagnosed with narcolepsy at age 23, following a 10-year 

journey to diagnosis:

“I’ve been labeled ‘sleepy’ for as long as I can remember. My symptoms began to become overwhelming 

during my teen years and into early college. In addition to being diagnosed with narcolepsy, I have also 

been diagnosed with . It’s hard to separate the impacts of the 

conditions, but at the foundation is sleepiness and narcolepsy.”

Narcolepsy has had a profound impact on ’s daily life:

“Prior to getting the diagnosis, I was sleeping through exams, and keeping up seemed nearly 

impossible.”

Medication provided with a new look on life:

“I often compare receiving my diagnosis and being medicated to putting on glasses for the first time. 

Medication opened my eyes to a world I didn’t realize was possible; however, even with current 

treatments, the outlook is foggy.”

 has difficulties making sure she takes both doses of oxybate:

“Making sure I get the second dose has been a huge hurdle for me. When I don’t get in both doses, it 

disrupts my schedule. This leads to waking up late or in a cloud of brain fog. This creates a cycle of 

missed doses causing more missed doses. Trying to measure out both doses at night and figure out 

timing is made more difficult because of the sleepiness.”

For taking Xyrem is often like balancing a mathematical equation:

“The process of figuring out the ‘Xyrem Math’ is a big part of my routine. My work and school schedules 

require flexibility. I need to have the medication out of my system to drive safely and function. Calculating 

how much medication to take and when to take the second dose is critical. Solving the ‘Xyrem Math’ 

problem when I have sluggish thinking complicates the decision.”

 also shared the impact dosing on her family:

“In order to wake up for my second dose, I have a ‘sonic boom’ alarm clock. Even though the noise is 

very disruptive to my partner, oftentimes I don’t wake up without his help.

For the benefits of a once-nightly formulation are apparent:

“My physician and I came up with workarounds due to frequently missing my second dose. I take a 

higher amount during my first dose (6 g) in case I miss my second. Creating a once-nightly, premeasured 

dose would allow me to get the full benefit of the medication. Equally as important, this once-nightly 

dose would not disrupt my partner’s sleep as well, reducing these unnecessary awakenings.”

(b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6) (b) (6)
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s message and question to the FDA:

“Inaction is not harmless! Why is it taking so long to bring this medication to market? Not approving this 

medication is causing real-world consequences. The safety and effectiveness of the medication are 

established. With the current twice-nightly option, many people can’t maximize the benefits of oxybate 

therapy. These delays are resulting in familial and employment consequences. We deserve to have 

options.”

(b) (6)
Data 

Exploration

 

Social listening and sodium 

oxybate

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Table of Contents

 																																																																																																																																		 



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Topic Modeling .......................................................................................................................................... 7


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Purpose

The purpose of this report is to understand the treatment impact of sodium oxybate (SO) in the 

narcolepsy community via social listening. The data sources being used in this report are two online 

support groups: -HJLIVVRHUK HZ\IYLKKP[Y5HYJVSLWZ`. 

TREND Community Technology

TREND Community harnesses machine learning and natural language processing techniques with 

KrystieTM, our proprietary analytics engine to capture the perspective and experiences shared online by

people living with rare and chronic diseases. Krystie was the daughter of one of our community

members and the inspiration driving everything we work towards. Krystie—and the millions of others

facing rare, chronic, and emerging diseases—is always at the heart of TREND Community.

Our Methodology

KrystieTM enables TREND to identify conversations in domains that tend to be prevalent in social mediabased discussions regarding chronic and rare diseases (e.g., disease burden, management, mental

health). After isolating conversations within domains of interest, we leverage a variety of analytical

techniques to characterize the language and emotions associated with patient experiences and 

perspectives. These techniques are implemented both independently and in conjunction with one 

another to offer converging support for discoveries. We offer a summary of the key methodologies:
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TOPIC MODELING

TREND implements various topic modeling approaches to determine language that 

tends to cluster together. These machine learning techniques rely on statistical 

probabilities and pre-trained knowledge of words, phrases, and their meanings to 

identify significant groupings. 

We use a variety of polarity and 

sentiment analysis techniques to 

broadly understand user 

emotions and feelings on given 

topics. These include both word 

and conversation level analyses. 

POLARITY ANALYSIS
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CLINICAL ENTITY RECOGNITION

We use a custom clinical 

entity recognition (CER) 

tagger to mark language 

based on its membership to 

10 clinical domains: clinical 

findings, substances, 

occupations, units of time, 

anatomical parts, persons, 

environments, objects, 
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Using our CER tagger, we use 

network analysis to evaluate 

relationships between entities. 

We can begin to understand 

trends in conversations when 

we know what entities occur 

often (e.g., count of a specific

substance) and what entities 

occur together (e.g., a 

substance and clinical finding 

co-occurrence). 

NETWORK ANALYSIS
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Data Set

15,280

People 

Participating

August 2011 - October 2022

Date Range

Data Sources: 

-HJLIVVR

Y5HYJVSLWZ`

229,626

Comments 

Elicited

25,018

Posts 

Shared
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Topic Modeling

First, we extracted the conversations that mention sodium oxybate from the entire data set. To be more 

inclusive, we used multiple names and synonyms to perform the extraction, including sodium oxybate, 

Xyrem, and Xywav, etc. The complete list can be found in Appendix A. The total number of 

conversations that mentioned sodium oxybate is 26,088 and the total number of reddit users who 

mentioned sodium oxybate is 4,275. We applied topic modeling on this filtered data set to get a general 

understanding of the topics being discussed and the results are meant to be taken in aggregate. The 

model identified several topics related to the sodium oxybate doses. The takeaway is that these topics 

are all highly related and represent "sodium oxybate and second doses" overall and are used for further 

analysis as a composite. Figure 1 below shows eight topics and their word representation (top five 

words).

From the topic model, we identified the following issues related to taking sodium oxybate in the 

community.

• Having difficulties taking second dose, including:

o Hard to wake up for second dose 

o Sleeping through the alarm(s) for second dose

o Dreaming that had taken the second dose

o Need help from parents/partners to wake up for second dose

o Worry the second dose alarm will wake up other people

• Issues on scheduling the doses

Figure 1
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• Insomnia after doses

• Skipped doses because of drinking

• Binge eating or craving foods after taking a dose

• Timing meals with the medication

By using the state-of-the-art deep learning language model, we are able to extract the posts and 

sentences discussing the above issues. The table below shows the statistics of each issue identified. 

The second column lists the number of occurrences and frequency out of all sodium oxybate

discussions (N=26,088). The third column is the number of distinct reddit users and its frequency out of 

all reddit users who have mentioned sodium oxybate (N=4,275).

Issue Entry Count (Frequency)

N=26,088

User Count (Frequency)

N=4,275

Difficulties taking the second dose 635 (2.43%) 398 (9.31%)

Issues scheduling the two doses 14 (0.05%) 4 (0.33%)

Insomnia after doses 161 (0.62%) 134 (3.13%)

Skipped doses due to drinking 3 (0.01%) 3 (0.07%)

Binge eating or food craving after doses 13 (0.05%) 13(0.3%)

Timing meals 27 (0.1%) 26 (0.61%)

Total 715 (2.74%) 439 (10.29%)
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The data show that there are 715 posts (2.74% of all sodium oxybate conversations) mentioning an 

issue when taking sodium oxybate. There were 439 distinct users (10.29% of total users) who mentioned 

sodium oxybate in their conversations. Please refer to Appendix B for comments from these patients.

Network Analysis

Using our CER tagger, we can build the co-occurrence network and examine the relationships between 

entities. We filtered conversations that mentioned (1) second dosage (e.g., second dose, 2nd, etc) and 

(2) sodium oxybate (e.g., xyrem, SO, etc) to build a unique co-occurrence network for all conversations

discussing second doses of sodium oxybate. The sub-network is shown in Figure 2 below. The red

nodes are clinical findings and blue nodes are substances. The size of the nodes corresponds to the

total number of occurrences. Entities mentioned together in the same post/comments are connected by

edges. The width of the edges corresponds to the number of co-occurrences; thicker edges imply

stronger relationships.

Clinical Finding

Substance

Co-occurrence

Figure 2
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Network analysis shows the top 20 most influential clinical finding nodes below, ordered by degree 

centrality. 

The results show that the second dose of sodium oxybate results in not only physical issues such as 

nausea, headaches, dizziness, and hunger but also mental health issues like anxiety, panic, and 

depression.

Summary

In this report we evaluated the impact of sodium oxybate based on the analysis of social media data. 

The results show that the need to take the second dose of sodium oxybate creates various issues and 

disruption for the patients and their caregivers. These issues range from challenges with waking up to 

take the second dose to then struggling with getting back to sleep in some cases or dealing with 

daytime sleepiness in other instances. After taking sodium oxybate, patients also experience physical 

symptoms such as nausea, headaches, dizziness, and hunger as well as mental health challenges like 

anxiety, panic, and depression.

1. side effect

2. cataplexy

3. nausea

4. anxiety

5. headache

6. ed (eating

disorders)

7. depression

8. insomnia

9. hypersomnia

10. hangover

11. dizziness

12. appetite

13. sleepiness

14. sleep attack

15. hallucination

16. medication

anxiety

17. sleep paralysis

18. tolerance

19. empty stomach

20. panic attack
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Appendix A

Words and synonyms used for concept

SO: oxybate, xyrem, xywav, jazz, nighttime med, ghb, gaba, date rape, gamma hydroxybutyrate, 

gamma-hydroxybutyrate

‘Skip’ verbs: skip, miss, skips, misses, skiping, missing, skipping, mising, skiped, missed

Alarm: alarm, fitbit, tracker, tracking

First dose: first dose,1st dose, first xyrem, first xywav, 1st xyrem, 1st xywav, one dose, one-dose, single 

dose, single-dose

Second dose: second dose, 2nd dose, second xyrem, second xywav, 2nd xyrem, 2nd xywav, double 

dose, between dose

Slow release: once nightly, once-nightly, slow release, extended release, extend release, once per night, 

long acting, slow-release, extended-release, extend-release, once-per-night, long-acting

‘Wake’ verb: wake me up, woke me up, wakes up, wake up, woke up, waking up

‘Sleep’ verb: sleep over, slept over, sleep through, slept through, sleeping over, sleeping through, sleeps 

over, sleeps through

Alcohol: alcohol

Titration: titrat

Accident: miss work, miss school, missing work, missing school, missed work, missed school, accident
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Appendix B

Quotes from the discussions

Difficulties taking the second dose

“I have difficulty waking up for a second dose too, even if I use an alarm and give myself a full 4 hours of 

sleep after the first dose (side note: excessive sleeping / oversleeping / hypersomnia has always been a 

part of my sleep problem / narcolepsy).”

“I cannot for the life of me seem to wake up for the second dose....”

“I struggle immensely with waking up to take a second dose and am at the point where I only take the

first one and don't bother preparing the second.”

“Waking up to take a second dose is jarring and I hate the drugged feeling I get.”

“It's been a miracle drug for me. It completely turned my life around but I'm having the darnedest time 

waking up for the second dose.”

“Part of the problem was a ton of anxiety about waking up for the second dose without disturbing my 

partner.”

Alcohol and food

“No alcohol with Xyrem unless somebody else is going home with you and will make sure you wait the 

appropriate amount of time.”

‘If I want to drink I skip it that night.”

“I take my first dose, the second it kicks in, I feel like I'm starving so I nibble on my premade meal.”

“Strangely enough, after taking my first dose, if I stay awake for more than a half hour I find myself 

becoming ravenous, even if I've eaten full meals throughout the day.”
UNDERSTANDING 

PATIENT EXPERIENCE WITH OXYBATE THERAPYSurvey Results November 16, 2022
OBJECTIVES & CRITERIA
Research Objectives and Screening Criteria

The purpose of this research is to better understand patient experience with tatherapy (Xyrem® or Xywav®) for narcolepsy.The following are the criteria to participate in the survey:#Age 

≥18 years

#Living in the United States#Patient or caregiver of a patient with a narcolepsy diagnosis#Currently taking or have previously taken oxybate therapy like Xyrem® or Xyw
FINDINGS
Survey Respondent Data

Total RespondentsN=87GroupPatient: 85Caregiver: 2Gender (patients)Female: 64Male: 19Intersex: 1Prefer not to answer: 1DiagnosesType 1 with Cataplexy: 44Type 2 without Cataplexy: 39Unsure: 2MedicationsCurrently taking Xyrem®: 19 Currently taking Xywav®: 45Previously taken Xyrem®: 34 Previously taken Xywav®: 11
Frequency of missing the second dose

When asked: during the time you have been on your oxybate therapy (Xyrem oyou accidentally missed your 2nd dose, a majority (75%) of the 85 patients who reported this experience. These patients were then asked: approximately how frequently do you experienissue? Of this group, 65% miss the second dose once a month or more often.

Frequency % (N=64)A few times a week 17%Once a week 20%Once a month 28%Every 6 months 25%Once a year 5%Less frequently than once a year 5%
Impact of missing the second dose 

When asked: please describe any impact or issues you typically experience due to missing your second dose, the most common responses included poor sleep quality, increased daytime sleepiness, missing work or school, brain fog, and decreased awareness thus impacting the ability to function the next day.
Injuries resulting from waking to take second d

To better understand the patient experience we asked: during the time you havyour oxybate therapy (Xyrem or Xywav), have you experienced injuries (such as waking to take your second dose?Almost one-third (32%) of the survey respondents have experienced injuries aftake the second dose of oxybate therapy.Of this group, the chart to the right shows the frequency of injuries with 33% experiencing issues once a month or more often.

Frequency % (N=27A few times a week 7%Once a week 7%Once a month 19%Every 6 months 22%Once a year 19%Less than once a year 26%
Injuries resulting from waking to take second d

When asked: please provide us with some additional details about this (for example, dethe event happened, seriousness, etc.), many patients reported falling or bumping into tbumps, bruises, and black eyes. Pulled muscles, stitches, and the need for physical theand shoulder injury have occurred. One person experienced confusion resulting in takintoo soon which led to a trip to the ER. Another suffered multiple concussions thus impafunction as well as their mental health.

“[I received] frequent minor injuries (mild bumps and bruises). I have had several concuss

serious issues and required treatment from a concussion clinic due to lingering concussiperiodic re-injury due to additional concussions under the same circumstances. Overall, taken a big toll on my overall functioning and mental health.”“Knocked over CPAP onto floor and walked around confused bumping into the wall and/for second dose & forgetting it was next to the bed all along.”“I got up to use the bathroom, fell asleep on the toilet and fell off, slamming my head on door.”“I've fallen out of bed when I sat up to take the 2nd dose. I hurt my neck and shoulder antherapy.”
Dose Timing: Taking the second dose more th

hours after the firstMore than half (59%) of the 85 survey respondents have taken the second dostherapy more than 4 hours after the first dose. These data were derived when wduring the time you have been on your oxybate therapy (Xyrem or Xywav), have your second dose more than 4 hours after your first dose?Of those taking the second dose more than four hours after the first, this is occ

month or more for almost three quarters (74%) of these patients.

Frequency % (N=50)A few times a week 6%Once a week 14%Once a month 54%Every 6 months 12%Once a year 6%Less than once a year 8%
Impact of taking the second dose more than 4 

after the first 

“Extended brain fog cauarrivals at work resulting “Missed morning activitimy daily life things for suin serious trouble from tigotten written up becaus“Ruined my work and life was too groggy. I also coto cancel events. I've alsmeetings more groggy th

When asked: please describe any impact or issues you typically experience due to takin

dose 4+ hours after your first dose, we learned about the disruption it causes. The biggemissing activities or missing/being late to school and work which has resulted in discipltermination for some patients. Many report grogginess and difficulty functioning the nex
Dose Timing: Taking the second dose less tha

hours after the firstA smaller group has taken the second dose less than 2.5 hours after the first doinformation was gleaned by asking: during the time you have been on your oxy(Xyrem or Xywav), have you taken your 2nd dose less than 2.5 hours after the fWe then asked: you indicated that you have taken your 2nd dose less than 2.5 the first dose. Approximately how frequently do you experience this issue? This once a month or more often for almost two fifths (39%) of these patients.

Frequency % (N=18)A few times a week 6%Once a week 11%Once a month 22%Every 6 months 11%Once a year 28%Less than once a year 22%
Impact of taking the second dose less than 2.5 

after the first 

Upon asking: please describe any impact or issues you typically experience due to takin

dose less than 2.5 hours after the first dose, a few patients expressed fear and anxiety a

doses too close together. Another small group spoke of confusion and disorientation woxybate therapy within 2.5 hours of the first dose. Others shared experiences of physicaillness, including headaches, dizziness, and upset stomach. For one patient, this impacto do things the next day and for another, they experienced EDS. Two patients felt the edecreased which led to them purposely take the second dose within 2 to 3 hours of the finds it useful and with no negative impact to take the second dose after only 2 hours. 

“I was terrified once I looked at the clock and realized what I had done, ended up in the Emom knocked out and with a respiration rate of 5 breaths per minute.”“Increased emotions, severe digestive upset, headache, increased EDS, and worsening o“I always take my first dose at 10 and my second at 12, it works the best for me and I habad symptoms. I wake up when I need to and taking the second dose after 2 hours has bsuccessful for me to wake up.”
Additional issues reported

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“I experienced extreme anxiety/depression for 4-6 hours after awakening from Xyrem. Thside effect that is not talked about or addressed.”“The bottles and measuring and diluting and waking up in the middle of the night for doswrong. I'm on a dose now that definitely gives me a better quality sleep and less daytime 

all it takes is sleeping through my second dose to screw everything up again. I feel like I'm 

rollercoaster, which then impacts my mental health. There has to be a better way to dose “Xyrem made me want to rip my own skin off. Xywav left me feeling very ill in the morningcould barely take care of my children.”
Belief that a once-nightly dose would be safer

As a final question, we asked: please indicate the extent to which you agree or disagree following statement: "I believe that a single bedtime dose of sodium oxybate, in a pre-mpacket, would be safer for me to take than the currently available versions, due to avoid2nd, middle-of-the-night dose7he majority (76%) of these patients either strongly agreagree.

% (N=87)

Top 2 Box 76%Strongly agree 46%Agree 30%Neither agree nor disagree 11%Disagree 6%Strongly disagree 7%

“I am awaiting approval of once nightno other medicinal or lifestyle regimencomplete my ADLs without significancannot spend the time I would like to husband due to my EDS, and am not anymore due to missing the second dshutting off my alarms, and going bacand thinking I took my second dose w“Accidentally poured a liquid that wascup. Accidentally poured water into abottle ruining an entire month script.”
Mat

mhorsnell

ldougherty

1635 Market StreetPhiladelphia, PA Lauren D