Schedules of Controlled Substances: Placement of Carisoprodol Into Schedule IV, 77330-77360 [2011-31542]

Agencies

• Drug Enforcement Administration
• Department of Justice

[Federal Register Volume 76, Number 238 (Monday, December 12, 2011)]
[Rules and Regulations]
[Pages 77330-77360]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-31542]



[[Page 77329]]

Vol. 76

Monday,

No. 238

December 12, 2011

Part II





Department of Justice





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 Drug Enforcement Administration





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21 CFR Part 1308





Schedules of Controlled Substances: Placement of Carisoprodol Into 
Schedule IV; Final Rule

Federal Register / Vol. 76 , No. 238 / Monday, December 12, 2011 / 
Rules and Regulations

[[Page 77330]]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-333]


Schedules of Controlled Substances: Placement of Carisoprodol 
Into Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Final rule.

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SUMMARY: With the issuance of this final rule, the Administrator of the 
Drug Enforcement Administration (DEA) places the substance 
carisoprodol, including its salts, isomers, and salts of isomers, 
whenever the existence of such salts, isomers, and salts of isomers is 
possible, into Schedule IV of the Controlled Substances Act (CSA). This 
action is pursuant to the CSA which requires that such actions be made 
on the record after opportunity for a hearing. The decision of the 
Administrator is reprinted in its entirety below.

DATES: Effective Date: January 11, 2012.

FOR FURTHER INFORMATION CONTACT: Rhea D. Moore, Drug Enforcement 
Administration, 8701 Morrissette Drive, Springfield, Virginia 22152; 
Telephone (202) 307-5268.

SUPPLEMENTARY INFORMATION: 

ALJ Docket No. 10-46

Background

    This is a proceeding under 21 U.S.C. 811(a) for the issuance of a 
rule placing carisoprodol in schedule IV of the Controlled Substances 
Act (CSA). Under this provision, ``the Attorney General may, by rule,'' 
add a ``drug or other substance'' to one of the five schedules of 
controlled substances, ``if he * * * finds that such drug or other 
substance has a potential for abuse, and * * * makes with respect to 
such drug or other substance the findings prescribed by [21 U.S.C. 
812(b)] for the schedule in which such drug is to be placed.'' 21 
U.S.C. 811(a). However, a rule made under this provision ``shall be 
made on the record after opportunity for a hearing pursuant to the 
rulemaking procedures prescribed by subchapter II of chapter 5 of Title 
5.'' Id.
    ``[W]ith respect to each drug * * * proposed to be controlled,'' 
the CSA requires that the Attorney General consider eight factors in 
making the findings required under both subsections 811(a) and 812(b). 
These are:
    (1) [The drug's] actual or relative potential for abuse.
    (2) Scientific evidence of its pharmacological effect, if known.
    (3) The state of current scientific knowledge regarding the drug or 
other substance.
    (4) Its history and current pattern of abuse.
    (5) The scope, duration, and significance of abuse.
    (6) What, if any, risk there is to the public health.
    (7) Its psychic or physiological dependence liability.
    (8) Whether the substance is an immediate precursor of a substance 
already controlled under this subchapter.

21 U.S.C. 811(c).

    However, ``before initiating proceedings * * * to control a drug * 
* * and after gathering the necessary data,'' the Attorney General is 
required to ``request from the Secretary a scientific and medical 
evaluation, and his recommendations, as to whether such drug * * * 
should be controlled.'' Id. 811(b). The statute further provides that 
``[i]n making such evaluation and recommendations, the Secretary shall 
consider the Factors listed in paragraphs (2), (3), (6), (7), and (8) 
of subsection (c) * * * and any scientific or medical considerations 
involved in paragraphs (1), (4), and (5) of such subsection. The 
recommendations of the Secretary shall include recommendations with 
respect to the appropriate schedule, if any, under which such drug * * 
* should be listed.'' Id.
    Finally, ``[t]he recommendations of the Secretary to the Attorney 
General shall be binding as to such scientific and medical matters, and 
if the Secretary recommends that a drug * * * not be controlled, the 
Attorney General shall not control the drug * * *. If the Attorney 
General determines that these facts and all other relevant data 
constitute substantial evidence of potential for abuse such as to 
warrant control * * * he shall initiate proceedings for control * * * 
under subsection (a) of this section.'' Id.

Procedural History

    Pursuant to section 811(b), in March 1996, the Drug Enforcement 
Administration (DEA) requested from the Department of Health and Human 
Services (HHS) a scientific and medical evaluation of carisoprodol, and 
a recommendation as to whether it should be controlled. ALJ Ex 1, at 3. 
In February 1997, however, the U.S. Food and Drug Administration's 
(FDA) Drug Abuse Advisory Committee concluded that the then-available 
data did not support controlling carisoprodol. Id.
    Thereafter, at the direction of the National Institute on Drug 
Abuse (NIDA) and the College of Problems of Drug Dependence (CPDD), 
additional pharmacological studies of carisoprodol's abuse liability 
were conducted. In the meantime, DEA gathered additional new data on 
actual abuse and law enforcement encounters involving the drug, as well 
as other information, which it sent to HHS on November 14, 2005. FDA 
also acquired new data from the Drug Abuse Warning Network (DAWN), the 
National Survey on Drug Use and Health (NSDUH), Florida Medical 
Examiners Commission reports, FDA's Adverse Event Reporting System, as 
well as other information from a variety of sources.
    On October 6, 2009, HHS concluded its review of the evidence 
pertaining to the eight factors set forth in 21 U.S.C. 811 and 
recommended that carisoprodol be placed in schedule IV. GX 6, at 1. 
Thereafter, on November 17, 2009, DEA issued a Notice of Proposed 
Rulemaking, which proposed placing carisoprodol in schedule IV. ALJ 
Ex., at 1 (74 FR 59108). Therein, DEA invited all persons to submit 
written comments or objections to the proposed rule; DEA also notified 
``interested persons'' of their right to request a hearing. Id. at 2 
(citing 5 U.S.C. 556 and 557).
    DEA received seventeen comments on the proposed rule; sixteen of 
the commenters (which included law enforcement officials, medical 
professionals and state regulators) supported the proposed 
rulemaking.\1\ One entity, Meda Pharmaceuticals, Inc. (Meda), which 
manufactures the branded drug Soma, objected to the proposed rule on 
the ground that the ``the administrative record does not include 
substantial and reliable evidence of potential for abuse sufficient to 
warrant scheduling carisoprodol and because the proposal gives 
inadequate weight to the negative impact on patient care of scheduling 
carisoprodol.'' ALJ Ex. 2, at 3. Meda also requested a hearing. Id. at 
1. On March 21, 2010, I granted Meda's request and assigned the matter 
to the Agency's Office of Administrative Law Judges (ALJ). ALJ Ex. 3, 
at 2.
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    \1\ None of the commenters raised any issue as to the various 
Regulatory Certifications contained in the Notice of Proposed 
Rulemaking. See 74 FR at 59111. One commenter, which represents 
wholesale distributors, requested that if the proposed rule is 
finalized, its effective date be set at 120 days from the date of 
publication to provide adequate time to comply with various 
regulations.
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    Following pre-hearing procedures, an ALJ conducted a hearing on 
July 6, 8,

[[Page 77331]]

and 9, as well as on August 3-6, 2010. At the hearing, both the 
Government and Meda elicited the testimony of witnesses and introduced 
various documents into evidence. Thereafter, both the Government and 
Meda filed briefs containing their proposed findings of fact and 
conclusions of law.

The ALJ's Recommended Decision

    On December 8, 2010, the ALJ issued her recommended decision. 
Therein, prior to discussing the eight ``factors determinative of 
control,'' 21 U.S.C. 811(c), the ALJ discussed the weight to be given 
the FDA's findings as to scientific and medical matters. ALJ at 6; see 
also 21 U.S.C. 811(b). As explained more fully below, the ALJ adopted 
the Government's argument that the statute ``limits the scope of the 
administrative hearing to those issues outside of the medical and 
scientific fact-findings of the FDA,'' ALJ at 11, and concluded that 
``the plain language and legislative history of Sec.  811(b), federal 
case law, and [HHS's] process for conducting its administrative review, 
make clear that Congress intended that the Secretary's scientific and 
medical fact-findings bind the DEA during the hearing and the 
subsequent scheduling determination.'' Id. at 18.
    However, the ALJ then noted that ``not all of the conclusions that 
the FDA made in its review are scientific and medical'' in nature and 
that the FDA's conclusions based on data obtained from the Drug Abuse 
Warning Network (DAWN), the National Survey on Drug Use and Health 
(NSDUH), and the Florida Medical Examiners/Coroners Reports ``could 
equally fall under the umbrella of law enforcement or science and 
medicine.'' Id. at 19-20. The ALJ ultimately concluded that ``the data 
gathered by these sources [was] primarily statistical, and not medical, 
and [is] therefore capable of review by this agency.'' Id. at 20. The 
ALJ thus concluded that FDA's conclusions based on this data are ``not 
binding.'' Id. Moreover, notwithstanding her statement as to the scope 
of the hearing, the ALJ allowed Meda to introduce extensive evidence 
including expert testimony as to the various scientific and medical 
matters considered by the FDA.
    The ALJ then made extensive findings as to each of the eight 
section 811(c) factors. With respect to Factor One--the actual or 
relative potential for abuse--the ALJ first explained that ``abuse is 
using a drug for nonmedical purposes for [its] positive psychoactive 
effects.'' Id. at 82. The ALJ then noted the testimony of one of Meda's 
expert witnesses, who runs a drug treatment center, that he could not 
recall a single case of a person being treated at his center for 
dependence on carisoprodol and his opinion that ``the data and 
information presented by the FDA and DEA do not establish that 
carisoprodol has a potential for abuse similar'' to schedule IV 
controlled substances. Id.
    However, the ALJ found ``more compelling'' data compiled by Meda 
and the predecessor holders of the New Drug Application for 
carisoprodol which had been submitted to the FDA's Adverse Events 
Reporting System (AERS). Id. at 82. This data, which includes reports 
from consumers and healthcare practitioners, showed that between 
January 1979 and May 1, 2010, there had been ``731 spontaneous adverse 
event'' reports of which eighty-three used such terms as abuse, 
dependency or withdrawal. Id. at 82-83.
    The ALJ further noted that in 2009, FDA required that Meda re-write 
the drug's label to note the effects of chronic use, that there are 
``published case reports of human carisoprodol dependence,'' and that 
various animal studies indicate the drug has ``effects similar to the 
use of barbital, meprobamate, and chlordiazepoxide,'' all of which are 
controlled substances. Id. at 83. The ALJ also noted that Meda 
eventually accepted the labeling change. Id. at n.42. Based on the AERS 
data and the drug's label, the ALJ concluded that carisoprodol's 
``abuse potential is recognized,'' and that ``the record contains 
substance evidence of a potential for abuse when carisoprodol is 
chronically used.''
    With respect to Factors Two and Three--the scientific evidence of 
carisoprodol's pharmacological effect and the state of current 
scientific knowledge regarding the drug--the ALJ noted that ``[b]oth 
the DEA and the FDA relied on animal studies of self-administration, 
drug discrimination, and physical dependence to support their position 
that carisoprodol should be classified as a schedule IV drug.'' Id. at 
84. The ALJ then noted the testimony of Meda's Expert that ``while the 
animals reflected behavior patterns with respect to carisoprodol that 
suggest patterns similar to barbiturates, the limitations of animal 
studies `do not provide an adequate basis to make decisions concerning 
abuse potential in humans,' '' and that `` `certain drugs will 
substitute for drugs of abuse without themselves being subject to any 
significant drug abuse.' '' Id. The ALJ, however, then held that ``the 
FDA's conclusions regarding carisoprodol's pharmacology and withdrawal 
patterns [were] binding on this proceeding.'' Id.
    The ALJ then discussed three different human studies. With respect 
to the Fraser study,\2\ the ALJ noted that Meda's Expert interpreted 
the results as showing that ``ingestions `did not induce a 
characteristic barbiturate intoxication pattern * * *, nor did the 
abrupt withdrawal of carisoprodol reveal any signs of barbiturate-like 
abstinence' behavior.'' Id. at 85. However, the ALJ then noted that 
``the FDA and the DEA found that the subjective and objective effects 
were similar to those of barbiturates or alcohol and different from 
those of opiates'' and that the drug ``has sedative-like effects.'' Id. 
Here again, the ALJ found FDA's findings binding on the proceeding. Id.
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    \2\ While both parties and the ALJ cited this study as if it was 
an exhibit in the case, it was not included in the record forwarded 
to this Office and there is no indication that it was entered into 
evidence.
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    Next, the ALJ discussed the studies Meda had conducted to obtain 
FDA approval to market a smaller-strength dose. While these studies, 
which involved 4,000 patients, showed no evidence of diversion, misuse, 
or abuse, and none of the patients experienced withdrawal following 
discontinuation of the drug, the ALJ noted that the studies' subjects 
received only therapeutic doses and did so only ``for a period of one 
to two weeks.'' Id. The ALJ thus concluded that these trials ``did not 
test the effects of prolonged use of carisoprodol at ingestion levels 
above the levels for therapeutic use.'' Id.
    The ALJ then discussed a case study by doctors from the Mayo Clinic 
of a 51-year old man who had taken up to six times the maximum 
recommended daily dose, which concluded that the case ``demonstrates 
adverse effects of both carisoprodol toxicity and withdrawal.'' Id. at 
85-86. More specifically, the ALJ noted the study's findings that 
``abrupt discontinuation of high-dose carisoprodol may result in 
withdrawal symptoms including anxiety, psychosis, tremors, myoclonus, 
ataxia and seizures,'' and that ``[t]his withdrawal syndrome is likely 
underrecognized.'' Id. at 86.
    Finally, the ALJ noted the FDA's findings that ``carisoprodol 
possesses sedative properties which may underlie its therapeutic 
usefulness and its potential for abuse,'' that ``[r]ecent in vitro 
studies demonstrated that carisoprodol `possesses barbiturate-like 
effects,' '' that the drug ``has positive reinforcing effects and 
[that] its discriminative stimulus effects are similar to other 
schedule IV drugs such as barbital, meprobamate and chlordiazepoxide.'' 
Id. While the ALJ

[[Page 77332]]

noted that Meda's Expert had challenged the FDA's reliance on an in 
vitro study, she held again that the FDA's ``conclusion is binding on 
this proceeding.'' Id. Based on ``the totality of the record,'' the ALJ 
thus concluded that ``the record demonstrates that excessive 
carisoprodol use creates similar toxicity and withdrawal symptoms to 
other schedule IV drugs.'' Id.
    With respect to Factors Four and Five--the history and current 
pattern of abuse, and the scope, duration, and significance of abuse--
the ALJ began by noting the testimony of several law enforcement 
officials including the head of the DEA Office of Diversion Control, 
the Executive Director of the Ohio State Board of Pharmacy, and a 
Special Agent in Charge with the Tennessee Bureau of Investigation, 
each of whom testified that carisoprodol was being obtained for other 
than a legitimate medical purpose and being either abused or sold on 
the street.
    The ALJ then discussed data obtained from the National Forensic 
Laboratory Information System (NFLIS), the National Survey on Drug Use 
and Health (NSDUH), the Drug Abuse Warning Network (DAWN), Florida 
Medical Examiners, and the National Poison Data System (NPDS). While 
noting that the NFLIS data, which showed that carisoprodol was 
consistently among the top twenty-five drugs being seized during 
criminal investigations and analyzed by state and local forensic 
laboratories are ``not direct evidence of abuse,'' the ALJ concluded 
these data ``lead[] to an inference that [the drug] has been diverted 
and abused.'' Id. at 88.
    As for the NSDUH data, the ALJ noted that data for the years 2004 
through 2007 estimate that between 2,525,000 and 2,840,000 million 
individuals have used carisoprodol during their lifetime for a non-
medical reason. Id. at 89. While observing that the yearly estimates 
``may remain relatively consistent,'' the ALJ observed that ``they are 
still a significant number of nonmedical uses.'' Id. However, the ALJ 
then noted that ``these numbers are significantly lower than comparable 
numbers for the nonmedical use of benzodiazepines.'' Id.
    Next, the ALJ discussed the DAWN data. With respect to the DAWN 
Emergency Department data, the ALJ noted that these data show that the 
abuse frequency of carisoprodol ``is similar to that of diazepam, a 
schedule IV drug,'' and that the data show an ``increasing frequency of 
nonmedical use emergency department visits associated with 
carisoprodol.'' Id. However, the ALJ then noted the credited testimony 
of another of Meda's expert witnesses that there is a ``lack of 
transparency in the methods used to collect * * * and statistically 
extrapolate'' the data, that without ``understanding the nature and 
extent of the changes in case findings(s) during the last several 
years, it is impossible to conclusively say what proportion of the 
increases in DAWN ED national estimates is attributable to changes in 
methodology versus changes in the actual number of DAWN cases 
associated with a particular drug,'' and that ``[t]his hinders any 
effort to interpret'' the trends over time. Id. The ALJ thus agreed 
with Meda's expert that DAWN ED data ``may not be the best evidence in 
this record for concluding that the abuse of carisoprodol is increasing 
over time.'' Id.
    As for the DAWN Medical Examiner data, the ALJ noted that the 
``reporting [of] a drug in this reporting system means that the drug 
need only be implicated or suspected in the death.'' Id. at 90. Quoting 
the testimony of Meda's Expert, the ALJ found that `` `carisoprodol may 
not have been the actual cause of death, and it is not possible to 
conclude that carisoprodol `abuse' was the cause of death in these 
cases.' '' Id. However, the ALJ noted that the data ``showed a link, 
even if not direct evidence of a cause, between carisoprodol use in 
combination with other drugs and death in 434 cases of death in 2006.'' 
Id.
    Turning to the Florida Medical Examiner data, which show that 415 
carisoprodol-related deaths occurred in 2008, and an increase of 
``about 62 percent'' in the ``total occurrence of carisoprodol/
meprobamate in Florida drug abuse deaths,'' the ALJ again noted the 
testimony of Meda's Expert that ``carisoprodol may not be the cause of 
death, but rather it may be merely present in the body at the time of 
death.'' Id. However, the ALJ then found that the FDA ``determined that 
carisoprodol was considered the cause of death in 88 cases in 2007.'' 
Id.
    Next, the ALJ noted that the NPDS data show that in 2007, `` 
`carisoprodol was associated with 8,821 toxic exposure cases, including 
3,605 cases in which [it] was the sole drug mentioned,' '' and that 
``[c]ases of individuals treated in health-care facilities because of a 
major adverse health-outcome total 122 out of the 2,821 single exposure 
cases.'' Id. at 91. The ALJ then acknowledged the testimony of Meda's 
Expert that because the cases are self-reported and ``the reporting 
individual may misidentify the substance during the call to the poison 
center, `it [is] impossible to conclude that a mentioned drug was 
causally implicated in the exposure.' '' Id. However, the ALJ also 
noted the testimony of Meda's Expert that the `` `poison center data 
have some use, but must be interpreted with caution.' '' Id.
    The ALJ further found that while the ``the intentional exposure 
data'' for the years 2006 and 2007 show that the number of deaths 
attributable to ``single exposure cases'' had remained at one per year, 
the number of cases with ``major effects went from 105 to 122,'' and 
the number of cases with ``moderate effects went from 688 to 720.'' Id. 
at 91-92. The ALJ thus concluded that the increases in the major and 
moderate effects cases support the ``conclusion that `individuals are 
taking carisoprodol in amounts sufficient to cause hazard to their 
health.' '' Id. at 92.
    Finally, the ALJ observed that the FDA had ``found that data from 
`2002-2006 indicate that more than 25 percent of patients used the drug 
[for] longer than one month and 4.3 percent used the drug more than 360 
days,' '' and that `` `[l]onger term use may contribute to increased 
risks of misuse and abuse.' '' Id. The ALJ then noted that she 
``agree[d] with the FDA's conclusion.'' Id.
    With respect to Factor Six--the risk, if any, to public health--the 
ALJ again noted the testimony of the head of DEA Office of Diversion 
Control, the Executive Director of the Ohio State Board of Pharmacy, 
and the Special Agent in Charge with the Tennessee Bureau of 
Investigation to the effect that ``the failure to schedule carisoprodol 
poses a great risk to public health.'' Id. at 92-93. The ALJ further 
noted the FDA's conclusion that because carisoprodol is metabolically 
converted to meprobamate, a schedule IV controlled substance, ``the 
public health risks of carisoprodol may be similar to those of 
meprobamate''; the poison control center data which ``show that 
`individuals are taking carisoprodol in amounts sufficient to cause 
hazard to their health' ''; and FDA's finding that `` `the risks of 
carisoprodol to the public health are typical of other central nervous 
system depressants that are controlled' '' and that `` `[t]hese risks 
include central nervous system depression, respiratory failure, 
cognitive and motor impairment, addiction, dependence, and abuse.' '' 
Id. (citations omitted). The ALJ again found that the FDA's conclusions 
were ``binding on this proceeding.'' Id. at 93.
    The ALJ then noted Meda's evidence showing a decline in the number 
of prescriptions that occurred in four States which have controlled

[[Page 77333]]

carisoprodol, as well as Meda's contention that controlling the drug 
would have a chilling effect on the legitimate prescribing of the drug 
because of the reluctance of physicians to prescribe a controlled 
substance and that this would be ``to the detriment of those patients 
who would be best treated with carisoprodol.'' Id. at 93-94. The ALJ 
found, however, that ``anecdotal evidence in this record contradicts 
this prediction,'' because one of Meda's Experts testified that if 
carisoprodol was controlled, he would continue to prescribe it. Id. at 
94. The ALJ then found that DEA data showed that controlling other 
drugs ``did not result in physicians ceasing to prescribe'' them. Id.
    Finally, the ALJ found that ``carisoprodol has been implicated in 
cases of impaired driving, with symptoms consistent with other central 
nervous system depressants, especially alcohol,'' and that ``[a] 
Norwegian study also supported this proposition.'' Id. The ALJ was 
unpersuaded by Meda's argument ``that many uncontrolled drugs have 
labels warning against driving while taking such drugs,'' noting that 
``[i]mpaired driving is a risk to the public health,'' and thus 
supports the ``conclusion that published scientific reports indicate 
that taking carisoprodol is associated with risk to the public 
health.'' Id.
    With respect to Factor Seven--the drug's psychic or physiological 
dependence liability--the ALJ observed that ``[d]ependence includes 
both physical and psychological dependence.'' Id. While noting that 
``there are noncontrolled drugs for which an individual may have a 
physical dependence,'' a drug-taker's conduct must be ``viewed in 
total'' to determine if the person ``has a psychic drive or craving to 
obtain the drug.'' Id. at 95. The ALJ then noted that based on various 
scientific studies, the FDA had ``found that carisoprodol has a 
dependence liability that is similar to that of barbital, a Schedule IV 
central nervous system depressant, in its dependence potential,'' and 
that the FDA's finding was binding on the proceeding. Id. The ALJ also 
cited the testimony of a DEA witness that carisoprodol is abused by 
individuals to obtain a ``mellow euphoria.'' Id.
    The ALJ also found that two studies had shown that carisoprodol 
produces ``subjective and objective effects'' in ``human subjects 
[that] were similar to those of barbiturates or alcohol,'' the former 
being controlled substances listed in both schedules III and IV. Id. at 
96. The ALJ then noted the testimony of Meda's Expert that if 
``carisoprodol induced a barbiturate intoxication pattern, [this] could 
be a possible indicator that carisoprodol possesses barbiturate-like 
abuse liability.'' Id.
    Finally with respect to Factor Eight--whether carisoprodol is an 
immediate precursor to a substance already controlled--the ALJ found it 
undisputed that the drug ``is not an immediate chemical precursor or 
intermediary of a controlled substance.'' Id.
    The ALJ then addressed the three section 812(b) placement factors. 
With respect to Factor One--whether the drug has a low potential for 
abuse relative to the drugs in schedule III--the ALJ began by noting 
the FDA's recommendation (and the concurrence of the National Institute 
on Drug Abuse (NIDA)), that carisoprodol should be placed in schedule 
IV. Id. The ALJ found that ``[e]mpirical evidence supports the FDA's 
conclusion,'' including the evidence that carisoprodol metabolizes into 
meprobamate, a schedule IV controlled substance,'' and that various 
studies support the conclusion that carisoprodol has effects similar to 
barbiturates, which are schedule III and IV controlled substances. Id. 
at 96-97. The ALJ also found that notwithstanding that the DAWN ED 
data, which show that the ``abuse frequency of carisoprodol is similar 
to that of diazepam, a schedule IV drug,'' ``may be overly inclusive,'' 
this limitation would not result in ``any significant difference in ED 
visits between the reported drugs.'' Id. at 98. While acknowledging 
that the NSDUH data show that ``carisoprodol is being abused * * * at a 
rate significantly less than that of benzodiazepines,'' the ALJ found 
that ``the NSDUH and DAWN are two distinct studies, both on methodology 
and measurement, and therefore cannot adequately be compared.'' Id. at 
98-99.
    With respect to Factor Two--whether the drug has a currently 
accepted medical use in treatment in the United States--the ALJ found 
it undisputed that carisoprodol has been approved by the FDA for the 
treatment of ``acute, painful musculoskeletal conditions.'' Id. at 99-
100. The ALJ thus found that ``carisoprodol has a currently accepted 
medical use in the United States.'' Id. at 100.
    With respect to Factor Three--whether abuse of the drug may lead to 
limited physical or psychological dependence relative to the drugs in 
schedule three--the ALJ credited the testimony of two of Meda's experts 
to the effect that carisoprodol ``does not create abuse liability 
patterns typical of controlled drugs'' and that ``[t]here does not 
appear to be any patient `liking' that would indicate an abuse 
potential.'' Id. at 101. The ALJ nonetheless found that ``there is 
substantial evidence in the record based on the animal data, AERS 
reports, and Mayo Clinic data that carisoprodol produces dependence and 
withdrawal symptoms similar to other controlled substances in schedule 
IV.'' Id. The ALJ further held that ``FDA's conclusions regarding the 
psychological and physiological dependence of carisoprodol [were] 
binding on this proceeding.'' Id.
    The ALJ thus concluded that substantial evidence supports the 
controlling of carisoprodol under the eight factors of section 811(c). 
Id. at 102. The ALJ further concluded that substantial evidence 
supported the placement of carisoprodol in schedule IV. Id. (citing 21 
U.S.C. 812).
    Meda filed Exceptions to the ALJ's decision. Thereafter, the ALJ 
forwarded the record to me for final agency action.
    Having considered the entire record, including Meda's Exceptions 
(which are discussed more fully below), I agree with its contention 
that the ALJ erred in holding that the FDA's scientific and medical 
findings are binding on this proceeding. However, because the ALJ 
allowed Meda to put on extensive evidence as to the scientific and 
medical matters considered by the FDA, and because, as ultimate 
factfinder (see 5 U.S.C. 557(b)), I have considered Meda's evidence in 
deciding whether substantial evidence supports the scheduling of 
carisoprodol, I conclude that the ALJ's error is not prejudicial. 
Because I hold that the record as a whole contains substantial evidence 
to support the findings required to control carisoprodol and place it 
in schedule IV of the CSA, I will issue a rule placing carisoprodol in 
schedule IV.

The ALJ's Ruling on the Binding Nature of the FDA's Scientific and 
Medical Evaluation

    As noted above, ``before initiating proceedings * * * to control a 
drug or other substance,'' the Attorney General is required to 
``request from the Secretary a scientific and medical evaluation, and 
[her] recommendations, as to whether such drug or other substance 
should be so controlled.'' 21 U.S.C. 811(b). Congress specified that 
``[i]n making such evaluation and recommendations, the Secretary shall 
consider the factors listed in paragraphs (2), (3), (6), (7), and (8) 
of subsection (c) * * * and any scientific or medical considerations 
involved in paragraphs (1), (4) and (5) of such subsection.' '' Id. The 
Secretary is directed to provide the Attorney General with her 
``evaluation and * * * recommendations,'' which

[[Page 77334]]

``shall include recommendations with respect to the appropriate 
schedule, if any, under which such drug or other substances should be 
listed.'' Id.
    Subsection (b) further provides that ``[t]he recommendations of the 
Secretary to the Attorney General shall be binding as to such 
scientific and medical matters, and if the Secretary recommends that a 
drug or other substance not be controlled, the Attorney General shall 
not control the drug or other substance.'' Id. Moreover, ``[i]f the 
Attorney General determines that these facts and all other relevant 
data constitute substantial evidence of potential for abuse such as to 
warrant control * * * he shall initiate proceedings for control * * * 
under subsection (a),'' the provision which requires that a rule 
scheduling a substance ``be made on the record after opportunity for a 
hearing pursuant to the rulemaking procedures prescribed by'' 5 U.S.C. 
556 and 557.
    The ALJ held that ``the CSA limits the scope of the administrative 
hearing to those issues outside of the medical and scientific fact-
findings of the FDA.'' ALJ at 11. According to the ALJ, the ``the plain 
language and legislative history of [sections 811(a) and (b)] and 
federal case law indicate [that] Congress intended that the Secretary's 
scientific and medical fact-findings bind the [Agency] throughout the 
scheduling process.'' Id. The ALJ further rejected Meda's contention 
that construing the statute in this manner would deny it a meaningful 
hearing and render the hearing ``largely superfluous,'' concluding that 
``Respondent will be afforded the opportunity for a meaningful APA 
hearing without the opportunity to litigate the factual underpinnings 
of the [HHS] report.'' Id.
    The ALJ thus rejected Meda's contention that the FDA's findings as 
to medical and scientific matters are only binding on the Agency's 
decision as to whether to initiate a scheduling proceeding and that the 
Secretary's findings are not binding on either the ALJ or the 
Administrator in evaluating the record of the hearing. Id. at 9-11 
(discussing Meda Br. 15-18). As noted above, throughout her 
consideration of the factors, the ALJ held that she was bound by FDA's 
findings as to scientific and medical matters and that Meda was not 
entitled to challenge the Secretary's medical and scientific findings. 
See, e.g., ALJ at 85-86 (holding FDA's findings as to Factor Two 
(Section 811(c)) binding notwithstanding Meda's contrary evidence).
    I find the ALJ's reasoning confusing,\3\ and that she gave 
insufficient consideration to the most relevant judicial decisions; I 
therefore reject her legal conclusion. To be sure, the Supreme Court 
has recognized that ``[t]he CSA allocates decision making powers among 
statutory actors so that medical judgments * * * are placed in the 
hands of the Secretary,'' and that the ``[t]he structure of the CSA * * 
* conveys unwillingness to cede medical judgments to an Executive 
official who lacks medical expertise.'' Gonzales v. Oregon, 546 U.S. 
243, 265 (2006). Yet, the ALJ's sweeping conclusion that this 
``language supports the inference that the Supreme Court interpreted 
811(b) to indicate that those medical judgments are final and not 
subject to litigation before the DEA,'' ALJ at 13 (emphasis added), 
cannot be squared with other provisions of the statute. Moreover, the 
Court did not decide the issue.
---------------------------------------------------------------------------

    \3\ Compare ALJ at 11 (noting that dicta in Reckitt & Coleman, 
Ltd., v. Administrator, 788 F.2d 22, 27 n.8 (DC Cir. 1977), 
``highlights the inherent ambiguity in the statutory language''), 
with id. at 18 (holding that ``the plain language'' of section 
811(b) ``make[s] clear that Congress intended that the Secretary's 
scientific and medical fact-findings bind the DEA during the hearing 
and the subsequent scheduling determination'').
---------------------------------------------------------------------------

    As noted above, upon receiving the Secretary's evaluation and 
recommendation, the Attorney General is charged with the duty to 
``determine that these facts and all other relevant data constitute 
substantial evidence of potential for abuse such as to warrant 
control.'' 21 U.S.C. 811(b) (emphasis added). In the event the 
Secretary's evaluation and the other relevant data constitute 
substantial evidence such as to warrant control, the Attorney General 
may then initiate proceedings to control the drug. However, Congress 
further provided that ``Rules of the Attorney General [to control a 
drug] shall be made on the record after opportunity for a hearing 
pursuant to the rulemaking procedures prescribed by'' the 
Administrative Procedure Act (APA). 21 U.S.C. 811(a).
    Under this provision, a rule may not be ``issued except on 
consideration of the whole record or those parts thereof cited by a 
party and supported by and in accordance with the reliable, probative, 
and substantial evidence.'' 5 U.S.C. 556(d) (emphasis added). Were it 
the case that the Secretary's findings as to medical and scientific 
matters are not subject to litigation in the subsequent rulemaking 
hearing, the only issues left to be litigated would be the drug's 
``actual'' abuse, its ``history and current pattern of abuse'' and the 
``scope, duration, and significance of abuse.'' 21 U.S.C. 811(b). 
However, an on-the-record hearing (as opposed to notice and comment 
rulemaking) would hardly be necessary to determine whether the data 
proffered by the Agency is adequate to support the findings necessary 
to control a drug. As the DC Circuit explained in Reckitt,\4\ if HHS's 
medical and scientific findings are binding throughout a proceeding, 
``it is difficult to see what purpose the agency's on-the-record 
hearing [would] serve[.]'' \5\
---------------------------------------------------------------------------

    \4\ At issue in Reckitt & Coleman was a rulemaking which 
rescheduled buprenorphine from schedule II to schedule V, but which 
designated the drug as a narcotic based on the ground that it is a 
derivative of thebaine. See 788 F.2d at 22. In a footnote, the Court 
of Appeals discussed an argument advanced in the brief of a third-
party intervenor (which the Department endorsed at oral argument) 
that the Agency's conclusion could be upheld on the ground that 
``HHS's initial communication to DEA stated that buprenorphine is a 
thebaine derivative, and the Act makes HHS's recommendations as to 
`scientific and medical matters' binding on the DEA.'' 788 F.2d 27 
n.8 (citing 21 U.S.C. 811(b)). While the court concluded that it was 
unnecessary to reach the issue, as noted above, it expressed 
considerable skepticism as to the reasonableness of the view that 
the Attorney General is bound by the Secretary's finding on a 
scientific issue notwithstanding contrary evidence presented at a 
hearing. While the DC Circuit's discussion is not binding, it is 
dictum which the Agency ignores at its peril.
    \5\ As support for her holding, the ALJ also cited United States 
v. Spain, 825 F.2d 1426, 1428 (10th Cir. 1987), and United States v. 
Pastore, 419 F.Supp. 1318 (S.D.N.Y. 1976). As for the ALJ's reliance 
on Spain, that case addressed the Attorney General's authority under 
21 U.S.C. 811(h), which authorizes the ``scheduling of a substance 
in schedule I on a temporary basis [when] necessary to avoid an 
imminent hazard to the public safety.'' See 825 F.2d at 1427. Under 
this provision, the Attorney General is not required to obtain a 
scientific and medical evaluation from the Secretary before acting. 
Id. at 148-29. Thus, the case does not address the issue of whether 
the Secretary's medical and scientific evaluation and 
recommendations are subject to re-litigation at the hearing. See 825 
F.2d at 1427.
     Pastore involved a motion to dismiss an indictment which 
charged various offenses involving the unlawful distribution and 
obtaining of the controlled substances phendimetrazine and 
phentermine. See 419 F. Supp. at 1334-35. While the defendants 
raised various challenges to the Attorney General's decision 
scheduling these drugs, both drugs were scheduled without a formal 
on-the-record hearing. Id. at 1346-48. Here again, the case did not 
address the issue of whether the Agency is bound by the Secretary's 
finding on a scientific or medical issue in a formal rulemaking 
proceeding. See id.
---------------------------------------------------------------------------

    The ALJ's also found unpersuasive Grinspoon v. DEA, 828 F.2d 881 
(1st Cir. 1987). Grinspoon involved a petition to review the Agency's 
issuance of a final rule placing MDMA in schedule I. 828 F.2d at 882. 
In Grinspoon, the petitioner raised four different challenges to the 
Agency's rule. Id. at 882-83. These included, inter alia, that the 
``Administrator applied the wrong legal standard'' because he 
interpreted the ``phrases `accepted medical use in treatment in the 
United States,' and `accepted safety for use * * * under

[[Page 77335]]

medical supervision' '' as meaning ``approved for interstate marketing 
* * * under the'' Food, Drug and Cosmetic Act, id. at 884 (quoting 21 
U.S.C. 812(b)(1)(A)), as well as that ``the rule [was] based upon 
incomplete and arbitrary recommendations from the Secretary.'' Id. at 
883.
    The First Circuit held that the Administrator had erroneously 
interpreted the phrases ``accepted medical use in treatment in the 
United States'' and ``accepted safety for use * * * under medical 
supervision'' as meaning that the drug had not been approved by FDA for 
interstate marketing. Id. at 891. The Court thus vacated the rule and 
ordered the Agency to reconsider the scheduling determination. Id.
    The Court, however, also addressed the Petitioner's other 
challenges to the rule, including that HHS had acted in an arbitrary 
and capricious manner because it ``failed to look beyond its own files 
upon receiving the Administrator's section 811(b) request,'' that it 
did not ``consult any organization of medical professionals'' or FDA's 
``Drug Abuse Advisory Committee,'' that it simply rubber-stamped DEA's 
eight-factor analysis, and that it had failed to forward a letter from 
NIDA which questioned evidence pertaining to MDMA's abuse potential in 
animals. Id. at 897. In rejecting the Petitioner's contention, the 
court explained:

    [T]he HHS recommendation to schedule a substance is not binding 
and, indeed, serves to trigger an administrative hearing at which 
interested persons may introduce evidence to rebut the Secretary's 
scheduling recommendation. Ultimately, of course, responsibility 
rests with the Administrator, not HHS, to ensure that the final rule 
rests on permissible legal standards and substantial evidence.

Id. (footnote omitted).

    As Grinspoon makes clear, while the Secretary is the expert as to 
the scientific and medical matters at issue in the scheduling decision, 
the Attorney General is obligated to conduct a hearing and to consider 
contrary evidence even as to these issues. The legislative history 
buttresses this conclusion.\6\ As the House Report explains:

    \6\ Throughout her discussion, the ALJ explained that ``the CSA 
limits the scope of the administrative hearing to those issues 
outside of the medical and scientific fact-findings of the FDA,'' 
that ``Congress intended that the Secretary's scientific and medical 
fact-findings bind the DEA throughout the scheduling process,'' that 
``Respondent will be afforded the opportunity for a meaningful APA 
hearing without the opportunity to litigate the factual 
underpinnings of the [HHS] report,'' ALJ at 11, and that Gonzales 
``indicate[s] that [the FDA's] medical judgments are final and not 
subject to litigation before the DEA.'' Id. at 13.
     However, after concluding that Grinspoon does not support Meda 
and was distinguishable because the Agency had blindly relied on FDA 
approval as the sine qua non of the ``currently accepted medical 
use'' and ``accepted safety for use * * * under medical 
supervision'' standards, the ALJ quoted the passage set forth above 
and observed that ``[i]n light of th[e Administrator's] 
independence, and Meda's opportunity to present evidence relevant to 
the Administrator's decision, this tribunal would be hard-pressed to 
conclude that there was `` `no opportunity for consideration of the 
views of persons who would be adversely affected by control of the 
drug.' '' Id. at 16 (quoting H. Rep. No. 91-1444, at 23 (1970)). 
Yet, she subsequently concluded that ``the plain language and 
legislative history * * *, federal case law, and [HHS's] process for 
conducting its administrative review, make clear that Congress 
intended that the Secretary's scientific and medical fact-findings 
bind the DEA during the hearing and the subsequent scheduling 
determination.'' Id. at 18.
---------------------------------------------------------------------------

    The procedure which the Attorney General must then follow to 
control a drug involves rulemaking proceedings on the record after 
opportunity for a hearing. This provides opportunity for 
consideration of the views of persons who would be adversely 
affected by control of a drug, with judicial review available 
thereafter; however, this administrative proceeding is more 
streamlined in its operation than the existing procedures under 
section 701(e) of the Federal, Food, Drug, and Cosmetic Act, so that 
controls may be established expeditiously where necessary, with full 
consideration of all factors involved in the decision-law 
enforcement problems, medical, and scientific determinations, and 
the interests of parties affected by the decision to control.

H. Rep. No. 91-1444, 1970 U.S.C.C.A.N. at 4589.

    The ALJ also reasoned that the FDA's ``detailed administrative 
process [for] making its scientific and medical fact findings suggests 
that Congress did not intend the DEA to secondarily review those 
filings.'' ALJ at 17. Citing a 1999 Hearing Report of the Subcommittee 
on Oversight and Investigations of the House Committee on Commerce, the 
ALJ noted that the `` `the scientific and medical evaluation process is 
a complex one which is part of the balancing of the interests of 
various agencies' '' and that the process ``may extend over many years, 
[and] is subject to review by various components of the FDA and 
interagency review.'' Id. The ALJ further noted that under two 
different FDA regulations, Meda could have requested a hearing before 
the FDA. ALJ at 17-18 n.5; see also id. at 4 n.2.
    However, in enacting subsection 811(a), Congress did not bifurcate 
the hearing between the two Agencies. Rather, it tasked the Attorney 
General with the responsibility for conducting the hearing. Moreover, 
neither the statute nor the legislative history evidences that Congress 
intended that challenges to the Secretary's scientific and medical 
findings be litigated in a proceeding before HHS.
    In addition, both the statute and the legislative history make 
plain that Congress was concerned that scheduling proceedings be done 
in an expeditious manner. For instance, section 811(b) requires that 
the Secretary submit his report ``to the Attorney General within a 
reasonable time.'' 21 U.S.C. 811(b) (emphasis added). Likewise, in 
discussing the hearing provision, the House Report manifests Congress' 
intent ``that controls may be established expeditiously where 
necessary.'' 1970 U.S.C.C.A.N. at 4589. The ALJ's suggestion that Meda 
was required to request a hearing under either 21 CFR 14.172 or 21 CFR 
15.1(a), see ALJ at 17 & n.5,\7\ runs counter to Congress's manifest 
interest in the expeditious resolution of proceedings to control a 
drug.
---------------------------------------------------------------------------

    \7\ Under 21 CFR 14.172, ``[a]ny interested person may request, 
under Sec.  10.30, that a specific matter relating to a particular 
human prescription drug be submitted to an appropriate advisory 
committee for a hearing and review and recommendations * * *. The 
Commissioner may grant or deny the request.'' Under 21 CFR 15.1(a), 
the Commissioner may ``conclude[], as a matter of discretion, that 
it is in the public interest to permit persons to present 
information and views at a public hearing on any matter pending 
before the Food and Drug Administration.'' Notably, under both 
provisions, the decision as to whether to grant a hearing is within 
the Commissioner's discretion.
---------------------------------------------------------------------------

    In its Exceptions, Meda contends that ``the ALJ's decision in this 
proceeding is predicated upon an erroneous belief that Meda had an 
opportunity to challenge the scientific and medical fact-finding 
underlying'' the HHS recommendation. Meda Exc. at 1. The exception is 
well taken. Indeed, as set forth in footnote seven above, under both of 
these provisions, the decision as to whether to grant a hearing is 
discretionary. Requiring that Meda litigate the medical and scientific 
findings before an FDA forum would likely add several years of delay, 
and would raise a host of additional issues, including whether DEA was 
required to stay its proceeding while the findings were being 
challenged before an FDA forum, whether those findings are entitled to 
res judicata effect if a formal evidentiary hearing was not held, 
whether the FDA's decision was a final decision triggering the right to 
judicial review, and likely others.
    Also unpersuasive is the ALJ's reasoning that because the FDA's 
process for evaluating a scheduling request is complex and time-
consuming, ``Congress did not intend the DEA to secondarily review 
those findings.'' ALJ at 17. As the House Report makes plain,

[[Page 77336]]

in enacting the scheduling provisions, Congress manifested its 
intention that scheduling proceedings would be done in an expeditious 
fashion, but with ``full consideration of all factors involved in the 
decision,'' including the medical and scientific determinations 
involved in the decision. 1970 U.S.C.C.A.N. at 4589 (emphasis added). 
The ALJ's conclusion that the medical and scientific findings of FDA 
are binding and cannot be ``secondarily review[ed]'' in this 
proceeding, is contrary to this intent.
    Accordingly, consistent with the APA's requirement that the record 
as a whole must be considered, I hold that, notwithstanding the 
Secretary's expertise as to the scientific and medical matters, the 
Agency is (and the ALJ was) obligated to consider Meda's contrary 
evidence even as to the Secretary's medical and scientific findings and 
to determine whether substantial evidence supports the finding that 
carisoprodol ``has a potential for abuse,'' as well as the findings 
made in support of placing the drug in schedule IV. See 21 U.S.C. 
811(a).
    However, while the ALJ misconstrued the statute, she did allow Meda 
to put on evidence to rebut the Secretary's evaluation of the medical 
and scientific evidence. Because ``[t]he Agency, and not the ALJ, is 
the ultimate factfinder,'' Reckitt & Colman, 788 F.2d at 26, I conclude 
that ALJ did not commit prejudicial error. Cf. 5 U.S.C. 706 (``due 
account shall be taken of the rule of prejudicial error''). 
Accordingly, a remand is not necessary and I proceed to consider the 
evidence with respect to the section 811(c) factors.

Findings of Fact

    Since 1959, carisoprodol has been approved for marketing in the 
United States under the brand name of Soma; the drug, which is also 
available as a generic drug, is approved by the FDA for the ``relief of 
discomfort associated with acute, painful musculoskeletal conditions.'' 
GX 6, at 1 (letter of Howard H. Koh, M.D., Asst. Sec. for Health, HHS, 
to the Administrator (Oct. 6, 2009)). As noted above, on October 6, 
2009, HHS completed its review and recommended that carisoprodol be 
controlled and placed in schedule IV of the CSA. Id.
    FDA made extensive findings as to each of the eight section 811(c) 
factors. These findings are discussed below,\8\ along with additional 
evidence provided by DEA's witnesses and the testimony and exhibits 
submitted by Meda.
---------------------------------------------------------------------------

    \8\ Meda argues that the FDA review ``is entitled to very little 
weight'' because ``DEA counsel did not call any HHS or FDA witness 
to testify and justify the scientific, medical, and legal basis 
underlying the HHS recommendation.'' Meda. Br. 22. However, most of 
the findings in the FDA's evaluation were supported by citations to 
publicly available articles, and it is not clear why an FDA witness 
was required to testify as to the contents of articles which have 
been published in scientific and medical journals. Moreover, Meda 
did not seek to subpoena any of the FDA officials who were involved 
in the review. Finally, while the Government did not call an FDA or 
HHS witness ``to answer questions about the numerous weaknesses in 
the data,'' Meda was clearly able to put on an effective challenge 
to some of the data cited by the Government.
---------------------------------------------------------------------------

Factor 1--Carisoprodol's Actual or Relative Potential for Abuse

    The terms ``abuse'' and ``potential for abuse'' are not defined in 
the CSA. See generally 21 U.S.C. 802. However, the legislative history 
of the CSA explains that a drug or ``substance has a potential for 
abuse because of its depressant or stimulant effect on the central 
nervous system or its hallucinogenic effect'' based on the following 
indicators:

    1. Individuals are taking the substance in amounts sufficient to 
create a hazard to their health or to the safety of other 
individuals or to the community; or
    2. There is significant diversion of the drug or substance from 
legitimate drug channels; or
    3. Individuals are taking the substance on their own initiative 
rather than on the basis of medical advice from a practitioner 
licensed by law to administer such substance; or
    4. The substance is so related in its action to a substance 
already listed as having a potential for abuse to make it likely 
that it will have the same potential for abuse as such substance, 
thus making it reasonable to assume that there may be significant 
diversions from legitimate channels, significant use contrary to or 
without medical advice, or that it has a substantial capability of 
creating hazards to the health of the user or to the safety of the 
community.

Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. 
No. 91-1444, reprinted in 1970 U.S.C.C.A.N. 4566, 4601.

    The legislative history also explains that a determination that a 
substance has ``potential for abuse'' should not ``be determined on the 
basis of isolated or occasional nontherapeutic purposes.'' Id. at 4602 
(other citation and int. quotations omitted). Rather, ``there must 
exist a substantial potential for the occurrence of significant 
diversions from legitimate channels, significant use by individuals 
contrary to professional advice, or substantial capability of creating 
hazards to the health of the user or the safety of the community.'' Id. 
However, the legislative history also makes clear that the Attorney 
General is not ``required to wait until a number of lives have been 
destroyed or substantial problems have already arisen before'' 
controlling a drug. Id.
    The legislative history further explains that ``[i]n speaking of 
`substantial' potential the term `substantial' means more than a mere 
scintilla of isolated abuse, but less than a preponderance.'' Id. Thus, 
evidence that ``several hundred thousand dosage units of a drug have 
been diverted would be `substantial' evidence of abuse despite the fact 
that tens of millions of dosage units of that drug are legitimately 
used in the same time period.'' Id. Moreover, ``[m]isuse of a drug in 
suicides and attempted suicides, as well as injuries resulting from 
unsupervised use are regarded as indicative of a drug's potential for 
abuse.'' Id.
    As the Assistant Secretary noted, ``there is no single test or 
assessment procedure that, by itself, provides a full and complete 
characterization of a substance's abuse potential, as this is a complex 
determination that is multidimensional.'' GX 6, at 3. Accordingly, in 
``assessing the abuse potential of a substance, the Secretary considers 
multiple factors, data sources and analyses,'' including ``the 
prevalence, frequency and manner of use in the general public and 
specific subpopulations, the amount of material that is available for 
illicit use, as well as evidence relevant to populations that may be of 
particular risk.'' Id.
    The Assistant Secretary further explained that:

[a]nimal, human, and epidemiological data are all used in 
determining a substance's abuse potential. Scientifically, a 
comprehensive evaluation of the relative abuse potential of a 
substance includes consideration of the drug's receptor binding 
affinity, preclinical pharmacology, reinforcing effects, 
discriminative stimulus effects, dependence producing potential, 
pharmacokinetics and routes of administration, toxicities, 
assessment[] of the clinical efficacy, safety database relative to 
actual abuse, clinical abuse potential studies and the public health 
risks following marketing of the substance. Epidemiological data can 
also be an important indicator of actual abuse. Finally, evidence of 
clandestine production and illicit trafficking of a substance are 
also important factors.

Id. Set forth below is the parties' evidence as to each of the four 
indicators of carisoprodol's potential for abuse.\9\
---------------------------------------------------------------------------

    \9\ I have considered Meda's argument that by relying on the 
four indicators of abuse set forth in the legislative history, the 
Agency ``has improperly attempted to redefine `abuse' to mean 
something much broader than what the Committee contemplated (i.e., 
use for nontherapeutic purposes).'' Med. Br. 13. However, as the 
Assistant Secretary noted, determining a substance's potential for 
abuse is a complex and multi-dimensional determination which 
includes an analysis of animal, human, and epidemiological studies, 
as well as other factors, GX 6, at 3; and the record contains 
extensive evidence as to the numerous considerations relevant in 
assessing a drug's abuse potential.

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[[Page 77337]]

1. Use of Carisoprodol Results in Harm to Individuals and the Public

    The FDA found that an evaluation of published case reports and case 
series, the FDA Adverse Event Reporting System (AERS), and the SAMHSA 
DAWN databases, show that carisoprodol as currently used raises 
concerns not only for the health and safety of the users of this 
substance, but also for the public because of exposure to those who use 
carisoprodol. More specifically, the FDA found that these sources of 
information indicate that serious adverse events, including death, drug 
dependence, drug withdrawal symptoms, and non-intentional and 
deliberate overdose are related to the abuse of carisoprodol.
    The FDA further noted that adverse events have occurred both when 
carisoprodol is the sole drug of use, as well as when it is used in 
combination with other drugs, both licit and illicit (polypharmacy). In 
addition, the use of carisoprodol has been implicated as a factor in 
vehicle accidents due to driver impairment. The FDA thus concluded that 
there is evidence that individuals are taking the substance in amounts 
sufficient to create a hazard to their health or to the safety of other 
individuals or to the community.\10\
---------------------------------------------------------------------------

    \10\ The FDA more fully discussed the data under Factor Four--
carisoprodol's history and current patterns of use, and Factor Six--
what, if any, risk there is to public health. GX 6, at 3.
---------------------------------------------------------------------------

Drug Abuse Warning Network (DAWN) Data
    The Substance Abuse Mental Health Service's Administration (SAMHSA) 
administers the Drug Abuse Warning Network (DAWN, 2007; https://dawninfo.samhsa.gov/). DAWN is a national probability survey of U.S. 
hospitals with emergency departments (EDs) which is designed to obtain 
information on ED visits in which recent drug use is implicated. The 
data are gathered from a representative sample of hospital EDs and are 
weighted to produce national estimates. In addition to the DAWN ED 
data, DAWN also collects data on drug-related deaths investigated by 
Medical Examiners and Coroners (ME/C).\11\
---------------------------------------------------------------------------

    \11\ According to the FDA's report, DAWN mortality cases now 
include the following deaths: Completed suicides, Overmedication, 
Adverse reactions, Accidental ingestions, Homicide by drugs, 
Underage drinking and Other deaths related to drugs. The FDA further 
noted that ``[t]he mortality component of DAWN is not national in 
scope, and Medical Examiners or Coroners (ME/Cs) that report to DAWN 
are concentrated in metropolitan areas.'' GX 6, at 17. The FDA then 
acknowledged that because ``the report does not represent a 
scientific sample, results from participating jurisdictions cannot 
be extrapolated nationally,'' and that ``because participants can 
vary from year to year, it is not appropriate to compare aggregated 
death data between years.'' Id. Moreover, because ``[c]ertain 
jurisdictions within the metropolitan area may not participate in 
DAWN * * * selected data can not necessarily be generalized to an 
entire metropolitan area.'' Id.
     FDA further noted that ``[a]pproximately half of the 
carisoprodol-related deaths reported involve the use of meprobamate 
in combination with carisoprodol'' and that ``[d]ue to reporting 
method variability, it is difficult to determine if both drugs were 
taken in combination or if meprobamate was present in the deceased 
as a result of carisoprodol metabolism.'' Id. Finally, FDA noted 
that ``[t]he reporting of carisoprodol found by the ME/C following a 
post mortem examination does not necessarily imply that carisoprodol 
was the ultimate cause of death * * *, only that it was identified 
by the ME/C as involved in the death,'' and that ``[v]ery few deaths 
from 2003 and 2004 involve the use of carisoprodol by itself and are 
consistent with other data indicating that carisoprodol is used most 
often in combination with a variety of other agents.'' Id. at 18. 
Because of the numerous limitations with this data, I give no weight 
to the DAWN ME/C data.
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DAWN ED Data
    According to FDA, many factors can impact the estimates of ED 
visits, GX 6, at 11; which ``are identified through a retrospective 
review of medical charts.'' MX 34, at 33 n.13. Individuals (whether 
patients or drug abusers) who use a drug may visit EDs for a variety of 
reasons, including treatment of a life threatening adverse event or to 
obtain a certification of need before entering a formal detoxification 
program. If multiple drugs are involved, DAWN may not be able to 
distinguish whether a single drug or the interaction of drugs caused 
the ED visit. Moreover, while ``DAWN tries to capture only drugs that 
are related to the ED visit and actively discourages the reporting of 
current medications that are unrelated to the visit[,] * * * it is not 
possible, given the limitations of medical record documentation, to 
eliminate completely the reporting of current medications.'' MX 34, at 
33.
    In addition, DAWN defines ``nonmedical use'' as ``use that does not 
meet the definition of medical use.'' Id. Under this definition, 
``nonmedical use of pharmaceuticals includes taking more than the 
prescribed dose of a prescription pharmaceutical * * *; taking a 
pharmaceutical prescribed for another individual; deliberate poisoning 
with a pharmaceutical by another person; and documented misuse or abuse 
of a prescription'' pharmaceutical. Id. Because of ``the limitations of 
medical record documentation, [DAWN has] concluded that distinguishing 
misuse from abuse reliably is not feasible.'' Id. n.13.
    Selected data from DAWN for 2004-2007 are shown in Table 1 below. 
These data show an increase in the frequency of nonmedical use ED 
visits associated with carisoprodol. More specifically, in 2004, DAWN 
estimated that there were 14,736 ED visits related to the nonmedical 
use of carisoprodol, and that in 2007, there were 27,505 nonmedical ED 
visits related to the nonmedical use of the drug. However, according to 
SAMHSA, the increase from 2004 through 2007 did not reach statistical 
significance. GX 6, at 12. Accordingly, the data do not support a 
finding that the rate of abuse of carisoprodol is increasing.
    The data do, however, support a finding that carisoprodol is 
resulting in ED visits at a level comparable to that of diazepam, a 
benzodiazepine and schedule IV controlled substance. As Table 1 shows, 
in 2004 there were an estimated 15,619 ED visits related to 
diazepam.\12\
---------------------------------------------------------------------------

    \12\ In 2007, DAWN ED carisoprodol visits also accounted for an 
increasing percentage of the nonmedical use ED visits associated 
with skeletal muscle relaxants, increasing each year from 59 percent 
in 2004, to 70 percent in 2007.

 Table 1--Selected Pharmaceutical ED Visits (Nonmedical Use): 2004-2007