# Schedules of Controlled Substances: Placement of Carisoprodol Into Schedule IV

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URL: https://www.frixlaw.com/law-library/documents/fr%3A2011-31542

## Record

- **Collection:** Federal Register
- **Document type:** Rule
- **Published:** December 12, 2011
- **Citation:** 76 FR 77330

## Text

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.

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.

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.

Following pre-hearing procedures, an ALJ conducted a hearing on July 6, 8,

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 § 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.

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.

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

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

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

“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

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 § 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,

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.

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;
http://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.

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 From DAWN
[Data output 08/02/2008]

Selected drugs
Estimates
2004
2005
2006
2007

Carisoprodol
14,736
20,082
24,505
27,128

Cyclobenzaprine
6,183
7,629
7,142
6,197

Diazepam
15,619
18,433
19,936
19,674

By dividing the number of ED visits by the number of prescriptions, FDA calculated “abuse frequencies” for carisoprodol; cyclobenzaprine, a non-scheduled muscle relaxant; and diazepam, which is also prescribed for its muscle relaxant properties. These calculations, which are found in Table 2 below, show that the “abuse frequency” of carisoprodol is in the same range as diazepam and greater than that of cyclobenzaprine. More specifically, even in 2004, the carisoprodol rate was 15.1 ED visits per 10,000 prescriptions, while diazepam's rate was 12.5. By contrast, cyclobenzaprine, another skeletal muscle relaxant had a rate of 4.1 ED visits per 10,000 prescriptions. Most significantly, even in 2004, and before the increase in the estimates of carisoprodol-related ED visits, carisoprodol had a greater frequency of ED related visits than diazepam.

Table 2—Frequency of DAWN ED Visits (Nonmedical Use) per 10,000 Rx for Carisoprodol, Cyclobenzaprine and Diazepam
[2004-2007]

Selected drugs
2004
2005
2006
2007

Carisoprodol
15.1
19.7
22.9
22.6

Cyclobenzaprine
4.1
4.61
4.1
3.3

Diazepam
12.5
14.5
15.0
14.1

Data derived from proprietary SDI data. SDI Vector One®: National, Years 2002-2007, Data Extracted April, 2008 File: VONA 2008-517 4-15
13

13
According to FDA, SDI's Vector One
TM
National (VONA) measures retail dispensing of prescriptions or the frequency with which drugs move out of retail pharmacies into the hands of consumers via formal prescriptions. GX 6, at 13 n.7. Information on the physician's specialty, the patient's age and gender, and estimates for the numbers of patients that are continuing or new to therapy are available.
Id.

The Vector One
TM
database integrates prescription activity from a variety of sources including national retail chains, mass merchandisers, pharmacy benefits managers and their data systems, and provider groups.
Id.
Vector One receives over 1.8 billion prescription claims per year, representing over 150 million unique patients.
Id.
The number of dispensed prescriptions is obtained from a sample of virtually all retail pharmacies throughout the United States, and represents approximately half of retail prescriptions dispensed nationwide.
Id.
SDI receives all prescriptions from approximately one-third of the stores and a significant sample of prescriptions from the remaining stores.
Id.

Carisoprodol has been reported as a primary or sole drug of abuse in DAWN only since 2006. According to the 2006 DAWN data, there were an estimated 24,505 ED visits related to carisoprodol, of which it was reported as the sole drug in 21 percent of the cases. This is consistent with the FDA's finding that the majority of the cases published in the scientific literature report that carisoprodol abuse has primarily been a component of multi-drug abuse.

FDA reviewed DAWN data and found that the drugs most frequently used in combination with carisoprodol that resulted in ED visits were opioids (hydrocodone, oxycodone), benzodiazepines (alprazolam, diazepam, clonazepam), alcohol, and illicit drugs (marijuana, cocaine). Table 3 below sets forth the respective levels of carisoprodol ED visits related to single use and as a component of multi-drug use.

Table 3—Estimated Nonmedical Use—Carisoprodol ED Visits From DAWN 2006, as Sole Drug and in Combination With Other Drugs

All patients
Drug
Number
Percent
Females only
Drug
Number
Percent
Males only
Drug
Number
Percent

Total Carisoprodol
24,505

Total Carisoprodol
14,219
42
Total Carisoprodol
10,286
58

Carisoprodol single-drug
5,055
21
Carisoprodol single-drug
3.870
27
Carisoprodol single-drug
1,185
12

Carisoprodol multi-drug
19,450
79
Carisprodol multi-drug
10,349
73
Carisoprodol multi-drug
9,101
88

Information received from SAMHSA on June 18, 2008.

FDA also found that although carisoprodol is approved for short term use (3 weeks), SDI Vector One data from 2002-2006
14

show that more than 25 percent of patients used the drug for longer than one month, and 4.3 percent used the drug for more than 360 days. GX 6, at 15. FDA concluded that longer term use may contribute to increased risks of misuse and abuse.
Id.

14
See Table 6 from the OSE “Duration of Use Analysis” for Soma (NDA 11-792) dated June 27, 2007.

MEDA's Evidence Regarding the DAWN Data

Meda offered the testimony of Mr. Nabarun Dasgupta as an expert witness in epidemiology and pharmacoepidemiology. MX 173; Tr. 628. Mr. Dasgupta offered a lengthy critique of the DAWN ED data and opined that “the DAWN ED data are subject to constraints that limit their potential reliability for use in scientific research and public health policy.” MX 173, at 3.

More specifically, Mr. Dasgupta criticized the sampling methodology used by DAWN, noting that DAWN uses an oversample of hospitals in select metropolitan areas and a sample of hospitals from the rest of the country and that “[t]he number of hospitals sampled is relatively small compared to the national estimates that are extrapolated from the sample.”
Id.
Mr. Dasgupta noted that for the year 2007, “207 hospitals submitted provided data on 300,983 drug related ED visits * * *.

which resulted in a national estimate of 3,998,228 drug-related ED visits.”
Id.
at 3-4. Mr. Dasgupta further stated that “[t]he location of all hospitals participating * * * is not disclosed due to privacy reasons,” and that “the number of hospitals can change
post hoc
in the published annual report tables.”
Id.
at 4. As support for the latter assertion, Mr. Dasgupta cited the 2005 and 2006 annual reports; however, only one of these (the 2006 report) was submitted for the record.

Later in his testimony, Mr. Dasgupta asserted that “[o]nce the cases in the participating hospitals are counted, DAWN applies statistical methods to extrapolate to a `national estimate,' ” and that each case is given “a weight from 1 to 60 to arrive at the national estimates,” and that while it is “routine to describe how weights are derived,” DAWN does not “completely describe the process.”
Id.
at 14. Mr. Dasgupta also explained that while such factors as “`non-response,' missing data, hospital size, physical location, whether it is an academic training hospital, and other factors are accounted for in the weight, * * * the method for doing this is not published.”
Id.
Mr. Dasgupta concluded that “the credibility of the national DAWN data * * * hinges on the statistical methods employed to analyze the sample data, but SAMHSA does not publicly disclose the current methods. We do not know how the weights of the individual hospitals are being applied, and we do not know what impact the extrapolations may be having on the reported national estimates.”
Id.
Mr. Dasgupta thus opined that “[t]he lack of information provided by DAWN concerning its statistical extrapolation methods hinders interpretation and hence limits the weight that can be given the DAWN national estimates.”
Id.
at 14-15.

On examination by the ALJ, Mr. Dasgupta was asked if, “within the community of epidemiologists, * * * the DAWN ED national estimation [is] still relied upon?” Tr. 652. Mr. Dasgupta replied that “[t]he DAWN ED data are important to look at,” and that “others would agree * * * in that it sets * * * it's the data that is used for policy making.”
Id.
Mr. Dasgupta then asserted that “[f]rom a scientific perspective, it doesn't carry much weight.”
Id.
However, DAWN ED does not purport to be anything other than an estimate, and Mr. Dasgupta's testimony suggests that epidemiologists still consider the estimates sufficiently reliable to make policy decisions.

Moreover, Mr. Dasgupta generally did not identify what practices (including what level of disclosure) the field of epidemiologists considers to be necessary to establish the validity of a methodology and the statistical methods used to extrapolate the data to develop a national estimate. While Mr. Dasgupta's criticisms of the DAWN ED data may be based on the generally accepted standards of epidemiology, in the absence of evidence establishing those standards, there is no basis for concluding that his criticisms of DAWN ED data reflect those of the community of epidemiologists rather than his personal opinion.

Mr. Dasgupta further asserted that the scientific validity of the data “is questionable” because it “does not conform with the FDA's published guidance on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessments.” MX 173, at 4-5. According to Mr. Dasgupta, this “call[s] into question whether DAWN ED data should be used by FDA and FDA-regulated entities for post-marketing surveillance.”
Id.
However, Mr. Dasgupta did not identify in what respect DAWN does not comply with the FDA's guidance.
See id.
Nor is it clear why compliance with the FDA's guidance is necessary to establish that the DAWN ED data, which is only an estimate, is not sufficiently reliable to support a finding that carisoprodol “has a potential for abuse.” 21 U.S.C. 811(a)(1)(A).

Mr. Dasgupta's next criticism was that the reporters of DAWN ED data “may identify an ED visit as a DAWN case even if the patient has a valid prescription for the drug(s) mentioned in the ED chart and is taking the drug(s) for therapeutic purposes.”
Id.
at 5. Mr. Dasgupta noted that “[w]hile Reporters are trained on selecting cases, no published studies have evaluated the consistency between Reporters or between hospitals, or over time.”
Id.
Mr. Dasgupta also noted that this “calls into question the reliability of reporting across sites, given the lack of published validation of the consistency between Reporters at different sites.”
Id.

Mr. Dasgupta further noted that “there has been a concerted effort by SAMHSA and the contractor to improve [the] selection of cases, [which is] aimed at identifying more ED visits for inclusion.”
Id.
at 5-6. Mr. Dasgupta stated that because there has been “no public documentation of this process,” it is not clear if “the increases in cases over time is due to better case finding or due to increases in the underlying sociobiologic phenomena that give rise to DAWN cases.”
Id.
at 6.

According to Mr. Dasgupta, “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 “[t]his hinders any effort to interpret the meaning of time trends.”
Id.

On examination by the ALJ, Mr. Dasgupta testified that this,
i.e.,
the increase “attributable to enhanced case-finding versus [that] attributable to the underlying actual abuse * * * is something that is routinely looked at in epidemiologic studies.” Tr. 657. He also suggested that in such circumstances, “a validation study” would be done to determine how well those persons who review the case files were doing.
Id.
at 658. However, even acknowledging the validity of this criticism, the FDA's recommendation stated that the increase in the estimates of carisoprodol-related ED visits between 2004 and 2007 was not statistically significant.

Mr. Dasgupta also observed that “DAWN has acknowledged the difficulty in identifying cases of abuse” because of the limitation of medical record documentation.
Id.
at 7. As Mr. Dasgupta observed, because DAWN defines “nonmedical use” to include a variety of scenarios beyond misuse/abuse, “ED visits counted as `nonmedical use' ” by DAWN “do not necessarily represent cases of abuse as that term is commonly understood,” and as “used for purposes of scheduling.”
Id.
at 9-10.

Mr. Dasgupta also noted that “[a]lthough current medications unrelated to the visit are not supposed to be recorded, distinguishing medications that pertain to the ED visit from those that do not requires a complex toxicological determination,” which hospitals may not conduct “in the interest of providing expedient medical care.”
Id.
at 10. Mr. Dasgupta stated that differences in how toxicology testing is conducted at different hospitals “may influence whether a drug is detected,” and that “the simple presence of a drug in toxicology results is not sufficient to implicate its involvement in an ED visit.”
Id.
at 12. He further noted that “it is highly probable that to some extent the determination of the involvement of unrelated medications may be inherently subjective, [and may] vary between Reporters,” who have different training and experience.
15

Id.
at 10.

However, Mr. Dasgupta then opined that “drugs are most often identified by patient self-reporting,” that “[o]nly a small percentage is confirmed by toxicology tests,” and that therefore, “DAWN data are subject to all of the uncertainties and potential misidentifications associated with self-reporting.”
16

Id.
at 13.

15
Mr. Dasgupta also testified that the DAWN data may be affected by diagnostic suspicion bias in that DAWN reporters may have become sensitized by news reports or other information as to the abuse of a particular drug, and therefore, may over-report such cases. MX 173, at 12. However, Mr. Dasgupta produced no evidence as to the existence of this

phenomenon among DAWN reporters either generally or with respect to carisoprodol.

16
Mr. Dasgupta further noted that DAWN may at times impute data when data is missing from certain hospitals. MX 173, at 18-19. While Mr. Dasgupta suggested that this practice is of “questionable validity,”
id.,
this is not the same as saying that this practice is not generally accepted by experts in the field. Indeed, on examination by the ALJ, Mr. Dasgupta testified that “it is valid to use imputation methods to fill in missing data, but it's a very, very sensitive issue that needs to be done carefully.” Tr. 669. Mr. Dasgupta then stated that “[t]here are three, four, maybe five major ways in which imputation is done in epidemiology to fill in missing data like these, and the choice of which of those imputation methods * * * can very strongly influence your results,” that “the onus is on the researcher to show that those assumptions have been met and that the method selected is the appropriate one,” and that “if there is kind of [a] referenced imputation[,] it's odd to not see those kinds of descriptions on which statistical imputation method is used.”
Id.
at 669-70. However, Respondent produced no evidence that the use of imputed data has affected the DAWN data for carisoprodol.

As explained above, DAWN explicitly recognizes the limitations inherent in medical record documentation. Moreover, even crediting Mr. Dasgupta's criticisms, as even he recognized, “[t]he DAWN ED data are important to look at” and “it's the data that is used for policymaking.” Tr. 652. The DAWN ED data provide only an estimate; the data constitute just one of many pieces of evidence which support the conclusion that persons are taking carisoprodol “in amounts sufficient to create a hazard to their health.”

FDA Adverse Event Reporting System (AERS) Data
17

17
The Adverse Event Reporting System (AERS) is a computerized database designed to support the FDA's postmarketing safety surveillance program for all approved drug and therapeutic biologic products. GX 6, at 15. The FDA receives adverse drug reaction reports from manufacturers as required by regulation.
Id.
Health care professionals and consumers send reports voluntarily through the MedWatch program, which become part of a database; the database complies with the international safety reporting guidance (ICH E2B) issued by the International Conference on Harmonization.
Id.

As noted above, FDA also reviewed the AERS data and found that through June 2007, there were a total of 472 reports related to potential carisoprodol abuse, including 48 reports identifying dependence and 19 identifying withdrawal syndrome. GX 6, at 15. In the majority of cases, multiple drugs were used, but there are 61 unique reports where carisoprodol was the only suspect drug.
Id.

Meda's Chief Medical Officer (CMO) provided more up-to-date data. In his written direct testimony, MEDA's CMO stated that “MEDA's database contains a total of 731 spontaneous adverse events for carisoprodol from January 1979 through May 1, 2010,” of which “only 83 reports included the terms abuse, dependency, or withdrawal.” MX 171, at 10. MEDA's CMO further noted that in the five-year period of 2005-2009, more than 54 million prescriptions, totaling nearly four billion tablets of carisoprodol, were dispensed.
Id.
at 11.

While the AERS data appears relatively small when compared with the total number of prescriptions, as explained in footnote fifteen, this data is obtained from health care professionals and consumers, both of whom voluntarily submit the reports. As FDA notes, it “does not receive all adverse event reports that occur with a product” as “[m]any factors can influence whether or not an event will be reported.” FDA, Adverse Events Reporting System, available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm
. Accordingly, “AERS cannot be used to calculate the incidence of an adverse event in the U.S. population.”
Id.
Indeed, the voluntary nature of the reports suggests that they are likely to under-represent the actual number of adverse events.

Florida Medical Examiners Commission Data

In 2008, Florida's medical examiners reported 8,556 drug-related deaths (whether the drug was the cause of death or merely present) through toxicology reports submitted to the Medical Examiners Commission. GX 7, at 11. The presence of carisoprodol and/or its metabolite, meprobamate, was found in 415 deaths (5 percent of the drug related deaths).
Id.
In 84 of these deaths (20%), carisoprodol was determined to be the cause of death.
Id.
The following table lists, for the years 2003 through 2008, the number of deaths in which carisoprodol and meprobamate were found in toxicology testing and the number of deaths in which carisoprodol and meprobamate were found to be a cause of death.

Table 4—Florida Medical Examiner's Data 2003-2008

Year
Drugs found in body

Total
occurrences

Cause
(% total)

Present
% Change from prior year

2003
18

Carisoprodol/Meprobamate
208
45 (22)
163
ND

2004
Carisoprodol/Meprobamate
289
81 (28)
208
39

2005
Carisoprodol/Meprobamate
314
96 (31)
218
9

2006
Carisoprodol/Meprobamate
313
74 (24)
239
−0.3

2007
Carisoprodol/Meprobamate
337
88 (26)
249
8

2008
Carisoprodol/Meprobamate
415
84 (20)
331
23

Id.; see also
GX 7, at 11

.

18
Carisoprodol was scheduled as C-IV in Florida in July 2002, but was not tracked until 2003. GX 6, at 18.

With respect to this data, Mr. Dasgupta stated that “[t]he presence of a drug in the body does not establish it as a cause of death” or necessarily “indicate drug abuse.” MX 173, at 23. As for the first contention, the data recognizes as much as it differentiates between those instances in which toxicology testing established that carisoprodol/meprobamate was present in a body and those in which
a medical examiner concluded
that the ingestion of carisoprodol or meprobamate
was a cause of death.
Likewise, while a drug's presence in the body does not necessarily establish that the person was engaged in “drug abuse,” it nonetheless is an indicator of drug abuse, especially where the deaths were found to be caused by an overdose.

Mr. Dasgupta further concluded that because the data combines carisoprodol and meprobamate, “it is not possible to determine * * * which drug * * * was a cause of death.”
Id.
at 23. However, carisoprodol metabolizes into meprobamate, and other data in the record (more specifically, the NSDUH

data,
see
Table 7) indicates that more than eleven times as many persons have engaged in the nonmedical use of carisoprodol than have engaged in the nonmedical use of meprobamate. This supports the conclusion that the great majority of the Florida Medical Examiner cases in which carisoprodol/meprobamate was determined to be a cause of death are attributable to carisoprodol.
19

19
Mr. Dasgupta also raised the possibility that the Florida Medical Examiner data is subject to diagnostic suspicion bias. MX17, at 23. Again, this is simply speculation.

Finally, Mr. Dasgupta asserted that the Florida data shows that “the proportion of total fatal overdose occurrences * * * has generally been decreasing annually since 2005.”
Id.
at 24. However, it is doubtful that this change is statistically significant, and even if it is, the data still show that a significant and disturbing number of persons have died from carisoprodol overdoses and are dying each year in this State alone.

National Poison Data System

Data from the National Poison Data Systems (NPDS), formerly known as the Toxic Exposure Surveillance System of the American Association of Poison Control Centers (AAPCC), show that carisoprodol products are involved in a number of toxic exposures (Table 5). Some of these carisoprodol exposures led to major adverse health outcomes (Table 6). For example, in 2007, carisoprodol was associated with 8,821 toxic exposure cases, including 3,605 cases in which it was the sole drug mentioned. A total of 122 of the 2,821 single exposure cases, which were treated in a health-care facility, had a major adverse health outcome.

Table 5—Carisoprodol Exposures Data From National Poison Data System (NPDS)

2003
2004
2005
2006
2007

Case Mentions
8,248
8,765
8,613
8,187
8,821

Single Exposures

3,515
3,605

Note:
Single exposure data is not available prior to 2006.

Table 6—Serious Adverse Health Outcomes in Carisoprodol Exposures Cases Who Were Treated in Health Care Facilities

2003
2004
2005
2006
2007

Treated in Health Care Facility *
6,617
7,032
7,501
2,687
2,821

Deaths
28
30
18
1
1

Major Effect **
406
468
525
105
122

Moderate Effect ***
1,710
1,882
1,953
688
720

Total
2,144
2,878
2,496
794
843

* The data for 2006 and 2007 are from single exposure cases.
** Major effect: The patient exhibited signs or symptoms as a result of the exposure that were life-threatening or resulted in significant residual disability or disfigurement.
*** Moderate effect: The patient developed signs or symptoms as a result of the exposure that were more pronounced, more prolonged or more systemic in nature than minor effects.

Regarding the NPDS data, Mr. Dasgupta acknowledged that the persons who answer the calls to the regional poison centers “are nurses, pharmacists, and physicians who have been trained in medical toxicology and are instructed on the proper ways of completing case report forms in a systematic manner” and that the data collection software has “[a]n extensive data quality assurance process.” MX 173, at 29-30. Mr. Dasgupta then stated that there is the “potential misidentification of the substance during the initial call to the poison center” and that researchers have “determined that, for some drugs, 25-30% are misclassified during the first call.”
Id.
at 30. However, Meda did not provide this research and Mr. Dasgupta did not provide evidence as to what the rate of misclassification is for carisoprodol. He then opined that the self-reporting and (apparently the lack of toxicology test results) showing the “presence and levels of drug * * * make it impossible to conclude that a mentioned drug was causally implicated in the exposure.”
Id.

Mr. Dasgupta also maintained that “the single exposure data presented by DEA combines single-entity carisoprodol and carisoprodol/aspirin combination products.”
Id.
at 31 (citing Meda Ex. 63).
20

However, as the data for 2007 show, even if single entity and combination products should not be counted together, the amount of case mentions and single exposures attributable to combination products is a small fraction of both the case mentions (163 v. 8658) and single exposures (69 v. 3536) attributable to single entity products.
See
MX 64, at 1020, 1026.

20
As support for this assertion, Mr. Dasgupta cited the 2008 annual report (MX 63); however, the above tables do not include data for that year.

Mr. Dasgupta also criticized the use of the NPDS data because the intentional exposures data includes suicide attempts and accidental pediatric exposures. MX 173, at 34. However, the Senate Report, which accompanied the CSA's enactment, expressly stated that “[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.” S. Rep. 91-613, 1970 U.S.C.C.A.N., at 4602. Thus, contrary to Mr. Dasgupta's understanding, the fact that Table 6 includes suicides, “suicide attempts,” and “accidental pediatric exposures,”
see
MX 173, at 34; does not reduce the data's probative value in assessing carisoprodol's abuse potential.

Mr. Dasgupta criticized Table 6 because it “purports to show `serious adverse health outcomes in carisoprodol exposure cases,’ ” but “[i]ntentional exposure cases can also include associated medical outcomes that are not serious.”
Id.
at 32. Mr. Dasgupta further asserted that “[t]he DEA Review does not present enough detail concerning methodology to determine

what type of cases were included in Table [6].”
Id.

However, it is apparent that Table 6 simply replicates the NPDS's classification of carisoprodol incidents by the severity of the outcome.
See
MX 64, at 940-41, 1020, 1026 (2007 report). Moreover, even if single entity and combination carisoprodol products should not have been added together, the number of cases attributable to combination products is a small fraction of those attributable to single entity products (15 v. 705 moderate effects outcomes, 2 v. 120 major effect outcomes, and 0 v. 1 death).
Compare id.
at 1020,
with id.
at 1026.

2. Is there significant diversion of carisoprodol from legitimate drug channels?

The NFLIS Data

Current data shows that there is significant diversion of carisoprodol from legitimate drug channels. Data collected by DEA establishes that carisoprodol has been seized from persons engaged (and places used) in illegal activities involving other controlled substances, including diazepam, marijuana, cocaine, methamphetamine, codeine, and hydrocodone. DEA has found carisoprodol present during the execution of search warrants at residences, offices, and pharmacies. According to data retrieved from DEA's National Forensic Lab Information System (NFLIS) database, which includes data on samples analyzed by DEA laboratories (STRIDE), as well as state and local forensic laboratories,
21

since 2000, carisoprodol has consistently ranked in the top 25 of the drugs most frequently seized and identified by state and local forensic laboratories during the course of criminal investigations.

21
Participating state and local laboratories handle 88% of the nation's 1.2 million analyses of state and local drug cases.

In terms of the number of seizures, in 2008, NFLIS reported 4,291 identifications of carisoprodol, thus ranking it above such controlled substances as codeine, psilocin, lorazepam, MDA, hydromorphone, and methylphenidate. MX 53, at 9. In 2007, NFLIS reported 4,420 identifications of carisoprodol, thus ranking it above such controlled substances as phencyclidine (PCP), psilocin, buprenorphine, MDA, methylphenidate, ketamine, lorazepam, and hydromorphone. MX 54, at 7. Because the primary focus of law enforcement agencies is on investigating the unlawful distribution of controlled drugs, the incidents in which carisoprodol has been found during law enforcement seizures supports a finding that the drug is being abused and diverted. Moreover, because carisoprodol is not controlled in most States, there is reason to believe that many laboratories may not report those incidents in which they have identified a substance as carisoprodol. GX 9, at 3.

Mr. Dasgupta opined that the NFLIS data are of “limited utility for making public health decisions.” MX 173, at 26. While he acknowledged that carisoprodol has been among the top twenty-five drugs analyzed, Mr. Dasgupta explained that “[t]he likelihood of a particular sample being analyzed is substantially affected by the prosecutor's perceptions of the available criminal charges, as well as politics, prosecutorial priorities, and bureaucratic influences.”
Id.
at 25. Mr. Dasgupta then noted that “[p]rosecutors in states where carisoprodol is a controlled substance would be more likely to submit a sample to NFLIS for identification,
22

as the state-level scheduling would be more likely to result in a stiffer criminal penalty,” and that “[f]orensic laboratory data from these states may be an artifact of state-level scheduling because more suspected carisoprodol samples may be sent for analysis once a controlled substance criminal charge is potentially available in a particular state.”
Id.
at 26. As Mr. Dasgupta noted, only seventeen States have controlled carisoprodol.
Id.
n.7.

22
Contrary Mr. Dasgupta's understanding, drug samples are not submitted “to NFLIS for identification.” MX 173, at 26. Rather, NFLIS collects reports of drugs items which have been seized and analyzed and identified as a drug by a forensic laboratory. However, I agree with Mr. Dasgupta's opinion that if a criminal charge is not available in a State, it is less likely that evidence which looks like carisoprodol tablets will be sent to a lab for analysis and subsequently reported to the NFLIS.

This argument, however, actually supports the Government's view that many laboratories do not report carisoprodol that is seized during criminal investigations, and thus the drug is being diverted at even greater levels than the NFLIS data suggests. According to U.S. Census data, of which I take official notice, the seventeen States, which have controlled carisoprodol, have a total population of approximately 108 million and thus comprise only 35% of the national population.
23

See
Appendix A. This suggests that carisoprodol would likely rank substantially higher in the NFLIS data were it controlled nationally.

23
Pursuant to 5 U.S.C. 556(e), Meda “is entitled, on timely request, to an opportunity to show the contrary.” In the event Meda disputes the census data, it may file a motion for reconsideration within fifteen days of the date of service of this rule, which shall begin on the date of mailing.

The testimony of various officials further supports a finding that carisoprodol is being diverted. The Deputy Assistant Administrator of DEA's Office of Diversion Control testified that carisoprodol was being distributed in combination with narcotic drugs and benzodiazepines through Internet schemes in which patients were issued prescriptions by physicians they never saw and could simply order the drugs through a Web site. GX 9, at 2-3; Tr. 343-44. As several courts have recognized, the dispensing of controlled substances in this manner is a violation of 21 U.S.C. 841(a)(1).
See United States
v.
Nelson,
383 F.3d 1227, 1231-32 (10th Cir. 2004);
United States
v.
Smith,
573 F.3d 639, 657-58 (8th Cir. 2009);
United States
v.
Fuchs,
467 F.3d 889 (5th Cir. 2006). The Deputy Assistant Administrator also noted that “DEA investigations reveal that thousands of customers throughout the United States seek carisoprodol, either alone or, most frequently, in combination with controlled substances from pain clinics, physicians, and from illicit street dealers.” GX 9, at 3.

A Special Agent in Charge with the Tennessee Bureau of Investigation, who oversees drug enforcement responsibilities in twenty-eight of the State's counties and who was formerly Coordinator of the Tennessee Drug Diversion Task Force, testified that in his experience, “carisoprodol has been used for non-medical purposes and illicitly distributed in circumstances that are similar to the non-medical use and illicit trafficking in controlled substances such as oxycodone, hydrocodone, and alprazolam. Law enforcement investigations have revealed that many Tennesseans seek carisoprodol, either alone or, most frequently, in combination with controlled substances from pain clinics [and] physicians,” who “conduct little or no physical examination of the patients” and who “issue prescriptions for the specific drugs requested by the `patients.' ” GX 10, at 3-4. The official also related that carisoprodol is being sold on the street.
Id.
at 4.

The official also testified that “carisoprodol abuse has been implicated in many overdose events in Tennessee including overdose fatalities,” and that reports from the State's medical examiner “from 2006 through 2008” show that carisoprodol has been “associated with approximately 100 deaths.”
Id.
at 3, 5. This official further stated that “[i]n the majority of these cases[,] carisoprodol is seen in combination with a `cocktail' of

other drugs[,]” such as “oxycodone or hydrocodone.”
Id.
at 5.

The Executive Director of the Ohio State Board of Pharmacy, who has worked as a pharmacist as well as held oversight/investigatory positions at the Board, testified that he has “personally investigated cases involving carisoprodol,” and that “carisoprodol has been abused in the State of Ohio for more than 20 years.” GX 8, at 3. The official testified that he was “aware from [his] experience that many abusers of narcotics and other drugs abuse carisoprodol to mellow the effect of the narcotics or other drugs.”
Id.

The official further testified that under Ohio law, pharmacies are required to report the dispensing of any controlled substance as well as carisoprodol. He then related that he had run a search of the Ohio prescription reporting system and found that carisoprodol “is always prescribed in combination with an opiate, a benzodiazepine, or both.”
Id.
at 4-5. Moreover, “even though * * * the use of a muscle relaxant such as carisoprodol in conjunction with an opiate and a benzodiazepine is rarely clinically indicated,”
24

the official “found that our top ten prescribers of this `trinity' have prescribed this combination [of drugs] to a range of 140 [to] 1,376 patients.”
Id.
at 5. The official further found that “many patients received carisoprodol from multiple prescribers,” that during 2009, the top ten patients “received prescriptions from 8 [to] 13 different prescriptions,” and that these “patients received between 1,020 [and] 1,863 days' supply” of the drug during the “365 day period.”
Id.
However, carisoprodol is indicated only for short-term use of up to two to three weeks, “because adequate evidence of effectiveness for more prolonged use has not been established and because acute, painful musculoskeletal conditions are generally of short duration.” MX 6, at 2 (prescribing information). As the official concluded, these statistics provide evidence of improper prescribing by physicians, as well as doctor shopping and over-utilization by patients, and show that “carisoprodol is a drug of abuse in Ohio.”
Id.

24
On cross-examination, the official explained that both carisoprodol and benzodiazepines have muscle relaxant and anti-anxiety effects, and that prescribing both drugs simultaneously “is duplication of therapy,” which is rarely warranted. Tr. 464-65.

3. Non-Medical Use of Carisoprodol

Review of the currently available data and other information shows that 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 substances. More specifically, the National Survey on Drug Use and Health (NSDUH)
25

data show that from 2004 through 2007, between 2.5 and 2.8 million persons admitted to having used carisoprodol for a non-medical purpose during their lifetime.
26

As Table 7 below shows, in 2007, approximately 2.7 million persons have at some point engaged in the non-medical use of carisoprodol. This figure is more than eleven times the number of persons who have used meprobamate products for a non-medical purpose.

25
The NSDUH is an annual survey sponsored by SAMHSA that obtains information on nine different categories of illicit drug use: use of marijuana, cocaine, heroin, hallucinogens, and inhalants; and the nonmedical use of prescription-type pain relievers, tranquilizers, stimulants, and sedatives in the civilian, non-institutionalized population of the United States age 12 or older. The survey interviews approximately 67,500 persons each year. The NSDUH provides yearly national and state level estimates of drug abuse, and includes prevalence estimates by lifetime (
i.e.,
ever used), past year and past year abuse or dependence. Substance Abuse and Mental Health Services Administration (SAMHSA), Office of Applied Studies,
Results from the 2007 National Survey on Drug Use and Health: National Findings
(2008).

26
“Lifetime prevalence” is a cumulative indicator of the total number of people who have ever tried drugs, including many in the distant past.

Moreover, many reports of carisoprodol abuse have been published both in the United States and in other countries. These cases include the use of carisoprodol by itself and in combination with other drugs of abuse.
See also infra
Factor 5.

Table 7—NSDUH Data on Nonmedical Use of Specific Tranquilizer in Lifetime
[Numbers in thousands and percentage]

Drugs

2004
# (%)

2005
# (%)

2006
# (%)

2007
# (%)

Benzodiazepines
18,643 (7.8)
19,686 (8.1)
19,662(8.0)
18,934 (7.6)

Valium or Diazepam
14,607(6.1)
14,914 (6.1)

14,824
b
(6
b
)

13,172 (5.3)

Meprobamate Products
1

245 (0.1)
305 (0.1)
216 (0.1)
236 (0.1)

Muscle Relaxants
2

3,907 (1.6)
3,773 (1.6)
4,449 (1.8)
4,274 (1.7)

Soma®
2,616 (1.1)
2,525 (1.0)
2,840 (1.2)
2,709 (1.1)

Flexeril®
1,968 (0.8)
1,891 (0.8)
2,405 (1.0)
2,438 (1.0)

1
Includes Equanil®, meprobamate, and Miltown®,
2
Includes Flexeril® and Soma®,
b
difference between 2006 and 2007 estimates statistically significant, p. ≤ 0.01. Source: SAMHSA, office of Applied Studies, National Survey on Drug Use and Health.

Mr. Dasgupta acknowledged that “NSDUH is a validated and generally scientifically defensible survey.” MX 173, at 28. However, he then criticized the study because it relies on self-reporting and because the study does not specifically ask whether carisoprodol or Soma have been used in the “past year” or “past 30 days,” although a survey participant may “spontaneously offer[]” that he/she has used the drug within the respective time frame.
Id.
Mr. Dasgupta further noted that the NSDUH data show that the level of lifetime nonmedical use “is essentially flat over time and not increasing.”
Id.
at 29.

Nonetheless, that the NSDUH survey has consistently shown that between 2.5 million and 2.8 million persons have engaged in non-medical use of carisoprodol is not evidence of “isolated or occasional nontherapeutic” use. S. Rep. 91-613;
reprinted in
1970 U.S.C.C.A.N., at 4602. Rather, it is substantial evidence of “significant use by individuals contrary to professional advice.”
Id.
Where, as here, a drug has been this widely abused, DEA is not required to develop evidence that the rate of abuse is increasing in order to control it.

4. Carisoprodol's Pharmacological Activities Are Similar to Other Drugs With Known Abuse Liabilities

According to the FDA, when originally marketed in 1959, carisoprodol was described as having qualitatively different kinds of central muscle relaxant properties than meprobamate, a schedule IV depressant

(FDA Reference 1).
27

However, the specific mechanisms of action of carisoprodol are not completely understood (2, 3).

27
The complete list of FDA References 1-58 is attached as Appendix B.

FDA found that although carisoprodol is classified as a muscle relaxant, it has little direct effect on skeletal muscle. GX 6, at 5. According to FDA, both carisoprodol and meprobamate possess sedative properties and their therapeutic utility in acute painful musculoskeletal problems may be in part due to these sedative properties.
Id.
FDA also found that the drugs may be abused for their sedative properties and that
in vitro
studies demonstrate that carisoprodol elicits barbiturate-like effects.
Id; See also
discussion
infra
under Factor Two.

Recent clinical reports addressing carisoprodol's abuse potential and its metabolic conversion to meprobamate have been published in scientific and medical journals. According to FDA, it was initially believed that carisoprodol's abuse potential was primarily related to its metabolic conversion to meprobamate.
Id.
at 6.

However, new animal data from NIDA demonstrate that the abuse potential and pharmacology of carisoprodol may be independent of the metabolic pathway in humans to meprobamate. More specifically, FDA cited NIDA studies by Gatch,
et al.,
which show that carisoprodol can be easily recognized by animals in drug discrimination studies as Schedule II, III or IV CNS depressants. (4-6). These studies are discussed more fully below under Factors Two (Scientific Evidence of the Drug's Pharmacological Effect) and Seven (Psychic or Physiological Dependence Potential).

Factor 2—The Scientific Evidence of Carisoprodol's Pharmacological Effect

Carisoprodol is a centrally-acting muscle relaxant used medically for relief of discomfort associated with acute, painful musculoskeletal conditions, including spasms and spasticity. GX 6, at 6. The original approved therapeutic dose of carisoprodol was 350 mg three times a day, and at bedtime.
Id.
In placebo-controlled studies, carisoprodol was found more effective than placebo in treatment of acute musculoskeletal disorders (7) and less effective or not different from placebo in chronic disorders. In 2007, FDA approved a 250 mg tablet to be taken three times a day and at bedtime, for up to three weeks. GX 6, at 6.

Although the exact mechanism of muscle relaxant action of this group of drugs is not known, it is believed to occur by depressing interneuronal cells and diminishing the facilitatory background activity on spinal motor neurons and by also inhibiting supraspinal influences, primarily in the lateral reticular area of the brain stem.
Id.
The polysynaptic reflexes are more readily depressed than monosynaptic reflexes.
Id.
These drugs produce sedation and drowsiness as their common side effects, which may reflect depressed neuronal activity essential for wakefulness, in the medial reticular ascending system.
Id.
Despite chemical structures that are unrelated, all muscle relaxants possess sedative properties.
Id.
The drugs also exhibit anticonvulsant activity in several animal models (3).

Receptor Binding Studies

According to FDA, the complete binding profile of carisoprodol has not been characterized. One study showed that carisoprodol has negligible affinity for the benzodiazepine site, using [
3
H]-diazepam as a ligand in rat brain tissue (8).

In Vitro Studies

The FDA concluded that the findings of
in vitro
studies demonstrate that carisoprodol elicits barbiturate-like effects. Whole-cell patch clamp studies were conducted to examine mechanistic similarities between carisoprodol and barbiturates (Schedules II, III or IV, depending on the particular barbiturate) using recombinant rat α1β2 GABA
A
R. GX 6, at 6. GABA-gated currents were potentiated by micromolar carisoprodol (EC
50
= 89 μM)).
Id.
At millimolar concentrations, currents began to be inhibited, and rebound currents were apparent upon termination of drug administration.
Id.

According to FDA, this barbiturate-like trend was consistent with a previous description of carisoprodol effects on human α1β2
y
2 GABA
A
R function, demonstrating that carisoprodol, like barbiturates, does not require the y subunit for its activity.
Id.
at 6-7. Carisoprodol directly activated human α1β2
y
2 GABA
A
R, producing inward currents in a concentration-dependent manner (EC
50
= 410 μM).
Id.
The amplitude of carisoprodol mediated currents (EC
40
) was reduced to 24 percent of control following incubation with bemegride (a barbiturate antagonist that has not been demonstrated to be specific for barbiturates).
Id.
By contrast, the benzodiazepine antagonist, flumazenil, had no significant effect on either the allosteric or direct effects of carisoprodol (9).

MEDA challenged the FDA's reliance on this study. More specifically, MEDA elicited the testimony of Dr. Donald Robert Jasinski, who is a Professor of Medicine at the Johns Hopkins University School of Medicine and the Chief of the Center for Chemical Dependence, Johns Hopkins Bayview Medical Center. MX 172, at 1. Dr. Jasinski testified that even assuming that the model used in this study was “sufficiently robust to establish an affinity of carisoprodol at a GABAα receptor, this does not establish that carisoprodol has barbiturate-like activity, but merely that it, like many other drugs including other non-controlled CNS depressants, has an affinity to attach to a GABAα receptor[].”
Id.
at 3. Dr. Jasinski then explained that “while barbiturates as a class have an affinity for GABAα receptors, not all drugs that have affinity for GABAα receptors have barbiturate-like activity and/or abuse liability profiles similar to the barbiturates.”
28

Id.
at 4. Dr. Jasinski further opined that the finding that “bemegride, a non-specific barbiturate antagonist, apparently reduced the amplit[ude] of carisoprodol-mediated currents by 24% [does not] indicate that carisoprodol will have barbiturate like effects.”
Id.

28
Dr. Jasinski further testified that in a subsequent article, the authors of this study wrote that “[a]lthough both our
in vivo
and
in vitro
studies are consistent with barbiturate-like effects of carisoprodol, we are not concluding that carisoprodol is acting at the barbiturate site of the receptor.” MX 172, at 3 n.1.

While Dr. Jasinski may be correct that the findings of the aforementioned study do not conclusively establish that carisoprodol has barbiturate-like effects, there is substantial other evidence in the record (including human studies) which supports this finding.
See
discussion under Factor Five.

Animal Pharmacology Studies

Berger,
et al.
(1, 10), described the muscle relaxant and analgesic properties of carisoprodol in animals. Reversible paralysis of voluntary muscles that lasts for nearly 15 minutes occurs in most mice administered carisoprodol (180 mg/kg, i.p.). Paralysis was preceded by signs of excitement manifested by aimless running and staggering, hyperextension of the neck, and clonic movement of extremities. After administration of high doses, pre-narcotic excitement was absent. During paralysis, respiration and heartbeat were regular, skeletal muscles were relaxed, tremors and twitchings were absent, and corneal reflex was present. Stimulation of the sciatic nerve during paralysis produced prompt muscular response of the leg, indicating that the peripheral

nerve, myoneural junction, and muscle were not significantly affected by the drug. Depression of motor activity, as measured by loss of the righting reflex, occurred in 50 percent of animals after oral administration of 400 mg/kg of carisoprodol in mice and 750 mg/kg in rats.

According to FDA, carisoprodol is a relatively poor strychnine antagonist in mice, which differs from other muscle relaxants such as mephenesin (a centrally-acting muscle relaxant that is not marketed in the United States). Carisoprodol depresses the electro-cortical activation response to electrical stimulation of the sciatic nerve, the midbrain reticular formation or of the diffuse thalamic system (nucleus centralis lateralis). Carisoprodol showed an antinociceptive action in response to injection of silver nitrate into joints of rats. Carisoprodol differs from meprobamate (Schedule IV) by not affecting the hippocampal seizures produced by stimulation of the fornix (10).

More recently, the National Toxicology Program of the National Institutes of Environmental Health Sciences examined the toxicity of carisoprodol (11). Male rodents in the 200 mg/kg carisoprodol group and female rodents in the 100 and 800 mg/kg carisoprodol groups had significantly greater mean body weight gains than animals that received vehicle (control group). The incidence of adverse events was dose-related, and females were more sensitive than males to the effects of carisoprodol. Carisoprodol induced ataxia and prostration in rats and mice, increases in liver weights in rats and mice, and nephropathy in male rats.

In cats, carisoprodol was very effective in abolishing decerebrate rigidity, whereas meprobamate and mephenesin had no effect on spasticity. Carisoprodol appeared to be eight times more potent than these drugs in alleviating decerebrate spasticity (10).

In dogs, carisoprodol (100 mg/kg p.o.) produced loss of muscle tone. At larger doses (200 mg/kg p.o.), signs of excitement characterized by tail wagging and howling were observed along with muscular weakness and ataxia with no tremors, convulsions or salivation (10).

Self-Administration Studies

The FDA found that carisoprodol has positive reinforcing effects, in that rhesus monkeys maintained self administration responding that was greater than rates maintained by saline, although less than rates maintained by i.v. injections of methohexital (C-IV). GX 6, at 8. However, because of the limited solubility of carisoprodol, doses larger than 0.3 mg/kg injection could not be tested. NIDA Research Monograph, volume 146:423-433 (1999). This dose (0.3 mg/kg/injection) is lower than the doses used orally in humans. GX 6, at 8.

Drug-Discrimination Studies

According to the FDA, “drug discrimination studies in animals are believed to be predictive of subjective effects in humans and are thus useful in assessing the abuse potential of drugs.”
Id.
Carisoprodol can stimulate the barbiturate site on the GABA-A receptor. In drug discrimination studies, pentobarbital (C-II) fully substitutes in carisoprodol-trained rats and bemegride fully antagonizes the subjective effects of carisoprodol.

FDA also noted that another study found that in dogs tolerant and dependent on barbital (C-IV), oral doses of 200 mg/kg of carisoprodol every six hours were completely effective and equivalent to 100 mg/kg of barbital in preventing the appearance of abstinence phenomena (12).

Bemegride fully blocked the discriminative stimulus effects of the training dose of carisoprodol (100 mg/kg p.o.), whereas the benzodiazepine antagonist, flumazenil, produced a moderate attenuation of the discriminative stimulus effects of carisoprodol across a wide range of doses. According to FDA, these findings suggest that carisoprodol may directly activate or allosterically modulate GABA
A
receptors which mediate the discriminative stimulus effects of carisoprodol. FDA further found that the actions of carisoprodol at the barbiturate site may be more relevant than actions at the benzodiazepine site and that certain effects of carisoprodol may be independent of its metabolism to meprobamate (C-IV) (9).

Gatch,
et al.,
(4) assessed the ability of rats to discriminate carisoprodol from vehicle. Rats were trained to discriminate carisoprodol and a carisoprodol dose-effect curve was established for doses from 25 to 100 mg/kg. Meprobamate (C-IV), pentobarbital (C-II
/
C-III), and chlordiazepoxide (C-IV) were each tested for their ability to substitute for the discriminative stimulus effects of carisoprodol; each was found to substitute fully for the discriminative stimulus effects produced by 100 mg/kg of carisoprodol.

In another study, Gatch,
et al.
(5), found that 5 mg/kg bemegride antagonized the discriminative stimulus effects produced by 100 mg/kg of carisoprodol in rats trained to discriminate carisoprodol and decreased the response rate to 79 percent of the carisoprodol control group. Gatch,
et al.
(6), also studied the effects of carisoprodol in the presence of Cimetidine, to determine if the effects of carisoprodol are produced by its active metabolite, meprobamate. Cimetidine, a P450 enzyme inhibitor, which prevents the conversion of carisoprodol to meprobamate, failed to inhibit the discriminative stimulus effects produced by 100 mg/kg of carisoprodol in rats trained to discriminate carisoprodol. According to FDA, these results suggest that carisoprodol can produce discriminative stimulus effects directly without being converted into meprobamate.

Dr. Jasinski disputed the FDA's reliance on the various animal studies it used to assess carisoprodol's abuse potential. MX 172, at 4-7. While Dr. Jasinski acknowledged that “in these studies the animals reflected behavior patterns with respect to carisoprodol that suggest patterns similar to barbiturates,” he then opined that “due to the inherent limitations of animal studies they simply do not provide an adequate basis to make decisions concerning abuse potential in humans.”
Id.
at 4. Dr. Jasinski offered no further explanation as to what those limitations are. Moreover, at the hearing, Dr. Jasinski testified that it is appropriate to rely on animal studies as one aspect of assessing a drug's abuse potential in humans.
29

Tr. 721.

29
In its brief, Meda argues that animal studies “are significantly less probative than human studies” in assessing a drug's abuse potential. Meda Br. 25. However, Meda did not establish the degree to which animal studies are less probative than human studies and even its Expert conceded that it is appropriate to rely on animal studies in assessing abuse potential in humans. Tr. 721. While Meda cites human data—in particular, the results of recent clinic trials it conducted and the Fraser study—and argues that this data should be given greater weight than the animal studies, as discussed below, both studies have significant limitations.

With respect to the self-administration study involving rhesus monkeys, Dr. Jasinski explained that the fact that “the monkeys seem[ed] to prefer carisoprodol over a saline, but less than a schedule IV substance, merely indicates that the * * * monkey prefers carisoprodol over saline” and that “[t]his preference could be due to factors unrelated to any potential for abuse in humans.”
Id.
at 5.

As for the drug-discrimination studies involving rats, Dr. Jasinski acknowledged that the study showed that “pentobarbital substitutes for carisoprodol in rats trained to discriminate carisoprodol and that” bemegride, a barbiturate antagonist, “blocked the discriminate stimulus

effects.”
Id.
Dr. Jasinski then opined that “these data at most are only indicative that carisoprodol may have certain effects similar to those of barbiturates (
e.g.,
they have activity at the GABA receptor site) and not that any such similarity translates into a similar potential abuse liability.”
Id.
Dr. Jasinski further explained that “it is well known that certain drugs will substitute for drugs of abuse without themselves being subject to any significant drug abuse.”
Id.

As for the study showing that 200 mg/kg of carisoprodol substituted for 100 mg/kg in dogs which are dependent on barbital, Dr. Jasinski noted that the authors had concluded that carisoprodol was an exception to the general rule that “whenever drugs produce physiological dependence in which abstinence syndrome is similar, these drugs must possess a common mechanism of action and abuse liability profiles.”
Id.
at 6 (citing MX 91). As Dr. Jasinski observed, based on several unpublished studies which showed that “the chronic administration of carisoprodol in 4 divided doses of 1 gm/day for 6 months [did] not result in the development of physiological dependence,” the authors concluded that “[t]he fact that carisoprodol did effectively substitute for sodium barbital in [their] study indicates that false positive results are possible from the substitution evaluation of barbiturate-like physiological dependence capacity.” MX 91;
see also
MX 172, at 6.

However, as the authors made clear, their conclusion that carisoprodol produced a false positive was based on studies which showed that taking one gram per day of the drug did not cause physiological dependence. Thus, this study does not foreclose the possibility that chronic use of carisoprodol in daily doses of greater than one gram per day could cause physiological dependence and calls into question the validity of the authors' conclusion that carisoprodol caused a false positive when substituted for barbital.

Accordingly, even discounting the rhesus monkey study, I find that substantial evidence supports the FDA's conclusion that the drug-discrimination studies in both dogs and rats indicate that carisoprodol has positive reinforcing and discriminative effects similar to other drugs currently regulated under C-IV, including barbital, meprobamate, and chlordiazepoxide.

Clinical Experience and Human Studies

Pharmacodynamic Effects

Beebe,
et al.
(13), reviewed the pharmacodynamic effects of carisoprodol. Lethargy, drowsiness, ataxia, dysmetria and fatigue are common side effects at therapeutic doses
30

and in overdose (14). More severe CNS-related effects including confusion, amnesia and coma occur less frequently at therapeutic doses, but occur with overdose (15; 16). Respiratory depression may occur in patients with significant CNS depression (17; 18).

30
See current label information for carisoprodol (Soma) (
http://www.fda~gov/cder/foil1abe1l2007/0_11792s0411bl.pdf
).

The primary toxic effect with poisoning or exposure to carisoprodol is CNS depression and, in severe cases, coma. Euphoria, CNS stimulation, muscular incoordination, confusion, headache, hallucinations and dystonic reactions have also been reported. Anti-cholinergic effects (tachycardia, dry, warm skin) are reported following carisoprodol poisoning. Fever is reported following carisoprodol overdose (14; 19). Both mild hypertension and mild hypotension are reported in conjunction with serotonin syndrome after carisoprodol overdose (19). Horizontal nystagmus, mydriasis, and blurred vision have also been reported with carisoprodol overdose (20).

In addition to the above adverse effects, drug abuse, dependence and tolerance are reported following long-term use of carisoprodol.
See infra
Factor Seven.

Human Behavioral Studies

Fraser,
et al.
(21), evaluated whether carisoprodol possessed morphine-like (C-II) or barbiturate like (C-II, C-III and C-IV) addictive properties in human subjects, all of whom “were former opiate addicts.” H.F. Fraser,
et al., Evaluation of carisoprodol and phenyramidol for addictiveness,
Bulletin on Narcotics 1 (Oct-Dec. 1961). The study had three arms: the first evaluated the effect of single oral doses in non-addicted patients, the second evaluated the 24-hour substitution of carisoprodol fo

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A2011-31542. Public record. Not legal advice.