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77330 Federal Register / Vol. 76, No. 238 / Monday, December 12, 2011/ Rules and Regulations

1None of the commenters raised any issue as tothe various Regulatory Certifications contained inthe Notice of Proposed Rulemaking. See 74 FR at59111. One commenter, which represents wholesaledistributors, requested that if the proposed rule isfinalized, its effective date be set at 120 days fromthe date of publication to provide adequate time tocomply with various regulations.

DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA333]

Schedules of Controlled Substances:

Placement of Carisoprodol IntoSchedule IV

AGENCY: Drug EnforcementAdministration, Department of Justice.

ACTION: Final rule.

SUMMARY: With the issuance of this finalrule, the Administrator of the DrugEnforcement Administration (DEA)places the substance carisoprodol,including its salts, isomers, and salts ofisomers, whenever the existence of suchsalts, isomers, and salts of isomers ispossible, into Schedule IV of theControlled Substances Act (CSA). This

action is pursuant to the CSA whichrequires that such actions be made onthe record after opportunity for ahearing. The decision of theAdministrator is reprinted in its entirety

below.

DATES: Effective Date:January 11, 2012.

FOR FURTHER INFORMATION CONTACT:Rhea D. Moore, Drug EnforcementAdministration, 8701 Morrissette Drive,Springfield, Virginia 22152; Telephone(202) 3075268.

SUPPLEMENTARY INFORMATION:

ALJ Docket No. 1046

Background

This is a proceeding under 21 U.S.C.811(a) for the issuance of a rule placingcarisoprodol in schedule IV of theControlled Substances Act (CSA). Underthis provision, the Attorney Generalmay, by rule, add a drug or othersubstance to one of the five schedulesof controlled substances, if he * * *finds that such drug or other substancehas a potential for abuse, and * * *makes with respect to such drug orother substance the findings prescribed

by [21 U.S.C. 812(b)] for the schedule in

which such drug is to be placed. 21U.S.C. 811(a). However, a rule madeunder this provision shall be made onthe record after opportunity for ahearing pursuant to the rulemakingprocedures prescribed by subchapter IIof chapter 5 of Title 5. Id.

[W]ith respect to each drug * * *proposed to be controlled, the CSArequires that the Attorney Generalconsider eight factors in making thefindings required under bothsubsections 811(a) and 812(b). Theseare:

(1) [The drugs] actual or relativepotential for abuse.

(2) Scientific evidence of itspharmacological effect, if known.

(3) The state of current scientificknowledge regarding the drug or othersubstance.

(4) Its history and current pattern ofabuse.

(5) The scope, duration, andsignificance of abuse.

(6) What, if any, risk there is to thepublic health.

(7) Its psychic or physiologicaldependence liability.

(8) Whether the substance is animmediate precursor of a substancealready controlled under thissubchapter.

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

However, before initiatingproceedings * * * to control a drug* * * and after gathering the necessarydata, the Attorney General is required

to request from the Secretary ascientific and medical evaluation, andhis recommendations, as to whethersuch drug * * * should be controlled.Id. 811(b). The statute further providesthat [i]n making such evaluation andrecommendations, the Secretary shallconsider the Factors listed in paragraphs(2), (3), (6), (7), and (8) of subsection (c)* * * and any scientific or medicalconsiderations involved in paragraphs(1), (4), and (5) of such subsection. Therecommendations of the Secretary shallinclude recommendations with respectto the appropriate schedule, if any,

under which such drug * * * should belisted. Id.

Finally, [t]he recommendations ofthe Secretary to the Attorney Generalshall be binding as to such scientificand medical matters, and if theSecretary recommends that a drug* * * not be controlled, the AttorneyGeneral shall not control the drug* * *. If the Attorney Generaldetermines that these facts and all otherrelevant data constitute substantialevidence of potential for abuse such asto warrant control * * * he shallinitiate proceedings for control * * *

under subsection (a) of this section. Id.Procedural History

Pursuant to section 811(b), in March1996, the Drug EnforcementAdministration (DEA) requested fromthe Department of Health and HumanServices (HHS) a scientific and medicalevaluation of carisoprodol, and arecommendation as to whether it should

be controlled. ALJ Ex 1, at 3. InFebruary 1997, however, the U.S. Foodand Drug Administrations (FDA) DrugAbuse Advisory Committee concluded

that the then-available data did notsupport controlling carisoprodol. Id.

Thereafter, at the direction of theNational Institute on Drug Abuse(NIDA) and the College of Problems ofDrug Dependence (CPDD), additionalpharmacological studies ofcarisoprodols abuse liability wereconducted. In the meantime, DEA

gathered additional new data on actualabuse and law enforcement encountersinvolving the drug, as well as otherinformation, which it sent to HHS onNovember 14, 2005. FDA also acquirednew data from the Drug Abuse WarningNetwork (DAWN), the National Surveyon Drug Use and Health (NSDUH),Florida Medical Examiners Commissionreports, FDAs Adverse Event ReportingSystem, as well as other informationfrom a variety of sources.

On October 6, 2009, HHS concludedits review of the evidence pertaining tothe eight factors set forth in 21 U.S.C.

811 and recommended that carisoprodolbe placed in schedule IV. GX 6, at 1.Thereafter, on November 17, 2009, DEAissued a Notice of ProposedRulemaking, which proposed placingcarisoprodol in schedule IV. ALJ Ex., at1 (74 FR 59108). Therein, DEA invitedall persons to submit written commentsor objections to the proposed rule; DEAalso notified interested persons oftheir right to request a hearing. Id. at 2(citing 5 U.S.C. 556 and 557).

DEA received seventeen comments onthe proposed rule; sixteen of thecommenters (which included lawenforcement officials, medicalprofessionals and state regulators)supported the proposed rulemaking.1One entity, Meda Pharmaceuticals, Inc.(Meda), which manufactures the

branded drug Soma, objected to theproposed rule on the ground that thethe administrative record does notinclude substantial and reliableevidence of potential for abusesufficient to warrant schedulingcarisoprodol and because the proposalgives inadequate weight to the negativeimpact on patient care of schedulingcarisoprodol. ALJ Ex. 2, at 3. Meda alsorequested a hearing. Id. at 1. On March

21, 2010, I granted Medas request andassigned the matter to the AgencysOffice of Administrative Law Judges(ALJ). ALJ Ex. 3, at 2.

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

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2While both parties and the ALJ cited this studyas if it was an exhibit in the case, it was notincluded in the record forwarded to this Office andthere is no indication that it was entered intoevidence.

and 9, as well as on August 36, 2010.At the hearing, both the Governmentand Meda elicited the testimony ofwitnesses and introduced variousdocuments into evidence. Thereafter,

both the Government and Meda filedbriefs containing their proposedfindings of fact and conclusions of law.

The ALJs Recommended DecisionOn December 8, 2010, the ALJ issued

her recommended decision. Therein,prior to discussing the eight factorsdeterminative of control, 21 U.S.C.811(c), the ALJ discussed the weight to

be given the FDAs findings as toscientific and medical matters. ALJ at 6;see also 21 U.S.C. 811(b). As explainedmore fully below, the ALJ adopted theGovernments argument that the statutelimits the scope of the administrativehearing to those issues outside of themedical and scientific fact-findings ofthe FDA, ALJ at 11, and concluded thatthe plain language and legislativehistory of 811(b), federal case law, and[HHSs] process for conducting itsadministrative review, make clear thatCongress intended that the Secretarysscientific and medical fact-findings bindthe DEA during the hearing and thesubsequent scheduling determination.Id. at 18.

However, the ALJ then noted thatnot all of the conclusions that the FDAmade in its review are scientific andmedical in nature and that the FDAsconclusions based on data obtainedfrom the Drug Abuse Warning Network(DAWN), the National Survey on Drug

Use and Health (NSDUH), and theFlorida Medical Examiners/CoronersReports could equally fall under theumbrella of law enforcement or scienceand medicine. Id. at 1920. The ALJultimately concluded that the datagathered by these sources [was]primarily statistical, and not medical,and [is] therefore capable of review bythis agency. Id. at 20. The ALJ thusconcluded that FDAs conclusions basedon this data are not binding. Id.Moreover, notwithstanding herstatement as to the scope of the hearing,the ALJ allowed Meda to introduce

extensive evidence including experttestimony as to the various scientificand medical matters considered by theFDA.

The ALJ then made extensive findingsas to each of the eight section 811(c)factors. With respect to Factor Onetheactual or relative potential for abusethe ALJ first explained that abuse isusing a drug for nonmedical purposesfor [its] positive psychoactive effects.Id. at 82. The ALJ then noted thetestimony of one of Medas expertwitnesses, who runs a drug treatment

center, that he could not recall a singlecase of a person being treated at hiscenter for dependence on carisoprodoland his opinion that the data andinformation presented by the FDA andDEA do not establish that carisoprodolhas a potential for abuse similar toschedule IV controlled substances. Id.

However, the ALJ found more

compelling data compiled by Medaand the predecessor holders of the NewDrug Application for carisoprodolwhich had been submitted to the FDAsAdverse Events Reporting System(AERS). Id. at 82. This data, whichincludes reports from consumers andhealthcare practitioners, showed that

between January 1979 and May 1, 2010,there had been 731 spontaneousadverse event reports of which eighty-three used such terms as abuse,dependency or withdrawal. Id. at 8283.

The ALJ further noted that in 2009,FDA required that Meda re-write the

drugs label to note the effects of chronicuse, that there are published casereports of human carisoprodoldependence, and that various animalstudies indicate the drug has effectssimilar to the use of barbital,meprobamate, and chlordiazepoxide,all of which are controlled substances.Id. at 83. The ALJ also noted that Medaeventually accepted the labeling change.Id. at n.42. Based on the AERS data andthe drugs label, the ALJ concluded thatcarisoprodols abuse potential isrecognized, and that the recordcontains substance evidence of a

potential for abuse when carisoprodol ischronically used.With respect to Factors Two and

Threethe scientific evidence ofcarisoprodols pharmacological effectand the state of current scientificknowledge regarding the drugthe ALJnoted that [b]oth the DEA and the FDArelied on animal studies of self-administration, drug discrimination,and physical dependence to supporttheir position that carisoprodol should

be classified as a schedule IV drug. Id.at 84. The ALJ then noted the testimonyof Medas Expert that while the

animals reflected behavior patterns withrespect to carisoprodol that suggestpatterns similar to barbiturates, thelimitations of animal studies do notprovide an adequate basis to makedecisions concerning abuse potential inhumans, and that certain drugs willsubstitute for drugs of abuse withoutthemselves being subject to anysignificant drug abuse. Id. The ALJ,however, then held that the FDAsconclusions regarding carisoprodolspharmacology and withdrawal patterns[were] binding on this proceeding. Id.

The ALJ then discussed threedifferent human studies. With respect tothe Fraser study,2 the ALJ noted thatMedas Expert interpreted the results asshowing that ingestions did notinduce a characteristic barbiturateintoxication pattern * * *, nor did theabrupt withdrawal of carisoprodolreveal any signs of barbiturate-like

abstinence behavior. Id. at 85.However, the ALJ then noted that theFDA and the DEA found that thesubjective and objective effects weresimilar to those of barbiturates oralcohol and different from those ofopiates and that the drug hassedative-like effects. Id. Here again, theALJ found FDAs findings binding onthe proceeding. Id.

Next, the ALJ discussed the studiesMeda had conducted to obtain FDAapproval to market a smaller-strengthdose. While these studies, whichinvolved 4,000 patients, showed no

evidence of diversion, misuse, or abuse,and none of the patients experiencedwithdrawal following discontinuation ofthe drug, the ALJ noted that the studiessubjects received only therapeutic dosesand did so only for a period of one totwo weeks. Id. The ALJ thus concludedthat these trials did not test the effectsof prolonged use of carisoprodol atingestion levels above the levels fortherapeutic use. Id.

The ALJ then discussed a case studyby doctors from the Mayo Clinic of a 51-year old man who had taken up to sixtimes the maximum recommended dailydose, which concluded that the case

demonstrates adverse effects of bothcarisoprodol toxicity and withdrawal.Id. at 8586. More specifically, the ALJnoted the studys findings that abruptdiscontinuation of high-dosecarisoprodol may result in withdrawalsymptoms including anxiety, psychosis,tremors, myoclonus, ataxia andseizures, and that [t]his withdrawalsyndrome is likely underrecognized.Id. at 86.

Finally, the ALJ noted the FDAsfindings that carisoprodol possessessedative properties which may underlieits therapeutic usefulness and its

potential for abuse, that [r]ecent invitro studies demonstrated thatcarisoprodol possesses barbiturate-likeeffects, that the drug has positivereinforcing effects and [that] itsdiscriminative stimulus effects aresimilar to other schedule IV drugs suchas barbital, meprobamate andchlordiazepoxide. Id. While the ALJ



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noted that Medas Expert hadchallenged the FDAs reliance on an invitro study, she held again that theFDAs conclusion is binding on thisproceeding. Id. Based on the totalityof the record, the ALJ thus concludedthat the record demonstrates thatexcessive carisoprodol use createssimilar toxicity and withdrawal

symptoms to other schedule IV drugs.Id.

With respect to Factors Four andFivethe history and current pattern ofabuse, and the scope, duration, andsignificance of abusethe ALJ began bynoting the testimony of several lawenforcement officials including the headof the DEA Office of Diversion Control,the Executive Director of the Ohio StateBoard of Pharmacy, and a Special Agentin Charge with the Tennessee Bureau ofInvestigation, each of whom testifiedthat carisoprodol was being obtained forother than a legitimate medical purpose

and being either abused or sold on thestreet.The ALJ then discussed data obtained

from the National Forensic LaboratoryInformation System (NFLIS), theNational Survey on Drug Use andHealth (NSDUH), the Drug AbuseWarning Network (DAWN), FloridaMedical Examiners, and the NationalPoison Data System (NPDS). Whilenoting that the NFLIS data, whichshowed that carisoprodol wasconsistently among the top twenty-fivedrugs being seized during criminalinvestigations and analyzed by state andlocal forensic laboratories are not

direct evidence of abuse, the ALJconcluded these data lead[] to aninference that [the drug] has beendiverted and abused. Id. at 88.

As for the NSDUH data, the ALJ notedthat data for the years 2004 through2007 estimate that between 2,525,000and 2,840,000 million individuals haveused carisoprodol during their lifetimefor a non-medical reason. Id. at 89.While observing that the yearlyestimates may remain relativelyconsistent, the ALJ observed that theyare still a significant number ofnonmedical uses. Id. However, the ALJ

then noted that these numbers aresignificantly lower than comparablenumbers for the nonmedical use of

benzodiazepines. Id.Next, the ALJ discussed the DAWN

data. With respect to the DAWNEmergency Department data, the ALJnoted that these data show that theabuse frequency of carisoprodol issimilar to that of diazepam, a scheduleIV drug, and that the data show anincreasing frequency of nonmedicaluse emergency department visitsassociated with carisoprodol. Id.

However, the ALJ then noted thecredited testimony of another of Medasexpert witnesses that there is a lack oftransparency in the methods used tocollect * * * and statisticallyextrapolate the data, that withoutunderstanding the nature and extent ofthe changes in case findings(s) duringthe last several years, it is impossible to

conclusively say what proportion of theincreases in DAWN ED nationalestimates is attributable to changes inmethodology versus changes in theactual number of DAWN casesassociated with a particular drug, andthat [t]his hinders any effort tointerpret the trends over time. Id. TheALJ thus agreed with Medas expert thatDAWN ED data may not be the bestevidence in this record for concludingthat the abuse of carisoprodol isincreasing over time. Id.

As for the DAWN Medical Examinerdata, the ALJ noted that the reporting

[of] a drug in this reporting systemmeans that the drug need only beimplicated or suspected in the death.Id. at 90. Quoting the testimony ofMedas Expert, the ALJ found that carisoprodol may not have been theactual cause of death, and it is notpossible to conclude that carisoprodolabuse was the cause of death in thesecases. Id. However, the ALJ noted thatthe data showed a link, even if notdirect evidence of a cause, betweencarisoprodol use in combination withother drugs and death in 434 cases ofdeath in 2006. Id.

Turning to the Florida Medical

Examiner data, which show that 415carisoprodol-related deaths occurred in2008, and an increase of about 62percent in the total occurrence ofcarisoprodol/meprobamate in Floridadrug abuse deaths, the ALJ again notedthe testimony of Medas Expert thatcarisoprodol may not be the cause ofdeath, but rather it may be merelypresent in the body at the time ofdeath. Id. However, the ALJ then foundthat the FDA determined thatcarisoprodol was considered the causeof death in 88 cases in 2007. Id.

Next, the ALJ noted that the NPDS

data show that in 2007, carisoprodolwas associated with 8,821 toxicexposure cases, including 3,605 cases inwhich [it] was the sole drugmentioned, and that [c]ases ofindividuals treated in health-carefacilities because of a major adversehealth-outcome total 122 out of the2,821 single exposure cases. Id. at 91.The ALJ then acknowledged thetestimony of Medas Expert that becausethe cases are self-reported and thereporting individual may misidentifythe substance during the call to the

poison center, it [is] impossible toconclude that a mentioned drug wascausally implicated in the exposure. Id. However, the ALJ also noted thetestimony of Medas Expert that the poison center data have some use, butmust be interpreted with caution. Id.

The ALJ further found that while thethe intentional exposure data for the

years 2006 and 2007 show that thenumber of deaths attributable to singleexposure cases had remained at oneper year, the number of cases withmajor effects went from 105 to 122,and the number of cases with moderateeffects went from 688 to 720. Id. at 9192. The ALJ thus concluded that theincreases in the major and moderateeffects cases support the conclusionthat individuals are taking carisoprodolin amounts sufficient to cause hazard totheir health. Id. at 92.

Finally, the ALJ observed that theFDA had found that data from 20022006 indicate that more than 25 percentof patients used the drug [for] longerthan one month and 4.3 percent usedthe drug more than 360 days, and that [l]onger term use may contribute toincreased risks of misuse and abuse. Id. The ALJ then noted that sheagree[d] with the FDAs conclusion.Id.

With respect to Factor Sixthe risk,if any, to public healththe ALJ againnoted the testimony of the head of DEAOffice of Diversion Control, theExecutive Director of the Ohio StateBoard of Pharmacy, and the SpecialAgent in Charge with the Tennessee

Bureau of Investigation to the effect thatthe failure to schedule carisoprodolposes a great risk to public health. Id.at 9293. The ALJ further noted theFDAs conclusion that becausecarisoprodol is metabolically convertedto meprobamate, a schedule IVcontrolled substance, the public healthrisks of carisoprodol may be similar tothose of meprobamate; the poisoncontrol center data which show thatindividuals are taking carisoprodol inamounts sufficient to cause hazard totheir health ; and FDAs finding that the risks of carisoprodol to the public

health are typical of other centralnervous system depressants that arecontrolled and that [t]hese risksinclude central nervous systemdepression, respiratory failure, cognitiveand motor impairment, addiction,dependence, and abuse. Id. (citationsomitted). The ALJ again found that theFDAs conclusions were binding onthis proceeding. Id. at 93.

The ALJ then noted Medas evidenceshowing a decline in the number ofprescriptions that occurred in fourStates which have controlled



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carisoprodol, as well as Medascontention that controlling the drugwould have a chilling effect on thelegitimate prescribing of the drug

because of the reluctance of physiciansto prescribe a controlled substance andthat this would be to the detriment ofthose patients who would be besttreated with carisoprodol. Id. at 9394.

The ALJ found, however, thatanecdotal evidence in this recordcontradicts this prediction, becauseone of Medas Experts testified that ifcarisoprodol was controlled, he wouldcontinue to prescribe it. Id. at 94. TheALJ then found that DEA data showedthat controlling other drugs did notresult in physicians ceasing toprescribe them. Id.

Finally, the ALJ found thatcarisoprodol has been implicated incases of impaired driving, withsymptoms consistent with other centralnervous system depressants, especially

alcohol, and that [a] Norwegian studyalso supported this proposition. Id.The ALJ was unpersuaded by Medasargument that many uncontrolleddrugs have labels warning againstdriving while taking such drugs, notingthat [i]mpaired driving is a risk to thepublic health, and thus supports theconclusion that published scientificreports indicate that taking carisoprodolis associated with risk to the publichealth. Id.

With respect to Factor Seventhedrugs psychic or physiologicaldependence liabilitythe ALJ observedthat [d]ependence includes both

physical and psychologicaldependence. Id. While noting thatthere are noncontrolled drugs forwhich an individual may have aphysical dependence, a drug-takersconduct must be viewed in total todetermine if the person has a psychicdrive or craving to obtain the drug. Id.at 95. The ALJ then noted that based onvarious scientific studies, the FDA hadfound that carisoprodol has adependence liability that is similar tothat of barbital, a Schedule IV centralnervous system depressant, in itsdependence potential, and that the

FDAs finding was binding on theproceeding. Id. The ALJ also cited thetestimony of a DEA witness thatcarisoprodol is abused by individuals toobtain a mellow euphoria. Id.

The ALJ also found that two studieshad shown that carisoprodol producessubjective and objective effects inhuman subjects [that] were similar tothose of barbiturates or alcohol, theformer being controlled substanceslisted in both schedules III and IV. Id.at 96. The ALJ then noted the testimonyof Medas Expert that if carisoprodol

induced a barbiturate intoxicationpattern, [this] could be a possibleindicator that carisoprodol possesses

barbiturate-like abuse liability. Id.Finally with respect to Factor Eight

whether carisoprodol is an immediateprecursor to a substance alreadycontrolledthe ALJ found it undisputedthat the drug is not an immediate

chemical precursor or intermediary of acontrolled substance. Id.

The ALJ then addressed the threesection 812(b) placement factors. Withrespect to Factor Onewhether the drughas a low potential for abuse relative tothe drugs in schedule IIIthe ALJ began

by noting the FDAs recommendation(and the concurrence of the NationalInstitute on Drug Abuse (NIDA)), thatcarisoprodol should be placed inschedule IV. Id. The ALJ found that[e]mpirical evidence supports theFDAs conclusion, including theevidence that carisoprodol metabolizesinto meprobamate, a schedule IVcontrolled substance, and that variousstudies support the conclusion thatcarisoprodol has effects similar to

barbiturates, which are schedule III andIV controlled substances. Id. at 9697.The ALJ also found thatnotwithstanding that the DAWN EDdata, which show that the abusefrequency of carisoprodol is similar tothat of diazepam, a schedule IV drug,may be overly inclusive, thislimitation would not result in anysignificant difference in ED visits

between the reported drugs. Id. at 98.While acknowledging that the NSDUH

data show that carisoprodol is beingabused * * * at a rate significantly lessthan that of benzodiazepines, the ALJfound that the NSDUH and DAWN aretwo distinct studies, both onmethodology and measurement, andtherefore cannot adequately becompared. Id. at 9899.

With respect to Factor Twowhetherthe drug has a currently acceptedmedical use in treatment in the UnitedStatesthe ALJ found it undisputedthat carisoprodol has been approved bythe FDA for the treatment of acute,painful musculoskeletal conditions. Id.

at 99100. The ALJ thus found thatcarisoprodol has a currently acceptedmedical use in the United States. Id. at100.

With respect to Factor Threewhether abuse of the drug may lead tolimited physical or psychologicaldependence relative to the drugs inschedule threethe ALJ credited thetestimony of two of Medas experts tothe effect that carisoprodol does notcreate abuse liability patterns typical ofcontrolled drugs and that [t]here doesnot appear to be any patient liking that

would indicate an abuse potential. Id.at 101. The ALJ nonetheless found thatthere is substantial evidence in therecord based on the animal data, AERSreports, and Mayo Clinic data thatcarisoprodol produces dependence andwithdrawal symptoms similar to othercontrolled substances in schedule IV.Id. The ALJ further held that FDAs

conclusions regarding the psychologicaland physiological dependence ofcarisoprodol [were] binding on thisproceeding. Id.

The ALJ thus concluded thatsubstantial evidence supports thecontrolling of carisoprodol under theeight factors of section 811(c). Id. at 102.The ALJ further concluded thatsubstantial evidence supported theplacement of carisoprodol in scheduleIV. Id. (citing 21 U.S.C. 812).

Meda filed Exceptions to the ALJsdecision. Thereafter, the ALJ forwardedthe record to me for final agency action.

Having considered the entire record,including Medas Exceptions (which arediscussed more fully below), I agreewith its contention that the ALJ erred inholding that the FDAs scientific andmedical findings are binding on thisproceeding. However, because the ALJallowed Meda to put on extensiveevidence as to the scientific and medicalmatters considered by the FDA, and

because, as ultimate factfinder (see 5U.S.C. 557(b)), I have considered Medasevidence in deciding whethersubstantial evidence supports thescheduling of carisoprodol, I concludethat the ALJs error is not prejudicial.

Because I hold that the record as awhole contains substantial evidence tosupport the findings required to controlcarisoprodol and place it in schedule IVof the CSA, I will issue a rule placingcarisoprodol in schedule IV.

The ALJs Ruling on the Binding Natureof the FDAs Scientific and MedicalEvaluation

As noted above, before initiatingproceedings * * * to control a drug orother substance, the Attorney Generalis required to request from theSecretary a scientific and medical

evaluation, and [her] recommendations,as to whether such drug or othersubstance should be so controlled. 21U.S.C. 811(b). Congress specified that[i]n making such evaluation andrecommendations, the Secretary shallconsider the factors listed in paragraphs(2), (3), (6), (7), and (8) of subsection (c)* * * and any scientific or medicalconsiderations involved in paragraphs(1), (4) and (5) of such subsection. Id.The Secretary is directed to provide theAttorney General with her evaluationand * * * recommendations, which



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

4At issue in Reckitt & Coleman was a rulemakingwhich rescheduled buprenorphine from schedule IIto schedule V, but which designated the drug as anarcotic based on the ground that it is a derivativeof thebaine. See 788 F.2d at 22. In a footnote, theCourt of Appeals discussed an argument advancedin the brief of a third-party intervenor (which theDepartment endorsed at oral argument) that theAgencys conclusion could be upheld on the groundthat HHSs initial communication to DEA statedthat buprenorphine is a thebaine derivative, and theAct makes HHSs recommendations as to scientificand medical matters binding on the DEA. 788F.2d 27 n.8 (citing 21 U.S.C. 811(b)). While thecourt concluded that it was unnecessary to reachthe issue, as noted above, it expressed considerable

skepticism as to the reasonableness of the view thatthe Attorney General is bound by the Secretarysfinding on a scientific issue notwithstandingcontrary evidence presented at a hearing. While theDC Circuits discussion is not binding, it is dictumwhich the Agency ignores at its peril.

5As support for her holding, the ALJ also citedUnited States v. Spain, 825 F.2d 1426, 1428 (10thCir. 1987), and United States v. Pastore, 419F.Supp. 1318 (S.D.N.Y. 1976). As for the ALJsreliance on Spain, that case addressed the AttorneyGenerals authority under 21 U.S.C. 811(h), whichauthorizes the scheduling of a substance inschedule I on a temporary basis [when] necessaryto avoid an imminent hazard to the public safety.See 825 F.2d at 1427. Under this provision, theAttorney General is not required to obtain ascientific and medical evaluation from the Secretarybefore acting. Id. at 14829. Thus, the case does not

address the issue of whether the Secretarys medicaland scientific evaluation and recommendations aresubject to re-litigation at the hearing. See 825 F.2dat 1427.

Pastore involved a motion to dismiss anindictment which charged various offensesinvolving the unlawful distribution and obtainingof the controlled substances phendimetrazine andphentermine. See 419 F. Supp. at 133435. Whilethe defendants raised various challenges to theAttorney Generals decision scheduling these drugs,both drugs were scheduled without a formal on-the-record hearing. Id. at 134648. Here again, the casedid not address the issue of whether the Agency isbound by the Secretarys finding on a scientific ormedical issue in a formal rulemaking proceeding.See id.

shall include recommendations withrespect to the appropriate schedule, ifany, under which such drug or othersubstances should be listed. Id.

Subsection (b) further provides that[t]he recommendations of the Secretaryto the Attorney General shall be bindingas to such scientific and medical

matters, and if the Secretaryrecommends that a drug or othersubstance not be controlled, theAttorney General shall not control thedrug or other substance. Id. Moreover,[i]f the Attorney General determinesthat these facts and all other relevantdata constitute substantial evidence ofpotential for abuse such as to warrantcontrol * * * he shall initiateproceedings for control * * * undersubsection (a), the provision whichrequires that a rule scheduling asubstance be made on the record afteropportunity for a hearing pursuant to

the rulemaking procedures prescribedby 5 U.S.C. 556 and 557.

The ALJ held that the CSA limits thescope of the administrative hearing tothose issues outside of the medical andscientific fact-findings of the FDA. ALJat 11. According to the ALJ, the theplain language and legislative history of[sections 811(a) and (b)] and federal caselaw indicate [that] Congress intendedthat the Secretarys scientific andmedical fact-findings bind the [Agency]throughout the scheduling process. Id.The ALJ further rejected Medascontention that construing the statute in

this manner would deny it a meaningfulhearing and render the hearing largelysuperfluous, concluding thatRespondent will be afforded theopportunity for a meaningful APAhearing without the opportunity tolitigate the factual underpinnings of the[HHS] report. Id.

The ALJ thus rejected Medascontention that the FDAs findings as tomedical and scientific matters are only

binding on the Agencys decision as towhether to initiate a schedulingproceeding and that the Secretarysfindings are not binding on either the

ALJ or the Administrator in evaluatingthe record of the hearing. Id. at 911(discussing Meda Br. 1518). As notedabove, throughout her consideration ofthe factors, the ALJ held that she was

bound by FDAs findings as to scientificand medical matters and that Meda wasnot entitled to challenge the Secretarysmedical and scientific findings. See,e.g., ALJ at 8586 (holding FDAsfindings as to Factor Two (Section811(c)) binding notwithstanding Medascontrary evidence).

I find the ALJs reasoning confusing,3and that she gave insufficientconsideration to the most relevantjudicial decisions; I therefore reject herlegal conclusion. To be sure, theSupreme Court has recognized that[t]he CSA allocates decision makingpowers among statutory actors so thatmedical judgments * * * are placed in

the hands of the Secretary, and that the[t]he structure of the CSA * * *conveys unwillingness to cede medicaljudgments to an Executive official wholacks medical expertise. Gonzales v.Oregon, 546 U.S. 243, 265 (2006). Yet,the ALJs sweeping conclusion that thislanguage supports the inference thatthe Supreme Court interpreted 811(b) toindicate that those medical judgmentsare final and not subject to litigationbefore the DEA, ALJ at 13 (emphasisadded), cannot be squared with otherprovisions of the statute. Moreover, theCourt did not decide the issue.

As noted above, upon receiving theSecretarys evaluation andrecommendation, the Attorney Generalis charged with the duty to determinethat these facts and all other relevantdata constitute substantial evidence of

potential for abuse such as to warrantcontrol. 21 U.S.C. 811(b) (emphasisadded). In the event the Secretarysevaluation and the other relevant dataconstitute substantial evidence such asto warrant control, the Attorney Generalmay then initiate proceedings to controlthe drug. However, Congress furtherprovided that Rules of the Attorney

General [to control a drug] shall bemade on the record after opportunity fora hearing pursuant to the rulemakingprocedures prescribed by theAdministrative Procedure Act (APA). 21U.S.C. 811(a).

Under this provision, a rule may notbe issued except on consideration ofthe whole record or those parts thereofcited by a party and supported by andin accordance with the reliable,

probative, and substantial evidence. 5U.S.C. 556(d) (emphasis added). Were itthe case that the Secretarys findings asto medical and scientific matters are notsubject to litigation in the subsequent

rulemaking hearing, the only issues leftto be litigated would be the drugsactual abuse, its history and currentpattern 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 andcomment rulemaking) would hardly benecessary to determine whether the dataproffered by the Agency is adequate tosupport the findings necessary tocontrol a drug. As the DC Circuitexplained in Reckitt,4 if HHSs medicaland scientific findings are binding

throughout a proceeding, it is difficultto see what purpose the agencys on-the-record hearing [would] serve[.] 5

The ALJs also found unpersuasiveGrinspoon v. DEA, 828 F.2d 881 (1st Cir.1987). Grinspoon involved a petition toreview the Agencys issuance of a finalrule placing MDMA in schedule I. 828F.2d at 882. In Grinspoon, the petitionerraised four different challenges to theAgencys rule. Id. at 88283. Theseincluded, inter alia, that theAdministrator applied the wrong legalstandard because he interpreted thephrases accepted medical use in

treatment in the United States, andaccepted safety for use * * * under



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6Throughout her discussion, the ALJ explainedthat the CSA limits the scope of the administrativehearing to those issues outside of the medical andscientific fact-findings of the FDA, that Congressintended that the Secretarys scientific and medicalfact-findings bind the DEA throughout thescheduling process, that Respondent will beafforded the opportunity for a meaningful APAhearing without the opportunity to litigate thefactual underpinnings of the [HHS] report, ALJ at11, and that Gonzales indicate[s] that [the FDAs]

medical judgments are final and not subject tolitigation before the DEA. Id. at 13.

However, after concluding that Grinspoon doesnot support Meda and was distinguishable becausethe Agency had blindly relied on FDA approval asthe sine qua non of the currently accepted medicaluse and accepted safety for use * * * under

medical supervision standards, the ALJ quoted thepassage set forth above and observed that [i]n lightof th[e Administrators] independence, and Medasopportunity to present evidence relevant to theAdministrators decision, this tribunal would behard-pressed to conclude that there was noopportunity for consideration of the views ofpersons who would be adversely affected by controlof the drug. Id. at 16 (quoting H. Rep. No. 911444, at 23 (1970)). Yet, she subsequentlyconcluded that the plain language and legislativehistory * * *, federal case law, and [HHSs] processfor conducting its administrative review, make clearthat Congress intended that the Secretarysscientific and medical fact-findings bind the DEAduring the hearing and the subsequent schedulingdetermination. Id. at 18.

7Under 21 CFR 14.172, [a]ny interested personmay request, under 10.30, that a specific matterrelating to a particular human prescription drug besubmitted to an appropriate advisory committee fora hearing and review and recommendations * * *.The Commissioner may grant or deny the request.Under 21 CFR 15.1(a), the Commissioner mayconclude[], as a matter of discretion, that i t is inthe public interest to permit persons to presentinformation and views at a public hearing on anymatter pending before the Food and DrugAdministration. Notably, under both provisions,the decision as to whether to grant a hearing iswithin the Commissioners discretion.

medical supervision as meaningapproved for interstate marketing* * * under the Food, Drug andCosmetic Act, id. at 884 (quoting 21U.S.C. 812(b)(1)(A)), as well as that therule [was] based upon incomplete andarbitrary recommendations from theSecretary. Id. at 883.

The First Circuit held that the

Administrator had erroneouslyinterpreted the phrases acceptedmedical use in treatment in the UnitedStates and accepted safety for use* * * under medical supervision asmeaning that the drug had not beenapproved by FDA for interstatemarketing. Id. at 891. The Court thusvacated the rule and ordered the Agencyto reconsider the schedulingdetermination. Id.

The Court, however, also addressedthe Petitioners other challenges to therule, including that HHS had acted in anarbitrary and capricious manner because

it failed to look beyond its own filesupon receiving the Administratorssection 811(b) request, that it did notconsult any organization of medicalprofessionals or FDAs Drug AbuseAdvisory Committee, that it simplyrubber-stamped DEAs eight-factoranalysis, and that it had failed toforward a letter from NIDA whichquestioned evidence pertaining toMDMAs abuse potential in animals. Id.at 897. In rejecting the Petitionerscontention, the court explained:

[T]he HHS recommendation to schedule asubstance is not binding and, indeed, serves

to trigger an administrative hearing at whichinterested persons may introduce evidence torebut the Secretarys schedulingrecommendation. Ultimately, of course,responsibility rests with the Administrator,not HHS, to ensure that the final rule restson permissible legal standards andsubstantial evidence.

Id. (footnote omitted).

As Grinspoon makes clear, while theSecretary is the expert as to thescientific and medical matters at issuein the scheduling decision, the AttorneyGeneral is obligated to conduct ahearing and to consider contrary

evidence even as to these issues. Thelegislative history buttresses thisconclusion.6 As the House Reportexplains:

The procedure which the Attorney Generalmust then follow to control a drug involvesrulemaking proceedings on the record afteropportunity for a hearing. This providesopportunity for consideration of the views ofpersons who would be adversely affected bycontrol of a drug, with judicial reviewavailable thereafter; however, thisadministrative proceeding is morestreamlined in its operation than the existing

procedures under section 701(e) of theFederal, Food, Drug, and Cosmetic Act, sothat controls may be establishedexpeditiously where necessary, with fullconsideration of all factors involved in thedecision-law enforcement problems, medical,and scientific determinations, and theinterests of parties affected by the decision tocontrol.

H. Rep. No. 911444, 1970 U.S.C.C.A.N.at 4589.

The ALJ also reasoned that the FDAsdetailed administrative process [for]making its scientific and medical factfindings suggests that Congress did notintend the DEA to secondarily review

those filings. ALJ at 17. Citing a 1999Hearing Report of the Subcommittee onOversight and Investigations of theHouse Committee on Commerce, theALJ noted that the the scientific andmedical evaluation process is a complexone which is part of the balancing of theinterests of various agencies and thatthe process may extend over manyyears, [and] is subject to review byvarious components of the FDA andinteragency review. Id. The ALJ furthernoted that under two different FDAregulations, Meda could have requesteda hearing before the FDA. ALJ at 1718

n.5; see also id. at 4 n.2.However, in enacting subsection811(a), Congress did not bifurcate thehearing between the two Agencies.Rather, it tasked the Attorney Generalwith the responsibility for conductingthe hearing. Moreover, neither thestatute nor the legislative historyevidences that Congress intended that

challenges to the Secretarys scientificand medical findings be litigated in aproceeding before HHS.

In addition, both the statute and thelegislative history make plain thatCongress was concerned that schedulingproceedings be done in an expeditiousmanner. For instance, section 811(b)requires that the Secretary submit his

report to the Attorney General withina reasonable time. 21 U.S.C. 811(b)(emphasis added). Likewise, indiscussing the hearing provision, theHouse Report manifests Congress intentthat controls may be establishedexpeditiously where necessary. 1970U.S.C.C.A.N. at 4589. The ALJssuggestion that Meda was required torequest a hearing under either 21 CFR14.172 or 21 CFR 15.1(a), see ALJ at 17& n.5,7 runs counter to Congresssmanifest interest in the expeditiousresolution of proceedings to control adrug.

In its Exceptions, Meda contends thatthe ALJs decision in this proceeding ispredicated upon an erroneous belief thatMeda had an opportunity to challengethe scientific and medical fact-findingunderlying the HHS recommendation.Meda Exc. at 1. The exception is welltaken. Indeed, as set forth in footnoteseven above, under both of theseprovisions, the decision as to whether togrant a hearing is discretionary.Requiring that Meda litigate the medicaland scientific findings before an FDAforum would likely add several years ofdelay, and would raise a host ofadditional issues, including whetherDEA was required to stay its proceedingwhile the findings were beingchallenged before an FDA forum,whether those findings are entitled tores judicata effect if a formal evidentiaryhearing was not held, whether theFDAs decision was a final decisiontriggering the right to judicial review,and likely others.

Also unpersuasive is the ALJsreasoning that because the FDAsprocess for evaluating a schedulingrequest is complex and time-consuming,Congress did not intend the DEA tosecondarily review those findings. ALJ

at 17. As the House Report makes plain,



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8Meda argues that the FDA review is entitled tovery little weight because DEA counsel did notcall any HHS or FDA witness to testify and justifythe scientific, medical, and legal basis underlying

the HHS recommendation. Meda. Br. 22. However,most of the findings in the FDAs evaluation weresupported by citations to publicly available articles,and it is not clear why an FDA witness was requiredto testify as to the contents of articles which havebeen published in scientific and medical journals.Moreover, Meda did not seek to subpoena any ofthe FDA officials who were involved in the review.Finally, while the Government did not call an FDAor HHS witness to answer questions about thenumerous weaknesses in the data, Meda wasclearly able to put on an effective challenge to someof the data cited by the Government.

9 I have considered Medas argument that byrelying on the four indicators of abuse set forth inthe legislative history, the Agency has improperlyattempted to redefine abuse to mean somethingmuch broader than what the Committeecontemplated (i.e., use for nontherapeutic

in enacting the scheduling provisions,Congress manifested its intention thatscheduling proceedings would be donein an expeditious fashion, but with fullconsideration of all factors involved inthe decision,including the medicaland scientific determinations involvedin the decision. 1970 U.S.C.C.A.N. at4589 (emphasis added). The ALJs

conclusion that the medical andscientific findings of FDA are bindingand cannot be secondarily review[ed]in this proceeding, is contrary to thisintent.

Accordingly, consistent with theAPAs requirement that the record as awhole must be considered, I hold that,notwithstanding the Secretarysexpertise as to the scientific andmedical matters, the Agency is (and theALJ was) obligated to consider Medascontrary evidence even as to theSecretarys medical and scientificfindings and to determine whether

substantial evidence supports thefinding that carisoprodol has apotential for abuse, as well as thefindings made in support of placing thedrug in schedule IV. See 21 U.S.C.811(a).

However, while the ALJ misconstruedthe statute, she did allow Meda to puton evidence to rebut the Secretarysevaluation of the medical and scientificevidence. Because [t]he Agency, andnot the ALJ, is the ultimate factfinder,Reckitt & Colman, 788 F.2d at 26, Iconclude that ALJ did not commitprejudicial error. Cf. 5 U.S.C. 706 (due

account shall be taken of the rule ofprejudicial error). Accordingly, aremand is not necessary and I proceedto consider the evidence with respect tothe section 811(c) factors.

Findings of Fact

Since 1959, carisoprodol has beenapproved for marketing in the UnitedStates under the brand name of Soma;the drug, which is also available as ageneric drug, is approved by the FDAfor the relief of discomfort associatedwith acute, painful musculoskeletalconditions. GX 6, at 1 (letter of HowardH. 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 andrecommended that carisoprodol becontrolled and placed in schedule IV ofthe CSA. Id.

FDA made extensive findings as toeach of the eight section 811(c) factors.These findings are discussed below,8

along with additional evidenceprovided by DEAs witnesses and thetestimony and exhibits submitted byMeda.

Factor 1Carisoprodols Actual orRelative Potential for Abuse

The terms abuse and potential forabuse are not defined in the CSA. See

generally21 U.S.C. 802. However, thelegislative history of the CSA explainsthat a drug or substance has a potentialfor abuse because of its depressant orstimulant effect on the central nervoussystem or its hallucinogenic effect

based on the following indicators:

1. Individuals are taking the substance inamounts sufficient to create a hazard to theirhealth or to the safety of other individuals orto the community; or

2. There is significant diversion of the drugor substance from legitimate drug channels;or

3. Individuals are taking the substance ontheir own initiative rather than on the basis

of medical advice from a practitionerlicensed by law to administer suchsubstance; or

4. The substance is so related in its actionto a substance already listed as having apotential for abuse to make it likely that itwill have the same potential for abuse assuch substance, thus making it reasonable toassume that there may be significantdiversions from legitimate channels,significant use contrary to or without medicaladvice, or that it has a substantial capabilityof creating hazards to the health of the useror to the safety of the community.

Comprehensive Drug Abuse Preventionand Control Act of 1970, H.R. Rep. No.911444, reprinted in 1970 U.S.C.C.A.N.

4566, 4601.The legislative history also explains

that a determination that a substancehas potential for abuse should not bedetermined on the basis of isolated oroccasional nontherapeutic purposes.Id. at 4602 (other citation and int.quotations omitted). Rather, there mustexist a substantial potential for theoccurrence of significant diversionsfrom legitimate channels, significant use

by individuals contrary to professionaladvice, or substantial capability ofcreating hazards to the health of the useror the safety of the community. Id.

However, the legislative history alsomakes clear that the Attorney General is

not required to wait until a number oflives have been destroyed or substantialproblems have already arisen beforecontrolling a drug. Id.

The legislative history furtherexplains that [i]n speaking ofsubstantial potential the termsubstantial means more than a merescintilla of isolated abuse, but less than

a preponderance. Id. Thus, evidencethat several hundred thousand dosageunits of a drug have been divertedwould be substantial evidence of abusedespite the fact that tens of millions ofdosage units of that drug arelegitimately used in the same timeperiod. Id. Moreover, [m]isuse of adrug in suicides and attempted suicides,as well as injuries resulting fromunsupervised use are regarded asindicative of a drugs potential forabuse. Id.

As the Assistant Secretary noted,there is no single test or assessment

procedure that, by itself, provides a fulland complete characterization of asubstances abuse potential, as this is acomplex determination that ismultidimensional. GX 6, at 3.Accordingly, in assessing the abusepotential of a substance, the Secretaryconsiders multiple factors, data sourcesand analyses, including theprevalence, frequency and manner ofuse in the general public and specificsubpopulations, the amount of materialthat is available for illicit use, as well asevidence relevant to populations thatmay be of particular risk. Id.

The Assistant Secretary furtherexplained that:

[a]nimal, human, and epidemiological dataare all used in determining a substancesabuse potential. Scientifically, acomprehensive evaluation of the relativeabuse potential of a substance includesconsideration of the drugs receptor bindingaffinity, preclinical pharmacology,reinforcing effects, discriminative stimuluseffects, dependence producing potential,pharmacokinetics and routes ofadministration, toxicities, assessment[] of theclinical efficacy, safety database relative toactual abuse, clinical abuse potential studiesand the public health risks followingmarketing of the substance. Epidemiological

data can also be an important indicator ofactual abuse. Finally, evidence of clandestineproduction and illicit trafficking of asubstance are also important factors.

Id. Set forth below is the partiesevidence as to each of the fourindicators of carisoprodols potential forabuse.9



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purposes). Med. Br. 13. However, as the AssistantSecretary noted, determining a substances potentialfor abuse is a complex and multi-dimensional

determination which includes an analysis ofanimal, human, and epidemiological studies, aswell as other factors, GX 6, at 3; and the recordcontains extensive evidence as to the numerousconsiderations relevant in assessing a drugs abusepotential.

10The FDA more fully discussed the data underFactor Fourcarisoprodols history and currentpatterns of use, and Factor Sixwhat, if any, riskthere is to public health. GX 6, at 3.

11According to the FDAs report, DAWNmortality cases now include the following deaths:Completed suicides, Overmedication, Adversereactions, Accidental ingestions, Homicide bydrugs, Underage drinking and Other deaths relatedto drugs. The FDA further noted that [t]he

mortality component of DAWN is not national inscope, and Medical Examiners or Coroners (ME/Cs)that report to DAWN are concentrated in

metropolitan areas. GX 6, at 17. The FDA thenacknowledged that because the report does notrepresent a scientific sample, results fromparticipating jurisdictions cannot be extrapolatednationally, and that because participants can varyfrom year to year, it is not appropriate to compareaggregated death data between years. Id. Moreover,because [c]ertain jurisdictions within themetropolitan area may not participate in DAWN* * * selected data can not necessarily begeneralized to an entire metropolitan area. Id.

FDA further noted that [a]pproximately half ofthe carisoprodol-related deaths reported involve theuse of meprobamate in combination withcarisoprodol and that [d]ue to reporting methodvariability, it is difficult to determine if both drugswere taken in combination or if meprobamate was

present in the deceased as a result of carisoprodolmetabolism. Id. Finally, FDA noted that [t]hereporting of carisoprodol found by the ME/C

following a post mortem examination does notnecessarily imply that carisoprodol was theultimate cause of death * * *, only that it wasidentified by the ME/C as involved in the death,and that [v]ery few deaths from 2003 and 2004involve the use of carisoprodol by itself and areconsistent with other data indicating thatcarisoprodol is used most often in combinationwith a variety of other agents. Id. at 18. Becauseof the numerous limitations with this data, I giveno weight to the DAWN ME/C data.

12 In 2007, DAWN ED carisoprodol visits alsoaccounted for an increasing percentage of thenonmedical use ED visits associated with skeletalmuscle relaxants, increasing each year from 59percent in 2004, to 70 percent in 2007.

1. Use of Carisoprodol Results in Harmto Individuals and the Public

The FDA found that an evaluation ofpublished case reports and case series,the FDA Adverse Event ReportingSystem (AERS), and the SAMHSADAWN databases, show thatcarisoprodol as currently used raises

concerns not only for the health andsafety of the users of this substance, butalso for the public because of exposureto those who use carisoprodol. Morespecifically, the FDA found that thesesources of information indicate thatserious adverse events, including death,drug dependence, drug withdrawalsymptoms, and non-intentional anddeliberate overdose are related to theabuse of carisoprodol.

The FDA further noted that adverseevents have occurred both whencarisoprodol is the sole drug of use, aswell as when it is used in combinationwith other drugs, both licit and illicit(polypharmacy). In addition, the use ofcarisoprodol has been implicated as afactor in vehicle accidents due to driverimpairment. The FDA thus concludedthat there is evidence that individualsare taking the substance in amountssufficient to create a hazard to theirhealth or to the safety of otherindividuals or to the community.10

Drug Abuse Warning Network (DAWN)Data

The Substance Abuse Mental HealthServices Administration (SAMHSA)administers the Drug Abuse Warning

Network (DAWN, 2007; http://

dawninfo.samhsa.gov/). DAWN is anational probability survey of U.S.hospitals with emergency departments(EDs) which is designed to obtaininformation on ED visits in whichrecent drug use is implicated. The dataare gathered from a representativesample of hospital EDs and are weightedto produce national estimates. In

addition to the DAWN ED data, DAWNalso collects data on drug-related deathsinvestigated by Medical Examiners andCoroners (ME/C).11

DAWN ED Data

According to FDA, many factors canimpact the estimates of ED visits, GX 6,at 11; which are identified through aretrospective review of medical charts.MX 34, at 33 n.13. Individuals (whetherpatients or drug abusers) who use a drugmay visit EDs for a variety of reasons,including treatment of a life threateningadverse event or to obtain a certificationof need before entering a formaldetoxification program. If multipledrugs are involved, DAWN may not beable to distinguish whether a singledrug or the interaction of drugs causedthe ED visit. Moreover, while DAWNtries to capture only drugs that arerelated to the ED visit and activelydiscourages the reporting of currentmedications that are unrelated to thevisit[,] * * * it is not possible, given thelimitations of medical recorddocumentation, to eliminate completelythe 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 useof pharmaceuticals includes taking morethan the prescribed dose of aprescription pharmaceutical * * *;taking a pharmaceutical prescribed foranother individual; deliberate poisoningwith a pharmaceutical by anotherperson; and documented misuse or

abuse of a prescription pharmaceutical.Id. Because of the limitations ofmedical record documentation, [DAWNhas] concluded that distinguishingmisuse from abuse reliably is notfeasible. Id. n.13.

Selected data from DAWN for 20042007 are shown in Table 1 below. Thesedata show an increase in the frequencyof nonmedical use ED visits associatedwith carisoprodol. More specifically, in2004, DAWN estimated that there were14,736 ED visits related to thenonmedical use of carisoprodol, andthat in 2007, there were 27,505

nonmedical ED visits related to thenonmedical use of the drug. However,according to SAMHSA, the increasefrom 2004 through 2007 did not reachstatistical significance. GX 6, at 12.Accordingly, the data do not support afinding that the rate of abuse ofcarisoprodol is increasing.

The data do, however, support afinding that carisoprodol is resulting inED visits at a level comparable to thatof diazepam, a benzodiazepine andschedule IV controlled substance. AsTable 1 shows, in 2004 there were anestimated 15,619 ED visits related to

diazepam.12

TABLE 1SELECTED PHARMACEUTICAL ED VISITS (NONMEDICAL USE): 20042007 FROM DAWN[Data output 08/02/2008]

Selected drugsEstimates

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



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13According to FDA, SDIs Vector OneTMNational (VONA) measures retail dispensing ofprescriptions or the frequency with which drugsmove out of retail pharmacies into the hands ofconsumers via formal prescriptions. GX 6, at 13 n.7.Information on the physicians specialty, thepatients age and gender, and estimates for thenumbers of patients that are continuing or new totherapy are available. Id.

The Vector OneTM database integratesprescription activity from a variety of sourcesincluding national retail chains, massmerchandisers, pharmacy benefits managers andtheir data systems, and provider groups. Id. VectorOne receives over 1.8 billion prescription claimsper year, representing over 150 million uniquepatients. Id. The number of dispensed prescriptionsis obtained from a sample of virtually all retail

pharmacies throughout the United States, andrepresents approximately half of retail prescriptionsdispensed nationwide. Id. SDI receives allprescriptions from approximately one-third of thestores and a significant sample of prescriptionsfrom the remaining stores. Id.

14See Table 6 from the OSE Duration of UseAnalysis for Soma (NDA 11792) dated June 27,2007.

By dividing the number of ED visitsby the number of prescriptions, FDAcalculated abuse frequencies forcarisoprodol; cyclobenzaprine, a non-scheduled muscle relaxant; anddiazepam, which is also prescribed forits muscle relaxant properties. Thesecalculations, which are found in Table

2 below, show that the abusefrequency of carisoprodol is in thesame range as diazepam and greaterthan that of cyclobenzaprine. Morespecifically, even in 2004, thecarisoprodol rate was 15.1 ED visits per10,000 prescriptions, while diazepamsrate was 12.5. By contrast,

cyclobenzaprine, another skeletalmuscle relaxant had a rate of 4.1 EDvisits per 10,000 prescriptions. Mostsignificantly, even in 2004, and beforethe increase in the estimates ofcarisoprodol-related ED visits,carisoprodol had a greater frequency ofED related visits than diazepam.

TABLE 2FREQUENCY OF DAWN ED VISITS (NONMEDICAL USE) PER 10,000 RX FOR CARISOPRODOL,CYCLOBENZAPRINE AND DIAZEPAM

[20042007]

Selected drugs 2004 2005 2006 2007

Carisoprodol ................................................................................................................................... 15.1 19.7 22.9 22.6Cyclobenzaprine ............................................................................................................................ 4.1 4.61 4.1 3.3Diazepam ....................................................................................................................................... 12.5 14.5 15.0 14.1

Data derived from proprietary SDI data. SDI Vector One: National, Years 20022007, Data Extracted April, 2008 File: VONA 2008517 415 13

Carisoprodol has been reported as a

primary or sole drug of abuse in DAWNonly since 2006. According to the 2006DAWN data, there were an estimated24,505 ED visits related to carisoprodol,of which it was reported as the sole drugin 21 percent of the cases. This isconsistent with the FDAs finding that

the majority of the cases published inthe scientific literature report thatcarisoprodol abuse has primarily been acomponent of multi-drug abuse.

FDA reviewed DAWN data and foundthat the drugs most frequently used incombination with carisoprodol thatresulted in ED visits were opioids(hydrocodone, oxycodone),

benzodiazepines (alprazolam, diazepam,clonazepam), alcohol, and illicit drugs(marijuana, cocaine). Table 3 below setsforth the respective levels ofcarisoprodol ED visits related to singleuse and as a component of multi-druguse.

TABLE 3ESTIMATED NONMEDICAL USECARISOPRODOL ED VISITS FROM DAWN 2006, AS SOLE DRUG AND INCOMBINATION WITH OTHER DRUGS

All patients Females only Males only

Drug Number Percent Drug Number Percent 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 althoughcarisoprodol is approved for short termuse (3 weeks), SDI Vector One data from20022006 14 show that more than 25percent of patients used the drug forlonger than one month, and 4.3 percentused the drug for more than 360 days.GX 6, at 15. FDA concluded that longer

term use may contribute to increasedrisks of misuse and abuse. Id.

MEDAs Evidence Regarding the DAWNData

Meda offered the testimony ofMr. Nabarun Dasgupta as an expertwitness in epidemiology andpharmacoepidemiology. MX 173; Tr.628. Mr. Dasgupta offered a lengthycritique of the DAWN ED data and

opined that the DAWN ED data aresubject to constraints that limit theirpotential reliability for use in scientificresearch and public health policy.MX 173, at 3.

More specifically, Mr. Dasguptacriticized the sampling methodologyused by DAWN, noting that DAWN usesan oversample of hospitals in selectmetropolitan areas and a sample ofhospitals from the rest of the countryand that [t]he number of hospitalssampled is relatively small compared to

the national estimates that areextrapolated from the sample. Id. Mr.Dasgupta noted that for the year 2007,207 hospitals submitted provided dataon 300,983 drug related ED visits * * *.



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15Mr. Dasgupta also testified that the DAWN datamay be affected by diagnostic suspicion bias in thatDAWN reporters may have become sensitized bynews reports or other information as to the abuseof a particular drug, and therefore, may over-reportsuch cases. MX 173, at 12. However, Mr. Dasguptaproduced no evidence as to the existence of this

Continued

which resulted in a national estimate of3,998,228 drug-related ED visits. Id. at34. Mr. Dasgupta further stated that[t]he location of all hospitalsparticipating * * * is not disclosed dueto privacy reasons, and that thenumber of hospitals can changeposthoc in the published annual reporttables. Id. at 4. As support for the latter

assertion, Mr. Dasgupta cited the 2005and 2006 annual reports; however, onlyone of these (the 2006 report) wassubmitted for the record.

Later in his testimony, Mr. Dasguptaasserted that [o]nce the cases in theparticipating hospitals are counted,DAWN applies statistical methods toextrapolate to a national estimate, and that each case is given a weightfrom 1 to 60 to arrive at the nationalestimates, and that while it is routineto describe how weights are derived,DAWN does not completely describethe process. Id. at 14. Mr. Dasgupta

also explained that while such factors asnon-response, missing data, hospitalsize, physical location, whether it is anacademic training hospital, and otherfactors are accounted for in the weight,* * * the method for doing this is notpublished. Id. Mr. Dasgupta concludedthat the credibility of the nationalDAWN data * * * hinges on thestatistical methods employed to analyzethe sample data, but SAMHSA does notpublicly disclose the current methods.We do not know how the weights of theindividual hospitals are being applied,and we do not know what impact theextrapolations may be having on the

reported national estimates. Id.Mr. Dasgupta thus opined that [t]helack of information provided by DAWNconcerning its statistical extrapolationmethods hinders interpretation andhence limits the weight that can begiven the DAWN national estimates.Id. at 1415.

On examination by the ALJ, Mr.Dasgupta was asked if, within thecommunity of epidemiologists, * * *the DAWN ED national estimation [is]still relied upon? Tr. 652. Mr. Dasguptareplied that [t]he DAWN ED data areimportant to look at, and that others

would agree * * * in that it sets * * *its the data that is used for policymaking. Id. Mr. Dasgupta then assertedthat [f]rom a scientific perspective, itdoesnt carry much weight. Id.However, DAWN ED does not purport to

be anything other than an estimate, andMr. Dasguptas testimony suggests thatepidemiologists still consider theestimates sufficiently reliable to makepolicy decisions.

Moreover, Mr. Dasgupta generally didnot identify what practices (includingwhat level of disclosure) the field of

epidemiologists considers to benecessary to establish the validity of amethodology and the statistical methodsused to extrapolate the data to developa national estimate. While Mr.Dasguptas criticisms of the DAWN EDdata may be based on the generallyaccepted standards of epidemiology, inthe absence of evidence establishing

those standards, there is no basis forconcluding that his criticisms of DAWNED data reflect those of the communityof epidemiologists rather than hispersonal opinion.

Mr. Dasgupta further asserted that thescientific validity of the data isquestionable because it does notconform with the FDAs publishedguidance on Good PharmacovigilancePractices and PharmacoepidemiologicAssessments. MX 173, at 45.According to Mr. Dasgupta, this call[s]into question whether DAWN ED datashould be used by FDA and FDA-

regulated entities for post-marketingsurveillance. Id. However, Mr.Dasgupta did not identify in whatrespect DAWN does not comply withthe FDAs guidance. See id. Nor is itclear why compliance with the FDAsguidance is necessary to establish thatthe DAWN ED data, which is only anestimate, is not sufficiently reliable tosupport a finding that carisoprodol hasa potential for abuse. 21 U.S.C.811(a)(1)(A).

Mr. Dasguptas next criticism was thatthe reporters of DAWN ED data mayidentify an ED visit as a DAWN caseeven if the patient has a valid

prescription for the drug(s) mentionedin the ED chart and is taking the drug(s)for therapeutic purposes. Id. at 5. Mr.Dasgupta noted that [w]hile Reportersare trained on selecting cases, nopublished studies have evaluated theconsistency between Reporters or

between hospitals, or over time. Id. Mr.Dasgupta also noted that this calls intoquestion the reliability of reportingacross sites, given the lack of publishedvalidation of the consistency betweenReporters at different sites. Id.

Mr. Dasgupta further noted that therehas been a concerted effort by SAMHSA

and the contractor to improve [the]selection of cases, [which is] aimed atidentifying more ED visits forinclusion. Id. at 56. Mr. Dasguptastated that because there has been nopublic documentation of this process,it is not clear if the increases in casesover time is due to better case findingor due to increases in the underlyingsociobiologic phenomena that give riseto DAWN cases. Id. at 6. According toMr. Dasgupta, it is impossible toconclusively say what proportion of theincreases in DAWN ED national

estimates is attributable to changes inmethodology versus changes in theactual number of DAWN casesassociated with a particular drug and[t]his hinders any effort to interpret themeaning of time trends. Id.

On examination by the ALJ, Mr.Dasgupta testified that this, i.e., theincrease attributable to enhanced case-

finding versus [that] attributable to theunderlying actual abuse * * * issomething that is routinely looked at inepidemiologic studies. Tr. 657. He alsosuggested that in such circumstances, avalidation study would be done todetermine how well those persons whoreview the case files were doing. Id. at658. However, even acknowledging thevalidity of this criticism, the FDAsrecommendation stated that the increasein the estimates of carisoprodol-relatedED visits between 2004 and 2007 wasnot statistically significant.

Mr. Dasgupta also observed that

DAWN has acknowledged thedifficulty in identifying cases of abusebecause of the limitation of medicalrecord documentation. Id. at 7. As Mr.Dasgupta observed, because DAWNdefines nonmedical use to include avariety of scenarios beyond misuse/abuse, ED visits counted asnonmedical use by DAWN do notnecessarily represent cases of abuse asthat term is commonly understood,and as used for purposes ofscheduling. Id. at 910.

Mr. Dasgupta also noted that[a]lthough current medicationsunrelated to the visit are not supposedto be recorded, distinguishingmedications that pertain to the ED visitfrom those that do not requires acomplex toxicological determination,which hospitals may not conduct inthe interest of providing expedientmedical care. Id. at 10. Mr. Dasguptastated that differences in how toxicologytesting is conducted at differenthospitals may influence whether adrug is detected, and that the simplepresence of a drug in toxicology resultsis not sufficient to implicate itsinvolvement in an ED visit. Id. at 12.He further noted that it is highly

probable that to some extent thedetermination of the involvement ofunrelated medications may beinherently subjective, [and may] vary

between Reporters, who have differenttraining and experience.15 Id. at 10.



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phenomenon among DAWN reporters eithergenerally or with respect to carisoprodol.

16Mr. Dasgupta further noted that DAWN may attimes impute data when data is missing fromcertain hospitals. MX 173, at 1819. While Mr.Dasgupta suggested that this practice is ofquestionable validity, id., this is not the same assaying that this practice is not generally acceptedby experts in the field. Indeed, on examination bythe ALJ, Mr. Dasgupta testified that it is valid touse imputation methods to fill in missing data, butits a very, very sensitive issue that needs to be donecarefully. Tr. 669. Mr. Dasgupta then stated that[t]here are three, four, maybe five major ways inwhich imputation is done in epidemiology to fill in

missing data like these, and the choice of which ofthose imputation methods * * * can very stronglyinfluence your results, that the onus is on theresearcher to show that those assumptions havebeen met and that the method selected is theappropriate one, and that if there is kind of [a]referenced imputation[,] its odd to not see thosekinds of descriptions on which statisticalimputation method is used. Id. at 66970.However, Respondent produced no evidence thatthe use of imputed data has affected the DAWNdata for carisoprodol.

17The Adverse Event Reporting System (AERS) isa computerized database designed to support theFDAs postmarketing safety surveillance program

for all approved drug and therapeutic biologicproducts. GX 6, at 15. The FDA receives adversedrug reaction reports from manufacturers asrequired by regulation. Id. Health care professionalsand consumers send reports voluntarily through theMedWatch program, which become part of adatabase; the database complies with theinternational safety reporting guidance (ICH E2B)issued by the International Conference onHarmonization. Id.

18Carisoprodol was scheduled as CIV in Floridain July 2002, but was not tracked until 2003. GX6, at 18.

However, Mr. Dasgupta then opined thatdrugs are most often identified bypatient self-reporting, that [o]nly asmall percentage is confirmed bytoxicology tests, and that therefore,DAWN data are subject to all of theuncertainties and potentialmisidentifications associated with self-reporting.16 Id. at 13.

As explained above, DAWN explicitlyrecognizes the limitations inherent inmedical record documentation.Moreover, even crediting Mr. Dasguptascriticisms, as even he recognized, [t]heDAWN ED data are important to lookat and its the data that is used forpolicymaking. Tr. 652. The DAWN EDdata provide only an estimate; the dataconstitute just one of many pieces ofevidence which support the conclusionthat persons are taking carisoprodol inamounts sufficient to create a hazard totheir health.

FDA Adverse Event Reporting System(AERS) Data 17

As noted above, FDA also reviewedthe AERS data and found that through

June 2007, there were a total of 472reports related to potential carisoprodolabuse, including 48 reports identifyingdependence and 19 identifying

withdrawal syndrome. GX 6, at 15. Inthe majority of cases, multiple drugswere used, but there are 61 uniquereports where carisoprodol was the onlysuspect drug. Id.

Medas Chief Medical Officer (CMO)provided more up-to-date data. In hiswritten direct testimony, MEDAs CMOstated that MEDAs database contains a

total of 731 spontaneous adverse eventsfor carisoprodol from January 1979through May 1, 2010, of which only83 reports included the terms abuse,dependency, or withdrawal. MX 171,at 10. MEDAs CMO further noted thatin the five-year period of 20052009,more than 54 million prescriptions,totaling nearly four billion tablets ofcarisoprodol, were dispensed. Id. at 11.

While the AERS data appearsrelatively small when compared withthe total number of prescriptions, asexplained in footnote fifteen, this data isobtained from health care professionals

and consumers, both of whomvoluntarily submit the reports. As FDAnotes, it does not receive all adverseevent reports that occur with a productas [m]any factors can influencewhether or not an event will bereported. FDA, Adverse EventsReporting System, available at http://

www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm. Accordingly, AERScannot be used to calculate theincidence of an adverse event in theU.S. population. Id. Indeed, thevoluntary nature of the reports suggeststhat they are likely to under-represent

the actual number of adverse events.

Florida Medical Examiners CommissionData

In 2008, Floridas medical examinersreported 8,556 drug-related deaths(whether the drug was the cause ofdeath or merely present) throughtoxicology reports submitted to theMedical Examiners Commission. GX 7,at 11. The presence of carisoprodol and/or its metabolite, meprobamate, wasfound in 415 deaths (5 percent of thedrug related deaths). Id. In 84 of thesedeaths (20%), carisoprodol was

determined to be the cause of death. Id.The following table lists, for the years2003 through 2008, the number ofdeaths in which carisoprodol andmeprobamate were found in toxicologytesting and the number of deaths inwhich carisoprodol and meprobamatewere found to be a cause of death.

TABLE 4FLORIDA MEDICAL EXAMINERS DATA 20032008

Year Drugs found in bodyTotal

occurrencesCause

(% total)Present

% Changefrom prior year

2003 18 .......... Carisoprodol/Meprobamate ................................................... 208 45 (22) 163 ND2004 ............. Carisoprodol/Meprobamate ................................................... 289 81 (28) 208 39

2005 ............. Carisoprodol/Meprobamate ................................................... 314 96 (31) 218 92006 ............. Carisoprodol/Meprobamate ................................................... 313 74 (24) 239 0.32007 ............. Carisoprodol/Meprobamate ................................................... 337 88 (26) 249 82008 ............. Carisoprodol/Meprobamate ................................................... 415 84 (20) 331 23

Id.; see also GX 7, at 11.

With respect to this data, Mr.Dasgupta stated that [t]he presence ofa drug in the body does not establish itas a cause of death or necessarilyindicate drug abuse. MX 173, at 23.As for the first contention, the datarecognizes as much as it differentiates

between those instances in which

toxicology testing established that

carisoprodol/meprobamate was presentin a body and those in which a medicalexaminer concludedthat the ingestionof carisoprodol or meprobamate was acause of death. Likewise, while a drugspresence in the body does notnecessarily establish that the person wasengaged in drug abuse, it nonethelessis an indicator of drug abuse, especially

where the deaths were found to becaused by an overdose.

Mr. Dasgupta further concluded thatbecause the data combines carisoprodoland meprobamate, it is not possible todetermine * * * which drug * * * wasa cause of death. Id. at 23. However,carisoprodol metabolizes intomeprobamate, and other data in the

record (more specifically, the NSDUH



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19Mr. Dasgupta also raised the possibility that theFlorida Medical Examiner data is subject to

diagnostic suspicion bias. MX17, at 23. Again, thisis simply speculation.

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

data, see Table 7) indicates that morethan eleven times as many persons haveengaged in the nonmedical use ofcarisoprodol than have engaged in thenonmedical use of meprobamate. Thissupports the conclusion that the greatmajority of the Florida MedicalExaminer cases in which carisoprodol/meprobamate was determined to be a

cause of death are attributable tocarisoprodol.19

Finally, Mr. Dasgupta asserted thatthe Florida data shows that theproportion of total fatal overdose

occurrences * * * has generally beendecreasing annually since 2005. Id. at24. However, it is doubtful that thischange is statistically significant, andeven if it is, the data still show that asignificant and disturbing number ofpersons have died from carisoprodoloverdoses and are dying each year inthis State alone.

National Poison Data System

Data from the National Poison DataSystems (NPDS), formerly known as theToxic Exposure Surveillance System of

the American Association of PoisonControl Centers (AAPCC), show thatcarisoprodol products are involved in anumber of toxic exposures (Table 5).Some of these carisoprodol exposuresled to major adverse health outcomes(Table 6). For example, in 2007,carisoprodol was associated with 8,821toxic exposure cases, including 3,605

cases in which it was the sole drugmentioned. A total of 122 of the 2,821single exposure cases, which weretreated in a health-care facility, had amajor adverse health outcome.

TABLE 5CARISOPRODOL EXPOSURES DATA FROM NATIONAL POISON DATA SYSTEM (NPDS)

2003 2004 2005 2006 2007

Case Mentions ......................................................................................... 8,248 8,765 8,613 8,187 8,821Single Exposures ..................................................................................... .................... .................... .................... 3,515 3,605

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

TABLE 6SERIOUS ADVERSE HEALTH OUTCOMES IN CARISOPRODOL EXPOSURES CASES WHO WERE TREATED IN

HEALTH CARE FACILITIES2003 2004 2005 2006 2007

Treated in Health Care Facility * .............................................................. 6,617 7,032 7,501 2,687 2,821Deaths ...................................................................................................... 28 30 18 1 1Major Effect** .......................................................................................... 406 468 525 105 122Moderate 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 thepersons who answer the calls to theregional poison centers are nurses,pharmacists, and physicians who have

been trained in medical toxicology andare instructed on the proper ways ofcompleting case report forms in asystematic manner and that the datacollection software has [a]n extensivedata quality assurance process. MX173, at 2930. Mr. Dasgupta then statedthat there is the potentialmisidentification of the substanceduring the initial call to the poison

center and that researchers havedetermined that, for some drugs, 2530% are misclassified during the firstcall. Id. at 30. However, Meda did notprovide this research and Mr. Dasguptadid not provide evidence as to what therate of misclassification is forcarisoprodol. He then opined that theself-reporting and (apparently the lackof toxicology test results) showing the

presence and levels of drug * * *make it impossible to conclude that amentioned drug was causally implicatedin the exposure. Id.

Mr. Dasgupta also maintained thatthe single exposure data presented byDEA combines single-entitycarisoprodol and carisoprodol/aspirincombination products. Id. at 31 (citingMeda Ex. 63).20 However, as the data for2007 show, even if single entity andcombination products should not beco

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