Appendix — Carter-Wallace, Inc. v. Finch

APPENDIX A

Opinion of the United States Court of Appeals,

For the Fourth Circuit

No. 12,200

Carter-Watiace, Inc.,

Petitioner,

—versus—

Joun W. Garpner, Secretary of Health, Education, and

Welfare, and James L. Gopparp, Commissioner of Food

and Drugs,

Respondents.

ON PETITION TO REVIEW AND SET ASIDE ORDER OF

THE COMMISSIONER OF FOOD AND DRUGS.

(Argued October 31, 1968. Decided November 4, 1969)

Before Haynswortu, Chief Judge, Burzner, Circuit Judge,

and Hurcueson, Senior District Judge.*

Stephen R. Lang (William L. Hanaway; Breed, Abbott

& Morgan; Ralph H. Ferrell, Jr., and Hunton, Williams,

Gay, Powell & Gibson on brief) for petitioner; and William

W. Goodrich, Assistant General Counsel, Department of

Health, Education, and Welfare (Joanne S. Sisk and

Eugene M. Pfeifer, Attorneys, Department of Health, Ed-

ucation, and Welfare; and Fred M. Vinson, Jr., Assistant

Attorney General, and William E. Ryan, Attorney, De-

partment of Justice, on brief) for respondents.

* Judge Hutcheson participated in the hearing and the decision

of this ease, but he died before the opinion was completed.

la

;

ar TOP LORRI LORS ss A eS

emg

2a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

Burzner, Circuit Judge:

The Commissioner of Food and Drugs subjected mepro.

bamate and compounds containing meprobamate in com.

bination with other drugs to special controls under the

Federal Food, Drug & Cosmetic Act.’ Carter-Wallace, Inc,

a manufacturer and distributor of the drug, petitioned for

review under the statutory proceedings authorized by the

Act and the general provisions of the Administrative Pro.

cedure Act.? We affirm the Commissioner’s order because

we believe that his decision is supported by substantia]

evidence and that it is warranted by law.

I.

In 1965, Congress amended the Federal Food, Drug &

Cosmetic Act to provide control over barbiturates, am-

phetamines, and other drugs having a similar effect on

the central nervous system.’ These drugs were classified as

“depressant or stimulant drugs.” Control over them is

accomplished through increased record keeping and inspec-

tion requirements, regulation of intrastate traffic, and by

making possession of the drugs, other than by the user,

illegal outside of the legitimate channels of commerce. A

prescription for a depressant or stimulant drug may not

be filled more than six months after the date on which it

was issued and it may not be refilled more than five times

unless renewed by the prescribing physician.‘

121 U.S.C. §§ 301 et seq.

221 U.S.C. §§ 321(v), 371(f), and 5 U.S.C. §§ 702, 704, and 706.

*H. R. Rep. No. 130, 89th Cong., Ist Sess. 1 (1965).

21 U.S.C. §360a; H. R. Rep. No. 130, 89th Cong., Ist Sess.

1, 3 (1965).

3a ¢

Opinion of the United States Court of Appeals, E

For the Fourth Circuit

The genesis of these proceedings is ¢ 201(v) of the amend-

ments [21 U.S.C. § 321(v)], which provides in part:

“The term ‘depressant or stimulant drug’ means—

“(1) any drug which contains any quantity of (A)

barbituric acid...

“(2) any drug which contains any quantity of (A)

amphetamine...

“(3) any drug which contains any quantity of a

substance which the Secretary, after investigation,

has found to have, and by regulation designates as

having, a potential for abuse because of its depressant

or stimulant effect on the central nervous system... .”

The legislative history of this section clearly reflects the

concern with which Congress viewed meprobamate. The

House Committee Report states :°

“The committee considered the advisability of spe-

cifically designating meprobamate [and five other

drugs] as ‘depressant or stimulant drugs.’ It was de-

cided that this should not be done because the Secre-

tary of Health, Education, and Welfare will, under

the provisions of proposed section 201(v)(3) of the

Federal Food, Drug, and Cosmetic Act, consider des-

ignating these drugs as ‘depressant or stimulant drugs’

and that it would be inadvisable to single out these

drugs while leaving out others having substantially

similar abuse potentials. The committee expects the

Secretary to take early action with respect to the con-

sideration of the listing of these six drugs.”

°H. R. Rep. No. 130, 89th Cong., 1st Sess. 13 (1965).

—

4a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

Against this background, the Food and Drug Adminis.

tration conducted extensive hearings that culminated jpn

subjecting meprobamate to control as a depressant drug.

In canvassing the record upon review. we are required to

give conclusive effect to the Commissioner’s findings of

fact that are supported by substantial evidence. 21 U.S.C.

§ 371(f).®

Meprobamate is one of a group of drugs known as minor

tranquilizers which are used for the symptomatic relief

of anxiety and tension associated with psychoneurotic dis.

orders. It was first used in clinical trials in 1952, and it

has been widely distributed commercially since 1955 in

tablets or capsules of 200 and 400 milligram doses. Carter-

Wallace has produced enough of the drug to make ap.

proximately 14 billion tablets. It may be dispensed only

by prescription, and an estimated 500 million prescriptions

have been written. The maximum recommended adult dos.

age is 2,400 milligrams daily. Meprobamate is a safe,

effective drug when it is taken in accordance with the

manufacturer’s recommendation under a physician’s di-

rection.

In order to subject meprobamate to the Act’s special

controls the Commissioner must find, first, that it has a

depressant effect on the central nervous system; second,

that it has a potential for abuse; and, third, that this po-

tential results from its depressant effect on the central

nervous system.

There can be no doubt about the sufficiency of the proof

of the first element. The regulations [21 C.F.R. § 166.2]

6 “Substantial evidence is more than a mere scintilla. It means

such relevant evidence as a reasonable mind might accept as ade-

quate to support a conclusion.” Consolidated Edison Co. v. NLRB,

305 U.S. 197, 229 (1938).

pre cen THD HIiinn PCHOOR COPY

NMEA BACON TEED Ro Fe COLE EN ARM ee |

Lael PEAT WR eeag

5a a

‘

Opinion of the Umited States Court of Appeals,

For the Fourth Circuit

provide that a drug has a depressant effect on the central

nervous system if there is substantial evidence that the

drug may produce (a) a calming effect or relief of emo-

tional tension or anxiety; or (b) drowsiness, sedation,

sleep, stupor, coma, or general anesthesia; or (¢) mood

depression or apathy. Nearly all of the medical witnesses

testified that the major therapeutic effects of meprobamate

are to calm the patient and to give relief from emotional

tension or anxiety. A number of witnesses established that

large dosages of meprobamate cause stupor and induce

apathy. The precise way in which meprobamate achieves

these effects is not known with certainty, but the undis-

puted evidence establishes that it acts upon the central

nervous system.

In selecting “potential for abuse” as one of the criteria

for subjecting a drug to special control, the House Com-

mittee did not intend this 1o be determined on the basis

of the drug’s having only a potential for isolated or occa-

sional nontherapeutic purposes. Instead, the committee

recommended that a drug’s potential for abuse should be

determined “on the basis of its having been demonstrated

to have such depressant or stimulant effect on the central

nervous system as to make it reasonable to assume that

there is a substantial potential for the occurrence of sig-

nificant diversions from legitimate drug channels, sig-

nificant 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.””’

7H. R. Rep. No. 130, 89th Cong., Ist Sess. 7 (1965). The source

of the committee’s definition is The President’s Advisory Commis-

sion on Nareotic and Drug Abuse, Final Report, p. 2 (1963), which

states :

“When this report speaks of ‘drug addiction’ it is using the

term in its full technical sense to include both the psycho-

6a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

The evidence on this issue is in sharp conflict. It ranges

from testimony of Carter-Wallace’s experts that the poten.

tial for abuse of candy or aspirin is greater than for

meprobamate to testimony from a government witness

that he became so uneasy about alcoholics’ affinity for the

drug he stopped prescribing it for them. A number of well.

qualified medical witnesses called by Carter-Wallace tes.

tified that while treating patients with meprobamate over

a period of years they had observed no evidence of the

drug’s abuse, or at the most they had seen only isolated

or occasional cases.

Doctors testifying for the government presented a dif.

ferent picture. They told of patients who used mepro-

bamate to the extent that they became intoxicated—with

staggering gait, slurred speech, and impaired coordina-

tion. Testimony also disclosed that some persons who

took excessive doses of meprobamate felt “high” or ex-

perienced euphoria. Credible evidence established that

continuous use of the drug produces tolerance to its effects,

logical and the physical dependence. When it speaks of ‘drug

abuse’ it is referring to the broader problem which includes

also those drugs which create only psychological dependency.

We will use the term ‘drug abuse’ in this report as existing

when an individual takes psychotoxic drugs under any of the

following circumstances :

“(a) in amounts sufficient to create a hazard to his own health

or to the safety of the community; or

“(b) when he obtains drugs through illicit channels; or

“(c¢) when he takes drugs on his own initiative rather than

on the basis of professional advice.

“Drug abuse today involves not only the narcotic drugs

and marihuana, but to an increasingly alarming extent other

drugs such as the barbiturates, the amphetamines and even

certain of the ‘tranquilizers’. This latter group will be re-

ferred to in this report as the ‘dangerous drugs’.”

mreerenmn TLIO HRIICh DHOOR CORY

7a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

This, in turn, requires more of the drug to achieve the

original effect. Kxcessive use of meprobamate creates

physical dependence upon the drug. Its withdrawal from

persons who use it to excess may be followed by nausea,

insomnia, muscle tremors, and anxiety.

Although complete statistics on the type of drugs used

for suicide and attempted suicide by poison are not avail- &

able, the evidence indicated that meprobamate had been

used alone or in conjunction with other drugs in a number

of cases. Several drugs are used more frequently than

meprobamate for successful suicides. But one qualified

researcher observed that meprobamate’s use in attempted

suicides was surpassed only by barbiturates.

The hearings disclosed significant diversion of mepro-

bamate from legitimate trade. During the 1956-1966 dec-

ade, the Food and Drug Administration recorded 1,515

convictions for illegal sales of prescription drugs. Of

these, 173 or approximately 11% involved meprobamate.

Evidence also exposed how easily the drug can be illegally

purchased.

The legislative history reveals that when the phrase

“potential for abuse” was adopted, the House Committee

rejected the suggestion that special controls should be

limited “to those drugs as to which substantial abuse had

been shown.” The Committee Report emphasizes that the

Commissioner should not be required to wait “until a num-

ber of lives have been destroyed or substantial problems

have already arisen before designating a drug as subject

to controls, .. .”® Thus, the existence of abuse is relevant

to forecast future abuse, but the incidence of present

abuse is not the test which the Commissioner must apply.

Instead, he has been charged with the responsibility of

Puente SEPSIS CCR ee emen a

*H. R. Rep. No. 130, 89th Cong., 1st Sess. 7 (1965).

2

paps: Bee eee scree |

irene PA ae AAR IY Ib CANO AE ET GPE TAR ENE AD pO SOOT

8a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

assaying future or potential abuse. As might be expected,

witnesses differed as much in their opinions about the

future as they had concerning their observations of the

present. However, a number of qualified experts expressed

the view that as access to barbiturates was limited by

controls, the abuse of meprobamate would increase unless

it also was controlled. Barbiturates and meprobamate can

suppress or relieve the withdrawal reaction that an exces.

sive user of alcohol suffers when he is abruptly deprived

of his intoxicant. Although most drug-prone alcoholics

seek barbiturates, a significant number take meprobamate,

The magnitude of the problem was illustrated by the tes.

timony of a knowledgeable witness who expressed the

opinion that of the six million alcoholics in the country,

approximately four per cent (240,000) would abuse mepro-

bamate if they had free access to it. As an additional

indicia of potential abuse, a well-informed student of sui-

cides made “a sophisticated guess” that use of meproba-

mate as a suicidal agent will increase.

Our examination of the record as a whole leads us to

conclude that meprobamate does have a potential for abuse

within the meaning of the drug abuse control amendments

to the Act.

The third element for subjecting meprobamate to spe-

cial control is proof that its potential for abuse results

from its depressant effect on the central nervous system.

Carter-Wallace complains that the government improperly

relied upon a presumption created by regulation to prove

this point.’ In its brief the government disclaims any

®The regulation follows the President’s Advisory Commission

on Narcotics and Drug Abuse, Final Report, p. 2 (1963), n. 7

supra. The regulation [21 C.F.R. § 166.2(e)] states in part:

“(e) The Commissioner may determine that a substance has

a potential for abuse because of its depressant or stimulant

mm: ۤ FER SFELIMAIICLI DAMHD CORY

9a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

reliance on the regulation to prove a causal relationship.

It contends that the regulation was intended, and used, to

list the criteria for establishing a drug’s potential for

abuse. The regulation is not a model of clarity, and we

agree with Carter-Wallace that it cannot be used to dis-

pense with proof of the causal relationship required by

the statute. Miller v. United States, 294 U.S. 4385, 440

(1935). However, our review of the record satisfies us

that the government’s case does not rest on a presumption.

In the initial stages of the proceedings neither party placed

great emphasis on this requirement of the statute, and the

hearing examiner’s proposed findings do not refer to it.

However, the Commissioner, after hearing oral argument,

remedied the hearing examiner’s omission by including a

new finding on this issue which states:

“The substantial evidence of record establishes that

meprobamate has a potential for abuse, as manifested

in the ways set forth in findings 8 through 27 above,

because of its depressant effect on the central nervous

system. Many of these abuses of meprobamate result

from the phenomenon of tolerance to the drug and

effect on the central nervous system or its hallucinogenic effect

if:

“(1) There is evidence that individuals are taking the

drug or drugs containing such a substance in amounts suffi-

cient to create a hazard to their health or to the safety of

other individuals or of the community; or

“(2) There is significant diversion of the drug or drugs

containing such a substance from legitimate drug channels;

or

“(3) Individuals are taking the drug or drugs containing

such a substance on their own initiative rather than on the

basis of medical advice from a practitioner licensed by law

to administer such drugs in the course of his professional

practice... .”

10a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

the phenomenon of withdrawal reactions upon discon.

tinuance after long-continued or excess use. These

phenomena of tolerance and withdrawal reactions are

a result of meprobamate’s central nervous system de-

pressant effect. Other abuses of meprobamate stem

from its euphoric effect which is a function of mepro-

bamate’s central nervous system depressant effect. In

short, meprobamate’s potential for abuse results from

its effect of depression on the central nervous system.”

Carter-Wallace, asserting this finding is not supported

by substantial evidence, takes the position that there is no

connection between the depressant effect of any drug and

its potential to affect the health of an individual or the

safety of the community.”

It is true that the finding is not supported by direct

evidence. The present state of medical knowledge does

not enable anyone to describe with certainty the means by

which depressant drugs produce their effects.

10 Dr. Frank M. Berger, who is president of Wallace Laboratories,

a wholly-owned subsidiary of Carter-Wallace, Inc., testified:

Q. “Dr. Berger, in your opinion does Meprobamate when

taken at recommended doses have such a depressant effect

on the central nervous system as to make it reasonable to

assume the drug has substantial capability of creating hazards

to the health of the user or the safety of the community?”

A. “I do not think that there is any connection between the

depressant effect of Meprobamate or for that matter any other

drug and its potential or capability to affect the health of an

individual or of the community.

“This is a very broad statement, a very broad question.

“Health of an individual is affected if a drug is abused,

if it is taken to excess. I have previously mentioned it is

exceedingly rare to abuse Meprobamate. The number of in-

dividuals who have abused it is very small. As I previously

mentioned, the only type of person who will abuse it is a

psychopathic individual.”

lla

Opinion of the Umited States Court of Appeals,

For the Fourth Circuit

Moreover, eminent scientists espouse different theories

to explain effects of central nervous system depressants.

Carter-W allace’s witnesses advanced the theory that thera-

peutic doses of meprobamate act as a depressant on the

sub-cortical region of the central nervous system, spe-

cifically the interneurons. In this manner it selectively

blocks or interrupts circulation of anxiety producing stim-

uli without affecting the cortical region of the brain. Lack

of effect on the cortex precludes the feeling of well-being

or euphoria that in other drugs leads to addiction. Ex-

cessive doses of meprobamate may affect the cortex, but

the theory postulates that by the time the cortex becomes

involved, the effect upon the subcortical regions produces

stupor and thus precludes a feeling of well-being. In con-

trast, the theory continues, barbiturates and alcohol have

a disinhibiting effect on the cortex, which is the seat of

reason. Disinhibition produces a sense of well-being, the

kind of kick that calls for repetition and abuse.

Proponents of this theory assert that meprobamate’s

suppression of withdrawal symptoms from barbiturates

and alcohol is irrelevant to the case. They believe physical

dependence on a drug, and its consequent withdrawal symp-

toms, result from the drug’s incorporation into and sub-

sequent withdrawal from a cell. Under this theory, physical

dependence and withdrawal symptoms have nothing to do

with central nervous system depression.

Carter-Wallace’s witnesses generally expressed opin-

ions approving of this theory. Without exception, they

saw no relation between meprobamate’s potential for abuse

and its depressant effect on the central nervous system.

They explained meprobamate abuse by attributing it to

people, not the drug. Only persons who are prone to be

12a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

dependent on drugs, not normal persons, will abuse it, their

argument runs. The difficulty with this thesis is that

while it defines the problem, it does not provide an answer,

The record describes many types of people who may be.

come dependent on drugs—including alcoholics, they are

legion. But the record does not explain the basic psycho.

logical and physiological reasons that cause a person to

abuse drugs. This is not unexpected, because present medi-

cal knowledge has no definitive explanation. We cannot,

however, attribute ignorance of this situation to Congress,

It knew that “[w]e lack considerable knowledge of drug

abuse and how to treat it.”"* But nothing in the legislative

history suggests that a drug is to escape coverage because

it attracts only drug-prone people. The Commissioner's

refusal to accept Carter-Wallace’s thesis was not arbitrary

or capricious, although the sincerity of its advocates is

unquestioned.

Though the record contains no direct evidence or veri-

fied theories to explain meprobamate’s effect, the Commis-

sioner’s order does not lack evidentiary support. Circum-

stantial evidence, or indirect proof, can satisfy the require-

ment that an administrative order be undergirded by sub-

stantial evidence. Dubin-Haskell Lining Corp. v. NLRB,

375 F.2d 568, 573 (4th Cir. 1967), cert. denied, 393 US.

824 (1968).

It is undisputed that the body’s tolerance to alcoho! and

barbiturates can lead to excessive use of these drugs,

which in turn can cause physical dependence on them.

Physical dependence may become so great that abrupt

deprivation of either barbiturates or alcohol will cause

™! The President’s Advisory Commission on Narcotic and Drug

Abuse, Final Report, p. 75 (1963).

BLEED THROUGH POOR COPY

13a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

withdrawal symptoms. These symtoms can be suppressed

or alleviated by readministering the drug. Moreover, phys-

jeal dependence and withdrawal symptoms of barbiturates

and alcohol are so similar that the withdrawal symptoms

of alcohol may be suppressed by administering barbitu-

rates.

Excessive use of meprobamate can cause physical de-

pendence and withdrawal symptoms similar to those caused

by barbiturates and alcohol. More significant than mere

similarity, however, is the fact that meprobamate can sup-

press withdrawal symptoms of both alcohol and barbitu-

rates.

A well-qualified witness testifying for the government

advanced a theory to explain physical dependence on bar-

biturates that differed considerably from the cellular in-

corporation theory urged by Carter-Wallace. The govern-

ment’s witness testified that his research led him to believe

that barbiturates have their primary site of action in the

sub-cortical region, and from his studies he drew the

inference that physical dependence on barbiturates seems

to be primarily the result of adapted changes in the sub-

cortical region alone. Other evidence tended to corroborate

this theory. The witness accepted the findings that the

primary site of action of meprobamate was in the sub-

cortical region of the central nervous system. Emphasiz-

ing that his theory of barbiturate dependence had not yet

been verified, he suggested that if it is valid for barbitu-

rates, it may be equally valid for meprobamate.

Another comparison of meprobamate, barbiturates, and

alcohol supports the Commissioner. The precise reason

why some drugs cause euphoria is unknown." However,

Euphoria is defined as “a feeling of well-being or elation,

especially one that is groundless, disproportionate to its cause, or

-

rer wy

SRC ee ae tf

Je oe “Oper

l4a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

credible evidence indicates that excessive use of barbity.

rates or alcohol can cause euphoria by depressing the

central nervous system. Whether the primary site of their

action is the cortex or sub-cortex is a matter of dispute,

but for the purposes of this comparison the exact site js

not decisive since both the cortical and sub-cortical regions

are parts of the central nervous system. Substantial evi.

dence also established that excessive use of meprobamate

can cause euphoria. Euphoria can also be caused by stimn.

lant drugs such as amphetamines. However, no evidence

was introduced that euphoria results from any effect other

than the action of depressant or stimulant drugs on the

central nervous system.

We conclude that although the evidence is largely cir.

cumstantial, it substantially supports the Commissioner's

findings that tolerance, withdrawal reactions, and euphoria

are a result of meprobamate’s central nervous system de.

pressant effects. Physical dependence (as manifested by

withdrawal symptoms and tolerance) and euphoria are

among the characteristics of a drug that lead to its abuse.

Therefore, taking into account our imperfect knowledge

of how drugs injure people, we hold that substantial evi-

dence supports the Commissioner’s finding of a causal re-

lation between meprobamate’s depressent effect upon the

central nervous system and its potential for abuse.

inappropriate to one’s life situation.” Webster's Third New In-

ternational Dictionary (unabridged 1964). Witnesses described

euphoria as a state of artificial happiness or elation of mood; or,

an abnormal state of well-being, quite different in quality and

intensity from a healthy state of well-being.

BLEED THROUGH POOR COPY

Opinion of the United States Court of Appeals,

For the Fourth Circuit

I.

Carter-Wallace manufactures five drugs containing mep-

robamate combined with other substances. It asserts that

the combination drugs should not have been included in

the Commissioner’s order because the examiner reported

there was a lack of substantial evidence that they have a

substantial potential for significant abuse. Carter-Wal-

lace’s position, however, is not supported by the Act. Title

21 U.S.C. § 321(v)(3) provides that the term depressant

drug means a drug which contains any quantity of a sub-

stance that has a potential for abuse because of its de-

pressant effect on the central nervous system. Since the

combination drugs contain meprobamate, a substance sat-

isfying the definition of a depressant drug, they are cov-

ered by the plain language of the Act. The Court empha-

sized in United States v. Dotterweich, 320 U.S. 277, 280

(1943), that the Act touches the lives and health of people,

and it should not be narrowly construed. Certainly we

see no reason for excluding drugs that are literally en-

compassed by its terms.

An exemption from coverage of combination drugs is

provided by 21 U.S.C. § 360a(f)(2), which states in part:

“(2) The Secretary shall by regulation exempt any

depressant or stimulant drug from the application of

this section, if—

“(B) he finds that such drug includes one or more

substances not having a depressant or stimulant effect

on the central nervous system ... and such substance

or substances are present therein in such combination,

quantity, proportion, or concentration as to prevent

léa

Opinion of the United States Court of Appeals,

For the Fourth Circuit

the substance or substances therein which do have such

an effect from being ingested or absorbed in sufficient

amounts or concentrations as, within the meaning of

section 321(v) of this title, to—

“(ii) have a potential for abuse because of their

depressant or stimulant effect on the central nervous

system... .”

In this hearing the government was required to show only

that meprobamate satisfied the Act’s definition of a depres.

sant drug and that the combination drugs contained mepro-

bamate. Lack of evidence concerning the effect of the

combination drugs cannot be substituted for the affirmative

findings required for exemption. Proceedings for exemp.

tion may be initiated by the Commissioner or by Carter.

Wallace. 21 C.F.R. § 166.7 (1968). Neither the Commis.

sioner’s order nor our affirmance precludes prompt action

to determine whether the combination drugs should be ex-

empted.

Il.

Carter-Wallace alleges that a number of the trial ex-

aminer’s rulings deprived it of a fair hearing. At a pre-

trial conference a week before the hearing, the government

indicated that it would use documents aggregating 2,550

pages. Carter-Wallace complains that the hearing exam-

iner denied its motion for a continuance of an additional

week to allow time for examination of the government's

documents. The grant or denial of continuances lies within

the sound discretion of a hearing examiner, NLRB vy. Siris

Products Corp., 186 F.2d 503 (4th Cir. 1951), and we find

BLEED THROUGH POOR COPY

S Pips “ lalate ati eet bien sh ae ae a ott Eee eee Lav ee

17a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

no abuse of discretion here. Carter-Wallace had six months

to prepare its case, and many of the documents proffered

by the government came from Carter-Wallace’s own files.

The hearings lasted for nearly three months, and during

that time Carter-Wallace had ample opportunity to ex-

amine the documents. Moreover, it has shown no specific

instances of how its lack of opportunity to study the docu-

ments for an additional week before the hearing prejudiced

its case.

Carter-Wallace objected to government exhibit 202, which

is a summary purporting to show, among other things,

that an audit of 99 pharmacies disclosed a shortage of

796,000 tablets of meprobamate. The shortage represented

77% of the total amount of the drug received by the phar-

macies in a one-year period. The witness through whom

the summary was introduced was not familiar with all

of the underlying data, and some of the underlying docu-

ments were not available for use in cross-examination.

While hearsay evidence is generally admissible in an ad-

ministrative hearing, we think the deficiencies concerning

the underlying data made it difficult for the government to

establish the reliability of its audit and precluded mean-

ingful cross-examination by Carter-Wallace. See McDaniel

v. United States, 343 F.2d 785, 789 (5th Cir.), cert. denied,

382 U.S. 826 (1965). In Re Shelley Furniture, 283 F.2d

540, 543 (7th Cir. 1960).

However, other evidence supports the finding that there

has been a significant diversion of meprobamate from le-

gitimate channels. Furthermore, proof of the drug’s po-

tential for abuse does not rest solely upon showing its

diversion. Other findings, amply supported, suffice to es-

tablish that meprobamate has a potential for abuse. Intro-

ten, b me

4 a eS ee pad rh .

} ec PLT | Sart -

poe bie oS neat ne ER Phy

LMT te

Mk NE TE te

18a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

duction of exhibit 202, therefore, is not cause for setting

aside the Commissioner’s order. Willapoint Oysters, Ing,

v. Ewing, 174 F.2d 676, 690 (9th Cir.), cert. denied, 338

U.S. 860 (1949).

Carter-Wallace’s complaint about the introduction of

other hearsay on the ground that it was denied its right of

cross-examination is without merit. Over Carter-Wallace’s

objection, the examiner permitted a physician employed by

the Food and Drug Administration to introduce records

showing adverse effects of meprobamate. Carter-Wallace

complained that the doctors and hospital officials who re.

ported the cases were not available for cross-examination

and that the witness could not attest to the accuracy of

the records by her own personal knowledge. The records,

however, had been furnished the Food and Drug Adminis.

tration by Carter-Wallace in accordance with a manufac-

turer’s duty to report adverse reaction in connection with

new drug applications. Thus Carter-Wallace had ample

opportunity to investigate the accuracy of the reports.

Indeed, considering the nature of the reports, it is unlikely

that it did not do so. Other documents admitted over

Carter-Wallace’s objection were articles concerning mepro-

bamate published in recognized scientific journals. Carter-

Wallace, of course, had full opportunity to examine the

government’s expert witness on her opinion of the validity

of the scientific opinions that were expressed. We find no

abuse of the examiner’s discretion in the admission of these

exhibits. Rocker v. Celebrezze, 358 F.2d 119, 122 (2d Cir.

1966); Montana Power Co. v. Federal Power Comm., 185

F.2d 491, 498 (D.C. Cir. 1950), cert. denied, 340 U.S. 947

(1951).

Carter-Wallace complains that in contrast to the exam-

iner’s admission of scientific papers offered by the govern-

BLEED THROUGH POOR COPY

LO LAI LIE ETE OP LS AES RU! “he ee pm Pe So:

19a

Opinion of the United States Court of Appeals,

For the Fourth Circuit

ment, a pertinent paper which it sought to introduce was

excluded. This unpublished paper was of recent origin.

Its author had conferred with Carter-Wallace’s attorneys

in the town where the hearings were held the night before

the session at which the paper was submitted. Carter-

Wallace, however, did not call the author as a witness, but

instead sought to introduce the paper through its vice-

president. Under these unusual circumstances, the exam-

iner did not abuse his discretion by ruling that the paper

could not be introduced unless the government had an

opportunity to cross-examine the author.

We agree with Carter-Wallace that the examiner erro-

neously ruled that three papers written by the president

of Wallace Laboratories, were irrelevant. However, the

author testified at great length, and the exhibits were

largely cumulative. Their exclusion was not reversible

error. Cf. United States v. Ross Corporation, 385 F.2d

564, 566 (6th Cir. 1967). See 2 Davis, Administrative Law

§ 14.09, p. 291 (1958). Carter-Wallace’s contention that

the examiner was biased is not supported by the record.

We find no merit in its other complaints about the conduct

of the hearing or in its charge that the examiner and the

Commissioner ignored its evidence.

The order of the Commissioner is affirmed.

20a

APPENDIX B

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

DEPARTMENT OF HEALTH, EDUCATION,

AND WELFARE

Foop anp Druc ADMINISTRATION

Docket No. FDA-DAC-1

This administrative proceeding involves the basic ques-

tion of whether or not the drug Meprobamate, and drugs

containing Meprobamate, have sufficient potential for abuse

because of their depressant effect on the central nervous

system to warrant bringing them under the control of the

Drug Abuse Control Amendments of 1965. This is the first

administrative proceeding to be conducted under these most

recent amendments to the Federal Food, Drug, and Cos-

metic Act of 1938.

In July of 1965, the Congress unanimously passed the

Drug Abuse Control Amendments of 1965' to the Federal

Food, Drug, and Cosmetic Act.2? These Amendments,

among other things, legislatively brought under more strict

control the manufacture, sale and distribution of specifi-

cally identified “depressant or stimulant drugs.” Thus,

one class of depressant drugs, the so-called barbiturate

drugs, and another class of stimulant drugs, the so-called

amphetamine drugs were specifically named in this legis-

lation and brought under its control. [21 U.S.C. 201(v);

21 U.S.C. 360 and 360a; 79 Stat 227, 231, 232, and 228).

1P.L. 89-74, July 15, 1965, hereinafter referred to as the

“Amendments.”

221 U.S.C. 321 et seq., hereinafter referred to as the “Act.”

BLEED THROUGH POOR COPY

2la

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

What other “depressant or stimulant” drugs are to be

controlled under these Amendments, if any, was left for

Administrative determination.’ Section 201(v)(3) of the

Act, [21 U.S.C. 321(v)(3)] defines the term “depressant

or stimulant” drugs to mean—

(3) “any drug which contains any quantity of a

substance which the Secretary, after investigation, has

found to have, and by regulation designates as having,

a potential for abuse because of its depressant or

stimulant effect on the central nervous system * * *”

The administrative process to be followed to arrive at

this determination was made subject to the public hearing

and appeal procedures set forth in the basic Federal Food,

Drug, and Cosmetic Act. [21 U.S.C. 321, 371].

Pursuant to the authority set forth in those Amend-

ments and delegated to the Commissioner of Food and

Drugs [21 CFR 2.90], the Acting Commissioner of Food

and Drugs on January 18, 1966, caused to be published in

the FeperaL Recister a proposal to designate all drugs

containing any amount of 17 named substances as having

a potential for abuse because of their depressant or stimu-

lant effect on the central nervous system or their hallu-

cinogenic effect. These drugs would thus be subject to the

controls of the Amendments. [Ex. A; 31 F.R. 565].

One of the drugs proposed for control, bears the estab-

lished name of “Meprobamate” and various and numerous

trade names, the most popular of which are Miltown and

Equanil. This proposal was published pursuant to the

statutory provisions of the Act and invited all interested

7(C, Ex. 2, p. 5, “Scope of Coverage.”

LOR At

NUN Pabd PI A arta ta oe 6 6 ssn tes wns ween ” *

SS SPATS Tg ners PE Mt SPs i mat ais emt te Rie te en ee FORO MNES PORN

TRS NAT TN O85” Mee Maite Tey Petit eet |

22a

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

persons to submit their views in writing regarding this

proposal. [21 U.S.C. 371(e)].

On March 19, 1966, the Commissioner of Food and

Drugs caused to be published in the Freprerat Recisrer an

Order by which 16 of the proposed 17 drugs were desig.

nated as being brought under control of the Amendments,

Meprobamate and all drugs containing any amount of

Meprobamate were designated in this Order as having a

potential for abuse because of their “depressant effect on

the central nervous system.” [Ex. B; 31 F.R. 4679].

Wallace Laboratories, a division of Carter-Wallace, Inc,

of Cranbury, New Jersey [hereinafter referred to as

Respondent], a pharmaceutical firm engaged in the manv-

facture, sale, and distribution of Meprobamate, through its

attorneys, filed timely objections to the Commissioner’s

Order of March 19, 1966, as it related to Meprobamate,

and requested a hearing on its objections.

Pursuant to statutory provisions there was published

in the Feperat Recister of May 17, 1966, a combined No-

tice and Order which, among other things, noted the filing

of objections by Respondent and stayed those provisions

of the Order of March 19, 1966, relating to Meprobamate.

This document further set forth four numbered issues

which were raised by the filing of objections to the March

19, 1966 Order and announced the time and place for a

prehearing conference and hearing concerning Meproba-

mate. [Ex. C; 31 F.R. 7174]. Three of the four numbered

issues set forth in this document concern Meprobamate,

the fourth concerns other drugs not the subject of these

proceedings.

In order to expedite the hearing as noted above, and

upon Respondent’s request, an additional] prehearing con-

BLEED THROUGH POOR COPY

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

ference was scheduled by Notice published in the FrprraL

Recister of May 26, 1966. [Ex. D; 31 F.R. 7573].

Two prehearing conferences were held in this matter,

the first on June 14, the second on June 21, 1966. The issues

upon which evidence would be taken during the hearing,

and as they related specifically to Meprobamate, were

particularized during these conferences as follows:

1. Whether there is evidence that individuals are tak-

ing Meprobamate, or drugs containing Meproba-

mate, in amounts sufficient to create a hazard to

their health or to the safety of other individuals

or of the community?

2. Whether there is evidence of significant diversion

of Meprobamate, or drugs containing Meproba-

mate, from legitimate drug channels?

3. Whether there is evidence that individuals are tak-

ing Meprobmate, or drugs containing Meproba-

mate, on their own initiative rather than on the

basis of medica] advice from a practitioner licensed

by law to administer such drugs in the course of

his professional practice? [Ex. C; PH. TR. 8, 12,

and 13].‘

During these prehearing conferences, Respondent’s

counsel objected to the wording of issues numbered one

and three, supra.

The grounds for the objections are that the issues

establish a burden of proof not consistent with the Amend-

‘PH. TR.—refers to pages of transcript of the prehearing con-

ferences. TR.—refers to pages of the transcript of the hearing.

G. Ex.—abbreviation for Government’s exhibits. R. Ex.—abbrevia-

tion for Respondent’s exhibits.

Senrnee ee “=

iY . EBERT: ERASER a Ra me ers Be TLS ESET Si Th

a)

24a

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

ments and their legislative history and therefore are jp

excess of statutory authority.

It is Respondent’s position that as worded, issues num.

bered one and three would allow the Food and Drug

Administration to list Meprobamate as a drug subject to

contro] under the Amendments upon proof of only a few

individuals having taken the drug in amounts hazardous

to their health or upon proof that only a few individuals

have taken the drug on their own initiative rather than

pursuant to a doctor’s prescription.

In short, Respondent contends that Congress intended

to demand proof of “substantial” potential for “signifi.

cant” abuse to warrant bringing a drug under the control

of the Amendments. The legislative history of the Amend-

ments are relied upon to support this contention.®

In order to answer the three issues as stated in the

Notice of Hearing with any degree of certainty, it becomes

necessary to first answer the legal question raised by

Respondent, namely, what quantum of proof is required

under the Amendments to justify the listing of a drug as

having a potential for abuse because of its depressant

effect on the central nervous system.

Because this matter is one of first impression under

the Amendments and the consequent lack of judicial pree-

edent, it may be helpful to trace the origin of the concepts

embodied in the issues as stated in the Notice of Hearing,

Exhibit C.

On January 27, 1966, the Commissioner of Food and

Drugs, pursuant to Sections 201(v), 511, and 701 of the

Act [21 U.S.C. 321(v), 360a, and 371] published in the -

5 PH. TR. 7-14, 167-177; R. Exs. 65 and 66 for identification;

Respondent’s brief, Part IA.

| —en tna ea Ln Faas

25a

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

FeperaL Recister regulations supplementing, interpreting,

and establishing procedures under the Amendments [31

FR. 1271; 21 C.F.R., 166.1 et seq]. Paragraph 166.2 of

these regulations established “Criteria applicable to terms

used or defined in paragraph 166.1” of these regulations,

which paragraph set forth definitions and interpretations

of terms used in the Amendments.

Subparagraphs (a), (b), (c), and (d) of paragraph

166.2 of these regulations, set forth criteria which, among

other relevant factors, the Commissioner will consider in

determining whether any given drug ‘has a “stimulant ef-

fect” (a); a “depressant effect” (b); is “habit forming”

(c); or has a “hallucinogenic effect” (d).

Subparagraph (e), most applicable to the question now

before us, reads as follows:

{e) The Commissioner may determine that a substance

has a potential for abuse because of its depres-

sant or stimulant effect on the central nervous

system or its hallucinogenic effect, if:

(1) There is evidence that individuals are taking

the drug or drugs containing such substances

in amounts sufficient to create a hazard to

their health or to the safety of other indi-

viduals or to the community; or

(2) There is significant diversion of the drug or

drugs containing such substances from legiti-

mate drug channels; or

(3) Individuals are taking the drug or drugs con-

taining such a substance on their own initia-

tive rather than on the basis of medical advice

from a practitioner licensed by law to admin-

RITE A Soe RRS aT ab abag ess sete

a Si ts an Ht df eee ea |

a |

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

ister such drugs in the course of his profes.

sional practice ;—

A reading of Exhibit C, the Notice of Hearing in this

matter, reveals that the issues for hearing therein stated

are framed substantially verbatim in the words of syb-

paragraph 166.2(e) above quoted.

One of the important and basic documents in the

legislative history of the Amendments of 1965 is the Final

Report of the President’s Advisory Commission on Nar.

cotics and Drug Abuse, dated November 1963. [G. Ex. 1},

The concepts set forth in paragraph 166.2 of the regulations

referred to above and refined into the issues for the hearing

in this matter are first clearly set forth in this Final Report

where, at page 2, the following appears:

“When this report speaks of ‘drug addiction’ it

is using the term in its full technical sense to include

both the psychological and the physical dependence,

When it speaks of ‘drug abuse’ it is referring to the

broader problem which includes also those drugs which

create only psychological dependence. We will use the

term ‘drug abuse’ in this report as existing when an

individual takes psychotoxic drugs under any of the

following circumstances:

(a) in amounts sufficient to create a hazard to his own

health or to the safety of the community; or

(b) when he obtains drugs through “illicit” channels;

or

(c) when he takes drugs on his own initiative rather

than on the basis of professional advice.

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

Drug abuse today involves not only narcotic drugs

and marihuana, but to an increasingly alarming extent

other drugs such as barbiturates, the amphetamines,

and even certain of the ‘tranquilizers.’ This latter

group will be referred to in this report as the ‘dan-

gerous drugs’.”

The above-quoted concepts were incorporated into the

formal legislative history of the Amendments in the Re-

port of the Committee on Interstate and Foreign Com-

merce on H.R. 2. [House Report No. 130, 89th Cong., 1st

sess, March 2, 1965; C. Ex. 2]. At page 7, the following

section entitled “Potential for Abuse” appears:

The bill provides that the term “depressant or

stimulant drug” includes, in addition to barbiturates

and amphetamines, any drug which contains any quan-

tity of a substance which the Secretary, after investi-

gation, “ * * * designates as having a potential for

abuse * * *.” The term “drug abuse” was defined

for purposes of the report of the President’s Advisory

Commission on Narcotic and Drug Abuse, submitted

November 1, 1963, as existing when an individual takes

drugs under any of the following circumstances:

(a) in amounts sufficient to create a hazard to his own

health or to the safety of the community; or

(b) when he obtains drugs through illicit channels;

or

(ec) when he takes drugs on his own initiative rather

than on the basis of professional advice.

It is not intended by the committee that a drug’s

potential for abuse be determined on the basis of the

RET

28a

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

drug’s having a potential for isolated or occasional

nontherapeutic purposes. The committee feels that g

drug’s “potential for abuse” should be determined op

the basis of its having been demonstrated to have such

depressant or stimulant effect on the central nervoys

system as to make it reasonable to assume that there

is a substantial potential for the occurrence of sig.

nificant diversions from legitimate drug 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,

It was recommended to the committee that the cov.

erage of drugs under this paragraph be limited to

those drugs as to which substantial abuse had been

shown. The committee felt that the Secretary of

Health, Education, and Welfare should not be required

to wait until a number of lives have been destroyed

or substantial problems have already arisen before

designating a drug as subject to controls of the bill.

Similarly, the committee considered but did not adopt

an amendment requiring that before a drug can be

classified as subject to the controls of the bill, the

Secretary must determine that it have a “potential for

abuse adversely affecting the public health” since the

committee felt that this limiting language was not

necessary.

The above-quoted paragraph also appears, substantially

verbatim, in the Report of the Committee on Labor and

Public Welfare, accompanying H.R. 2, dated June 21, 1965.

[Senate Report No. 337, 89th Cong., Ist sess., June 21,

1965; G. Ex. 3].

OE ee AP ~~

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

An exhaustive review of the legislative history of the

Amendments fails to reveal nor has our attention been

directed to any additional material bearing directly on

the question now under consideration. The answer to our

question is thus contained in the House and the Senate

Reports accompanying the Amendments, and is arrived at,

hopefully, through the application of common sense and

the principals [sic] of statutory construction.

“Legislative language is generally most faithfully

construed when it is held to mean simply what it says,

read with common sense.”

United States v. Vitamin Industries, Inc., et al., 130 F.

Supp. 755 (D. Neb., 1955). See also: National Labor Re-

lations Board v. Coca-Cola Bottling Co., 350 U. S. 264

(1956).

The two key words involved here are “substantial” and

“significant,” and the common, ordinary meaning to these

words must be used. “Substantial” has been authorita-

tively defined by many courts, in relation to the phrase

“substantial evidence.” The widely accepted definition is:

“more than a mere scintilla”; “sufficient for a rea-

sonable mind to accept as adequate to suport a con-

clusion.”

Consolidated Edison Co. v. Labor Board, 305 U. S. 197,

229; Labor Board v. Columbian Enameling and Stamping

Co., 360 U.S. 292, 300; Universal Camera Corp. v. National

Labor Relations Board, 340 U. S. 474 (1951); National

Labor Relations Board v. Walton Manufacturing Co., 369

U.S. 404 (1962).

To RR SSN ORR mR ROAR» eet |

30a

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

“Significant” is commonly understood to mean “meap.

ingful,” “having meaning,” “important,” “deserving of

consideration.’”*

When the legislative history set out supra is studied

and the above-stated definitions are applied with common

sense to our problem, it is clear that Respondent’s conten.

tion must be sustained. Therefore, the answer to the basic

legal question presented here, is, that Congress did intend

to demand proof of a “substantial” potential for “signif-

cant” abuse to justify bringing a drug under the contro]

of the Amendments.

As a corollary to its basic contention, Respondent also

argues that in order to prove potentiality for abuse, evi-

dence must be adduced showing that a “significant” num-

ber of individuals have abused Meprobamate. Further, the

significance of the number of individuals must be measured

by comparing the numbers of individuals who have abused

Meprobamate with the number of individuals who have

abused those drugs specifically designated by Congress as

having a potentiality for abuse and legislatively brought

under the control of the Amendments, that is, the bar-

biturates and amphetamines.

Certainly, in the light of the legislative history present

here, evidence of an “isolated or occasional” individual's

use of Meprobamate for nontherapeutic use would not be

sufficient to prove “significant” abuse. The number of

individuals must be “significant,” that is, “meaningful,”

“important,” and “deserving of consideration.” Thus, this

portion of Respondent’s corollary argument is correct.

* Webster's Third New International Dictionary, Unabridged,

1961, p. 2116.

3la

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

However, we are unable to find, nor are we cited to,

any provision either in the Amendments themselves or in

their legislative history which indicates any intention of

Congress to requre that the evidence establish that any

specific or arbitrary number of individuals have abused a

drug in the past to support a finding of significant abuse.

Indeed, in view of the “in future” nature of the “poten-

tiality for abuse” concept embodied in the Amendments,

as commented on next in this Opinion, and because accu-

rate and specific numbers of individuals who have abused

drugs is not known and cannot be reasonably ascertained

with any reliable degree of certitude as set forth in the

Findings of Fact which follow, no such numerical criteria

is either feasible or desirable. Additionally, the Amend-

ments and legislative history are equally devoid of any

indication that Congress intended the significance of the

abuse of a drug under consideration to be measured by

comparing the number of individuals who have abused it

with the number of individuals who have abused the bar-

biturates and amphetamines. For the above-stated rea-

sons, such a criteria is equally unfeasible and undesirable.

Thus, this portion of Respondent’s corollary argument

must fail as unsupported by law or logic.

In the Amendments Congress dealt with a “potentiality”

for abuse, that is, a “possibility” or a “capacity” not yet

realized, or “having the capacity or a strong possibility

for development into a state of actuality”—a “state of that

which is not yet fully realized.””

Thus, there is the concept of future attainment or ful-

fillment inherent in the statutory phrase “potential for

abuse.”

‘Webster's Third New International Dictionary, Unabridged,

1961, p. 1775.

32a

Opinion of the FDA Hearimg Examiner,

Dated January 13, 1967

Consequently, as to when a drug may be listed as sub-

ject to the controls of the Amendments, it is clear from

the last paragraph of the House Report, quoted supra,

that the Secretary need not wait until “* * * a number of

lives have been destroyed or substantial problems have

already arisen before designating a drug as subject to

(the) controls of the bill.” Indeed, the main purpose of

the Amendments is to prevent such destruction of lives

and to avoid the creation of abusive drug practices, where

possible.

However, in this case, where Meprobamate has been on

the market for over ten years, the surest means of estab-

lishing a “potential for abuse” is to ascertain whether the

drug has been abused in the past.

Thus, under the conclusions set forth in this Opinion,

and under applicable law, the quantum of proof necessary

in this proceeding is substantial evidence establishing that

Meprobamate has a substantial potential for significant

abuse as shown by the past abuse of this drug.®

Consequently, the ultimate questions to be decided here

are as follows:

Is there substantial, probative, and reliable evidence

of—

(1) significant use of Meprobamate, or drugs contain-

ing Meprobamate, in amounts sufficient to create

a hazard to the health of the individual or to the

safety of other individuals or the community?

(2) significant diversion of Meprobamate, or drugs

containing Meprobamate, from legitimate drug

channels?

$21 U.S.C. 371(a) (3).

33a

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

(3) significant use of Meprobamate, or drugs contain-

ing Meprobamate, by individuals on their own ini-

tiative rather than on the basis of medical advice

from a practitioner licensed by law to administer

such drugs in the course of his professional prac-

tice?

The substantial, probative, and reliable evidence intro-

duced at the hearing in this matter, and a consideration of

the record in its entirety, including all arguments and

briefs submitted, leads to the conclusion, as more fully

detailed in the Findings and Conclusions hereinafter set

forth, that Meprobamate does have a substantial potential

for significant abuse because of its depressant effect on the

central nervous system, within the meaning of 21 U.S.C.

321(v) (3). It therefore is subject to the provisions of the

Drug Abuse Control Amendments of 1965.

The Respondent further argues that there is no evi-

dence of record proving that its products consisting of

Meprobamate combined with other drugs; i.e., Milpath,

Deprol, Milprem, Miltrate, and Appetrol, have a potential

for even isolated or occasional abuse. [R. Brief, pp. 49-51,

60-61].

There is a lack of substantial evidence in this record

that Meprobamate combined with other drugs, manufac-

tured by either the Respondent or others, have ea substan-

tial potential for significant abuse. However, such evidence

is not determinative of the question of whether such com-

bination products should be brought under the control of

the Amendments. This question is determined by the

clear wording of section 201(v)(3) of the Amendments.

NEL RY IIT LT ID OF COE il

LOIRE PIR ERED NEIG O 5 SRE ILE PELE ELIE IN OIE RG ALS APR LS

34a

Opinion of the FDA Hearing Examiner,

Dated January 13, 1967

[21 U.S.C. 321(v)(3)]. In pertinent part, this section

provides:

“(v) The term ‘depressant or stimulant drug’

means—

(3) any drug which contains any quantity of a sub-

stance which the Secretary, after investigation,

has found to have, and by regulation designates

as having, a potential for abuse because of its

depressant or stimulant effect on the central ner-

vous system or its hallucinogenic effect ;—”

Meprobamate, after the investigation here involved,

is found to be a substance having a potential for abuse

because of its depressant effect on the central nervous sys-

tem. Based upon this finding, all drugs containing any

quantity of Meprobamate are “depressant or stimulant

drugs” by operation of law, and as such, are subject to

the controls of the Amendments.

It is recommended that the proposed Findings of Fact,

Conclusions of Law and Order attached hereto, be adopted

by the Commissioner and published in the Frprrat Rec-

ISTER.

Dated: January 13, 1967

WruiM E. Brennan

Hearing Examiner

‘ YO En te et ea ea MDA AGERL OK SS ae A ORR & —_

Pk APRA A DELO RNY Ra ALD a Mas RT OCDE ULE FL ESSN ES IIR Ge LAN Oe SS TNT RES

see ie 2 a

= _— .

*

35a

APPENDIX C

Findings of Fact and Conclusions of Law

of the Commissioner of Food and Drugs,

Dated November 28, 1967

Meprobamate; Listing Drug as Subject to Control

In the matter of listing meprobamate as a drug subject

to control under the Drug Abuse Control Amendments of

1965:

Acting on a proposal published in the Feprrat RecisTer

of January 18, 1966 (31 F.R. 565), an order was published

in the Feperau Recister of March 19, 1966 (31 F.R. 4679),

listing meprobamate, among other drugs, as a drug subject

to control under the Federal Food, Drug, and Cosmetic Act

as amended by the Drug Abuse Control Amendments of

1965 because of its potential for abuse due to its depressant

effect on the central nervous system. Subsequently, Wal-

lace Laboratories, a division of Carter-Wallace, Inc., Cran-

bury, N.J., filed objections to such listing of meprobamate

and requested a public hearing, and it was concluded that

the objections stated reasonable grounds.

Accordingly, an order was published in the FrprRaL

Recister of May 17, 1966 (31 F.R. 7174), that, among other

things, stayed the effectiveness of so listing meprobamate

and scheduled a public hearing for the purpose of receiving

evidence relevant and material to the issues set forth in

that order plus a prehearing conference for certain pur-

poses. An additional prehearing conference in this matter

was announced in the Feprra Recister of May 26, 1966 (51

F.R. 7573).

Prehearing conferences were held on June 14 and 21,

1966, and the public hearing began June 27, 1966, and ended

September 16, 1966. The transcript of testimony (4,891

pages) sets forth the testimony of 31 witnesses on behalf of

36a

Findings of Fact and Conclusions of Law

the Government and 31 on behalf of the respondent. Fifty

witnesses were medical doctors covering a wide range of

medical training, experience, and expertise. On behalf of

the Government, 118 exhibits were introduced into evidence,

and 24 were introduced by the respondent. Written briefs

were timely-filed by the respondent and the Government.

In the Feperau Recister of April 13, 1967 (32 F.R. 5933),

a tentative order including proposed findings of fact and

conclusions in this matter was published providing for the

filing of exceptions thereto within 30 days by any interested

person whose appearance was filed at the hearing. There-

after, the Commissioner of Food and Drugs considered the

exceptions received to the tentative order and listened to

oral arguments on behalf of Wallace Laboratories, a divi-

sion of Carter-Wallace, Inc.

Now, therefore, on the basis of the evidence received at

the hearing, and after consideration of the written and oral

arguments, proposed findings and conclusions, and excep-

tions to the tentative order, which are adopted in part or

rejected in part as is apparent from the detailed findings

herein made, and pursuant to the authority vested in the

Secretary of Health, Education, and Welfare by the Federal

Food, Drug, and Cosmetic Act (secs. 201(v), 511, 701, 52

Stat. 1055, as amended, 79 Stat. 227 et seq.; 21 U.S.C.

321(v), 360a, 371) and delegated by him to the Commis-

sioner (21 CFR 2.120), the following order is issued:

Findings of fact.! 1. Meprobamate, N.F., is the “estab-

lished name” for a white crystalline substance having the

1 The citations following each finding of fact refer to the pages

of the transcript of testimony and the exhibits received in evidence

at the hearing, unless specified otherwise. “TR” refers to the

transcript, “G. Ex.” refers to exhibits on behalf of the Govern-

ment, and “R. Ex.” refers to exhibits introduced by the respondent.

aaa Sh Ua nD RR FONT aan

37a

Findings of Fact and Conclusions of Law

chemical formula 2-methyl-2-n-propyl-1,3-propanedial dicar-

bamate. It is a carbamate compound which was developed

by Berger and Ludwig from an earlier developed short-

acting tranquilizer named “mephenesin.” Meprobamate

was first used in clinical trials in 1952 as an antianxiety

agent and has been widely distributed commercially since

1955. (TR. 1679-1681; R. Ex. 47.)

2, Meprobamate is one of a group of drugs known col-

lectively as “tranquilizers.” It is recommended by its

manufacturer and is widely used for the symptomatic relief

of anxiety and tension states. It is used in the treatment of

tension headaches, nervousness, muscular tension, various

complaints related to the gastrointestinal tract, and nerv-

ousness and tension associated with psychoneurotic dis-

orders. It is widely used in the treatment of individuals

with neurotic personalities and as an adjunct in psycho-

analytical therapy. It is also prescribed by some physicians

to relieve the anxiety and tension associated with such

physical disorders as coronary diseases, pre- and post-

operative care, neuromuscular pain, gastrointestinal disor-

ders, menopausal disorders, ear and throat disorders, and

aleyholism. Based on its most frequent use, meprobamate

is classified as a “minor” tranquilizer in contradistinction

to a group of drugs known as “major” tranquilizers. This

latter class of tranquilizers is recommended for use in treat-

ing the anxiety states associated with psychotic disorders,

whereas the “minor” tranquilizers are recommended for

use in treating the anxiety states associated with psycho-

neurotic disorders. (TR. 793, 945, 1680, 1685, 1966-1967,

2015, 2255, 2300, 2935-2936, 3030-3031, 3099, 3187, 3439, 3519,

3613, 3812; R. Ex. 13.)

3. Since its first introduction into the commercial chan-

nels of drug distribution in 1959, meprobamate may be

YP SEER RRL I IIIA SNORE “f

h syns

ee SaaS an a Wd ey CC S|

38a

Findings of Fact and Conclusions of Law

legally dispensed only upon the written prescription of a

practitionér licensed by law to administer such drugs, or

upon an oral prescription of such practitioner that is re.

duced promptly to writing and filed by the pharmacist, or

by the refilling of any such written or oral prescription if

such refilling is authorized by the prescriber either in the

original prescription or by oral order that is reduced

promptly to writing and filed by the pharmacist (21 U.S.C.

353(b) (1) (B)).

4. Meprobamate is manufactured and distributed by the

respondent in these proceedings, Wallace Laboratories, a

wholly owned subsidiary of Carter-Wallace, Inc. It is

commercially available in two tablet strengths, 200 and 400

milligrams, It is also available in the same strengths in

time-release capsule form under the trade name Meprospan.

It is most widely marketed by Wallace Laboratories in tab-

let form under the trade name Miltown. The respondent

states that since 1955, it has manufactured approximately

12,500 pounds of meprobamate, which, if all of this material

were converted into 400-milligram tablets, would represent

approximately 14 billion tablets. It has been estimated that

approximately 500 million prescriptions have been written

for meprobamate and that it has been prescribed for ap-

proximately 100 million patients in the United States. It

clearly has been widely distributed in this country for the

past 10 years. The usual adult dosage recommended by

the respondent is one or two 400-milligram tablets three

times daily. The maximum adult dosage recommended is

six 400-milligram tablets daily, or 2,400 milligrams of me-

probamate. Doses above 2,400 milligrams are not recom-

mended by the respondent. (TR. 1159, 1681-1683, 1751-1752,

1967, 2023, 2036, 2617-2618)

nal ee eee ieee Sree a tery. eerie ere er eee ee eee Ord aa ee eee Cee

39a

Findings of Fact and Conclusions of Law

5. The respondent also manufactures and distributes

the following drugs in tablet and/or capsule form, which

consist of meprobamate combined with other drugs. These

drugs have been distributed commercially since the year in-

dicated in the following listing of these products:

Appetrol: Meprobamate plus dextro-amphetamine sul-

fate; 1959 (1962 in sustained-released form).

Deprol: Meprobamate plus benactyzine hydrochloride ;

1958.

Milpath: Meprobmate plus tridihexethyl cliloride;

1957.

Milprem: Meprobamate plus conjugated estrogens;

1957.

Miltrate: Meprobamate plus pentaerythrityl tetrani-

trate; 1958. (Tr. 1750-1754)

6. Meprobamate is a drug having a “depressant effect

on the central nervous system” within the meaning of the

Drug Abuse Control Amendments and the regulations pro-

mvigated thereunder. (21 U.S.C. 201 (v) (3)).

In §166.2 Criteria applicable to terms used or defined in

(166.1 of the depressant and stimulant drug regulations (21

CFR 166.2), “depressant effect” is explained in paragraph

(b) in part as follows:

(b) In determining whether a drug has a “depressant

effect” on the central nervous system, the Commissioner

will consider, among other relevant factors, whether there

is substantial evidence that the drug may produce one of

the following: |

(1) Calming effect or relief of emotional tension or

anxiety.

oe

EIN OG EE GOEL CO EE 6 A EO IT iy + eA OE tl en at

40a

Findings of Fact and Conclusions of Law

(2) Drowsiness, sedation, sleep, stupor, coma, or gen-

eral anesthesia.

(3) eee

(4) Mood depression or apathy.

(5) *ee

Substantially all of the medical witnesses appearing on

behalf of both the respondent and the Government, testified

in substance that the major pharmacological effects of me-

probamate are to calm the individual, to give relief of emo-

tional tension or anxiety, and to produce drowsiness, seda-

tion, and sleep. The unrebutted testimony of a number of

witnesses established that meprobamate in sufficiently large

dosages produces stupor and coma and will depress mood

and induce apathy.

Meprobamate is classified by its developer as, and is

represented by the respondent to be, a tranquilizer belong-

ing to the “central depressant” class of tranquilizers.

It is the respondent’s position that meprobamate has a

potential for only isolated or occasional abuse and that such

abuse is not due to its “depressant effect on the central

nervous system.” (R. Brief 4, 10, 43-49, 53, 54.)

The substantial evidence of record, conclusively estab-

lishes that meprobamate acts upon the central nervous sys-

tem and that such action is a depressant action which re-

sults in the calming of individuals who take the drug and

the relieving of their anxiety and emotional tension. This

drug is known to produce drowsiness, sedation, and sleep.

Individuals consuming meprobamate in sufficiently high

dosages for extended periods of time have experienced

apathy and a depression of mood.

The precise way in which these effects are brought about

is the subject of differing medical opinions and views and

Findings of Fact and Conclusions of Law

is not known with precise certitude. Some medical opinions

hold that meprobamate exerts a “selective action” in the

central nervous system, affecting primarily the subcortical

area of the brain. This causes a blocking of the interneu-

ronal transmission of anxiety-producing electrical dis-

charges or stimuli within the various areas of the brain, the

cortex, thalamus, and hypothalamus. It is believed that the

site of action of this drug is in the subcortical structures of

the brain, such as the thalamus and limbic system. These

anatomical structures are thought to be the seat of human

emotions; however, it is generally recognized that these

structures are part of the central nervous system. When

taken not in excess of the maximum recommended dose,

meprobamate appears not to significantly affect the func-

tions of the upper area of the brain, the cortex, which is

associated with intellectual and judgmental functions, nor

the hypothalamus, associated with autonomic functions such

as circulation and respiration ; however, when meprobamate

is taken in dosages higher than those recommended, it does

affect the hypothalamus and cortex.

Although the precise mechanism of meprobamate is not

known with certainty, nor are there adequate clinical studies

clearly delineating its mechanisms, what effects this drug

does produce are due to its depressant effect on the central

nervous system.

Of those drugs whose principal effect is on the central

nervous system, only those with a chiefly depressant effect

will, upon sudden withdrawal following chronic administra-

tion, produce withdrawal symptoms or an abstinence reac-

tion characterized by insomnia, nausea, vomiting, tremors,

the twitching of muscles, anxiety, weakness, headaches,

anorexia, unsteady gait or motor ataxia, hallucinations, de-

lusions, depression, convulsions, and, in extreme cases,

death.

soa

42a

Findings of Fact and Conclusions of Law

Carefully controlled clinical studies conclusively estab-

lish that when meprobamate is given to individuals in dos-

ages of from 8 to 16 400-milligram tablets daily, for a period

of 40 days, and a chemically inert substance, a placebo, is

abruptly substituted for the meprobamate, the withdrawal

symptoms of insomnia, vomiting, tremors, ataxia, overt

anxiety, anorexia, muscle twitching, hallucinations, and

convulsions occur. These clinical studies have been con-

firmed by animal studies.

Other widely recognized central nervous system depres-

sant agents, such as the barbiturates and alcohol, if taken

at sufficient dosage levels over sufficient periods of time, will

cause withdrawal symptoms when abruptly withdrawn from

individuals. On the other hand widely recognized central

nervous system stimulant drugs, such as the amphetamines,

when suddenly withdrawn from individuals after long use

at sufficient dosage levels do not cause withdrawal symp-

toms.

It is therefore concluded that irrespective of the precise

mechanisms of meprobamate, the substantial evidence of

record conclusively establishes that this drug does have a

“depressant effect on the central nervous system” within

the meaning of the amendments. (TR. 39-47, 456-481, 1674-

1688, 1705-1706, 1708, 1732, 1851, 2061-2062, 2310, 2350-2353,

2381-2383, 2493-2497, 3027-3028, 3396, 3410, 3677-3678, 4690-

4699, 4705-4726, 4748-4762; R. Ex. 10, 11, 13, 19, 33, 44, 47;

G. Ex. 1, 12, 17, 19, 24, 28, 150, 162.)

7. Section 166.2(e) of the depressant and stimulant

drug regulations (21 CFR 166.2(a)) sets forth the criteria

for determining whether a substance has a potential *°.

abuse because of its depressant effect on the central nervous

system. Subparagraphs (1), (2), and (3) of §166.2(e) are

————<_ ' — °°, © -EY 8) an ant oo a od ot =

GLO ALLA LAL LLL OLED Pe PLGA LE LE TLE CAEP EE A AYO! ory

43a

Findings of Fact and Conclusions of Law

applicable to this proceeding and the criteria are set forth

therein, as follows:

(e) The Commissioner may determine that a substance

has a potential for abuse because of its depressant * * *

effect on the central nervous system * * * if:

(1) There is evidence that individuals are taking the

drug or drugs containing such a substance in amounts sufii-

cient to create a hazard to their health or to the safety of

other individuals or of the community; or

(2) There is significant diversion of the drug or drugs

containing such a substance from legitimate drug channels;

or

(3) Individuals are taking the drug or drugs containing

such a substance on their own initiative rather than on the

basis of medical advice from a practitioner licensed by law

to administer such drugs in the course of his professional

practice; or

Respondent argues that Congress intended the Drug

Abuse Control amendments to apply only to those sub-

stances where there is “demonstrated” a “substantial”

potential for “significant” abuse (Part I of respondent’s

brief). The legislative history of the amendments as set

forth in Government Exhibits 1, 2, and 3 does support re-

spondent’s argument to the extent that Congress intended

to bring under the control of the amendments those sub-

stances having a “substantial” potential for “significant”

abuse. However, the legislative history does not support

the argument that a substance may be brought under the

control of the amendments only after substantial abuse has

taken place.

The following language appearing at page 5 of the re-

port of the Senate Committee on Labor and Public Welfare

LOLI OLIG PDE LOI AIO GLE LE ODL LLP NINE AM ICE RELEASE eS ee

POA. CHP

d4a

Findings of Fact and Conclusions of Law

accompanying the amendments, explicitly states: “The

Secretary of Health, Education, and Welfare should not be

required to wait until a number of lives have been destroyed

or substantial problems have already arisen before desig.

nating a drug as subject to controls of the bill.” (G. Ex. 3,

Sen. Rept. No. 337, 89th Cong., Ist sess., June 21, 1965, p. 5.)

Substantially identical language appears also at page 7

of the report of the House Committee on Interstate and

Foreign Commerce accompanying the amendments. (G, Ex.

2, H. Rept. No. 130, 89th Cong., 1st sess., Mar. 2, 1965, p. 7.)

Consequently the criterion of “substantial” potential for

“significant” abuse has been used in reviewing and evalu-

ating the evidence of record in this matter.

8. The substantial evidence of record establishes that a

significant number of individuals have taken meprobamate

in amounts sufficient to create a hazard to their health or

to the safety of other individuals or to the community,

Included within the term “hazard” are:

a. Use of meprobamate to achieve intoxication;

b. Use of meprobamate to attempt suicide, successfully

or unsuccessfully.

Meprobamate when taken by certain types of individuals

in amounts in excess of six 400-milligram tablets per day,

has produced in the past and will produce intoxication

marked by slurred speech, incoordination, pleasurable feel-

ings simulating alcoholic intoxication (sometimes referred

to as euphoria) and nystagmus. While the complex psycho-

logical reasons which induce some individuals to ingest in-

toxicating doses of depressant drugs are not known, it is

known that individuals with drug-dependency-prone per-

45a

Findings of Fact and Conclusions of Law

sonalities (immature, neurotic, inadequate, dependent-type

personalities) will chronically ingest drugs which produce

euphoria, variously described as exaggerated feelings of

well-being not in conformity with reality, feelings of happi-

ness or elevation of mood, the relaxation and relief of

tensions caused by psychological stress, a general dulling

of the sensorium, or a sense of intoxication. Meprobamate

causes these effects through its pharmacological action upon

the central nervous system. Such effects have been reported

by the ingestion of a single dose of meprobamate of 1,200

to 1,600 milligrams; however, with chronic ingestion of me-

probamate a tolerance to its effects develops. Tolerance is

a physiological process whereby an organism develops in-

sensitivity to a drug, thus requiring the administration of

gradually increasing doses in order to achieve the initial

effect. It is believed that tolerance occurs when the body

gradually adapts to the presence of a drug by altering the

functions of certain systems and by increasing the rate at

which the drug is metabolized. Thus, in order to achieve

the initial physiological response, increasingly larger doses

of the drug need to be ingested. Clinical observation to-

gether with data derived from animal experiments conclu-

sively establish that meprobamate is a drug to which a

tolerance is built when taken over extended periods of time.

It is because such a tolerance is established that some indi-

viduals, in an attempt to relieve their symptoms of anxiety,

will gradually increase the amounts of meprobamate they

ingest to the point of intoxication. (TR. 40, 45, 86, 87, 106,

107, 135, 234-244, 261-262, 330-334, 462-463, 469, 484, 499,

504, 511-514, 586, 611-612, 795, 823-842, 875-881, 897-904, 993,

1836, 2744, 4033-4034, 4383-4386, 4698-4721; G. Ex. 19, 29,

49, 68, 71, 83, 97, 171, 179.)

a MET! Le Os Teen aS I I ARE lh RB Bad EET AE AE AEA OO as Ange EY Ne Ty IY erty A Nt —— owe

46a

Findings of Fact and Conclusions of Law

9. The substantial evidence of record establishes that

persons have consumed meprobamate in amounts sufficient

to cause chronic intoxication. Consumption by individuals

of meprobamate in this manner is generally characterized

by:

a. Staggering gait, slurred speech, and incoordination

as well as temporary loss of memory and dulling of mental

capacities. (TR. 504-514, 823-841, 875-881; G. Ex. 29, 49,

78, 83, 171.)

b. Ingestion of the drug in daily dosages in excess of

those recommended for therapeutic use and varying gener-

ally between 8 and 50 400-milligram tablets daily. (TR. 504

514, 741-780, 823-841, 875-881; G. Ex. 29, 49, 52A; 74, 77,

79.)

e. A gradual elevation by individuals of their drug

intake from prescribed dosage levels to levels which cause

intoxication. (TR. 234-248, 260-262, 311-316, 504-514, 747,

798, 817-844; G. Ex. 29, 178, 179, 186.)

10. The substantial evidence of record shows that the

chronic ingestion of meprobamate at intoxicating dosage

levels deprives individuals of the ability to properly operate

motor vehicles and to prevent injury to themselves and

others. TR. 190-194, 248, 504-508; G. Ex. 18, 163.)

11. The substantial evidence of record shows that the

chronic ingestion of meprobamate at intoxicating dosage

levels causes personality changes in the users manifested

by anger, antagonism, irrational behavior, and antisocial

conduct. Such ingestion of this drug has led to the com-

mission of crimes, neglect of children, and deterioration of

marital and family relationships. (TR. 246, 509-510, 767,

SESSMENT LORE NIE Ot PRE CORED TET,

47a

Findings of Fact and Conclusions of Law

1127-1147, 1334-1363, 1364-1390, 1390-1402; G. Ex. 29, 49,

54, 50, 58, 68, 73, 77, 79, 163.)

12. The substantial evidence of record shows that in-

dividuals consume meprobamate in intoxicating doses in

order to achieve a mental condition that has been described

as pleasurable and to achieve a feeling or sense of intoxica-

tion or well-being. This condition simulates intoxication

caused by the ingestion of excessive amounts of alcohol or

barbiturates. A significant number of individuals who

have a propensity for becoming dependent on certain types

of drugs, have found that they can take meprobamate in in-

creasing doses and obtain somewhat the same effect that

they get from alcohol or barbiturates. The most prominent

group of such individuals are alcoholics. It has been ob-

served by qualified and reliable experts in the field of

alcoholism treatment that alcoholic patients have a partic-

ular liking for meprobamate and have repeatedly asked

for this drug at more frequent intervals than for other

drugs.

Because of these factors, alcoholics tend to become de-

pendent on and to abuse meprobamate. Meprobamate pre-

sents special problems for the alcoholic population of this

country, which has been estimated to number approximately

6 million. One conservative estimate is that four out of

every 100 alcoholics to whom meprobamate is administered

develop problems with meprobamate by taking to the point

of intoxication more than prescribed. The potentiality for

significant abuse presented by these reliable estimates is

obvious. (TR. 35-38, 195-197, 234-248, 260-262, 288-289, 296-

297, 311-316, 323-334, 488-519, 525-564, 559, 762, 1334-1350,

1523-1548; G. Ex. 20, 79, 171, 178, 179.)

IEE) OER OLE INE PLO ATE BNI GEE ANGLE DS a EE DROID AOI REL ILO EPR, LSE BIE AED GONE oe PI MD

48a

Findings of Fact and Conclusions of Law

13. Clinical experience shows that the prolonged uge

of meprobamate, even at therapeutic dose levels, causes or

aggravates depressive states in certain individuals suffer.

ing from neurotic disorders. Persons who have chronically

ingested meprobamate report that the psychological] ef.

fect of the drug upon them was an aggravation of a feel.

ing of depression to the point of suicidal thoughts and sui-

cidal attempts. Medical experts are of the opinion that

meprobamate and other tranquilizing drugs of similar types

have a pharmacological effect which may either cause

depression or aggravate a preexisting, underlying depres.

sive state that may lead to suicide. (TH. 238-249, 1422.

1435, 1453-1455, 2765, 2786, 3370, 3594; G. Ex. 63, 79, 8,

110, 111.)

14. The substantial evidence of record conclusively es

tablishes that a significant number of individuals have used

meprobamate as an ingestant either alone or in combina-

tion with other depressant drugs, for the purpose of com-

mitting suicide. (TR. 661-699, 1163-1164, 1427, 1430-1456,

2124, 2727-2729, 3114-3115, 3885-3886, 4632-4639; G. Ex. 30-

42, 44-47, 86-88, 90, 94, 97, 112, 117, 119, 122, 126, 129, 163,

182.)

15. The substantial evidence of record conclusively

establishes that meprobamate either alone or in combina-

tion with other depressant drugs has been used by a sig-

nificant number of individuals in suicidal attempts. (TR.

214-216, 363-366, 2124, 3114-3115; G. Ex. 8, 55, 68, 71, 87-89,

91, 92, 94, 104, 106, 108, 110, 111, 164, 166, 188, 192, 194,

195, 198, 199.)

16. The sociological reasons why meprobamate has

been used in the past by a significant number of individuals

nan aetna ee eee eee Oa rmmarer Prmovy

49a

Findings of Fact and Conclusions of Law

in successful and unsuccessful suicidal attempts were, in

part at least, explained by an expert in the field of public

health and preventive medicine. This expert has studied

extensively and written on the phenomena of suicide both

in this country and many foreign lands.

There are three major sociological or cultural factors

that operate in determining the manner and means used by

individuals in suicidal gestures. These are the gross avail-

ability, accessibility and fashionability of agents used to

commit suicide. Gross availability was explained to mean

the presence of the agent in an individual’s environment;

for example, firearms are grossly available in the United

States but not so available in other foreign countries, such

as England. Accessibility was defined to mean the degree

of ease by which individuals can obtain any given agent

which is grossly available. Fashionability was defined as

the popularity of any given agent as a suicidal agent which

is determined in part by the frequency that an agent is

used by society’s ostensible leaders and the publicity ac-

corded the suicides of such individuals. As far as phar-

maceutical suicidal agents are concerned, factors such as

frequency that a drug is prescribed, the length of time that

a drug has been available, and the practice of pharmacists

in making the drug available, as well as the knowledge

of the lay population of these factors, exert influences on

the frequency that a pharmaceutical agent is used in sui-

cidal gestures.

The evidence of record clearly establishes that for the

past decade in the United States meprobamate has been

manufactured and distributed in large quantities; the re-

spondent’s estimate is approximately 14 billion tablets.

Thus mepromabate has been grossly available. In addi-

tion, this drug has been widely prescribed during this time;

50a

Findings of Fact and Conclusions of Law

the respondent estimates that approximately 500 million

prescriptions have been written for meprobamate. Fur-

ther, meprobamate has to a significant extent been pre-

scribed and dispensed with considerable laxity in the past

(see Findings Nos. 18, 19, and 21). Meprobamate thus has

been accessible. Its use as a suicidal agent has also received

publicity, and its use as such an agent is thus known to the

lay population.

Based upon the above considerations, as well as -past

studies of suicidal agents of the ingestant class, this ex-

pert made an authoritative prediction, which is reasonable

and merits weight in this matter that meprobamate will

be used more frequently in the future as a suicidal agent

than it has been in the past. This prediction is based in

major part on the past history of other pharmaceutical

agents, notably the barbiturates. The longer these agents

were on the market (grossly available), and the more

accessible they became to potential suicidal individuals

through lax dispensing and prescribing practices (acces-

sibility), and the more the lay population learned of the

use of these agents in suicidal gestures through the pub-

licity afforded such cases (fashionability), the more such

agents have been used in suicidal gestures.

It is reasonable to expect that meprobamate will have

somewhat the same history as these other agents, notably

the barbiturates, unless it is placed under the same controls.

Although the barbiturates in the past have been the drugs

most frequently used as suicidal ingestants, tranquilizing

drugs are being used with increasing frequency and, among

the latter, meprobamate is the drug most frequently used

by suicide-prone individuals. (TR. 410-453, 712-713; G.

Ex. 44, 55, 71, 83, 145, 165, 177, 202.)

Aa I See * ee OSPR 2-2 MALT We SALE PLO VE LAE DIMES LNT ERE MNO AS TOTNES ANTI ETE N AI MRE IMIS

Se ie ae ae ead 2

x

dla

Findings of Fact and Conclusions of Law

17. The second criterion contained in the regulations

promulgated under the amendments to be used to deter-

mine whether a substance has a potential for abuse because

of its depressant effect on the central nervous system states,

in substance, that a drug may have a potential for abuse

if there is significant diversion of the drug from legitimate

drug channels (see Finding No. 7).

Included within the term “diversion” are sales of a drug

outside legitimate channels by manufacturers, wholesalers,

or retail pharmacies. Thus, the sale of meprobamate by a

retail pharmacy without the required prescription and not

in complete conformity with the law regulating the sale

of drugs restricted to sale only upon prescription (21 U.S.C.

353(b)) constitutes diversion of this drug from legitimate

drug channels because such sales are contrary to law and

are illegitimate. (G. Ex. 2, p. 2; 21 U.S.C. 331(k), 353(b).)

18. The substantial evidence of record conclusively

proves that there has been significant diversion of

meprobamate from legitimate drug channels. Substantial

amounts of meprobamate have been sold by retail phar-

macists without proper prescription authorization and not

in conformity with those provisions of law regulating

the sale of prescription drugs. The official files of the

Food and Drug Administration were reviewed for the 10-

year period from 1956 through 1966. The information

contained therein relevant to meprobamate was testified

to by an Administration official and summarized in Gov-

ernment Exhibit No. 202.

During this 10-year period, there were 1,515 prosecu-

tions for illegal sales of prescription drugs terminated by

convictions after initial investigation by the Food and

Drug Administration. Of these cases, 173 involved 797

EUS i ET

52a

Findings of Fact and Conclusions of Law

separate illegitimate sales of meprobamate to individuals,

the sales being made either without any prescription or by

refilling a prescription without proper authorization con-

firmed by a written record of the transaction as required

by law. These illegitimate sales were made at 170 dif-

ferent retail pharmacies throughout the United States, by

two peddlers, and by one medical doctor outside a doctor-

patient relationship.

At 99 of the 170 retail pharmacies, investigators were

permitted to audit the prescription dispensing records re-

quired to be maintained by law (21 U.S.C. 353(b), as well

as invoices reflecting the amounts of prescription drugs re-

ceived at these establishments. These records were audited

for approximately a l-year period prior to the time that

this audit inspection took place. In 71 of the retail phar-

macies, no audit was conducted because permission to

review the necessary records was denied the investigators.

In the 99 drugstores where an audit was conducted, a

comparison of the amounts of meprobamate received at the

stores (as reflected by drug invoice recerds) with the

amounts on hand at the stores and the amounts accounted

for by prescription dispensing records, for the approximate

1-year period, showed that between 22 percent and 100 per-

cent of the meprobamate received by these pharmacies

could not be accounted for. Since meprobamate may be

legitimately dispensed only upon prescription, and since

the law requires the maintenance of records reflecting the

dispensing of prescription drugs, the conclusion follows

that the unaccounted for meprobamate was either sold with-

out proper prescriptions or no recorcs were maintained of

prescription sales as required by law. In either case, the

sales were illegitimate and represented a diversion of

meprobamate from legitimate drug channels.

call REINS SER LA AES AARON LE ATE SAREE ITT Dm NIRS

oes

53a

Findings of Fact and Conclusions of Law

An average of 77 percent of the total amount of mepro-

bamate received by these 99 pharmacies could not be ac-

counted for. This 77-percent-average shortage represents

over 796,000 tablets of meprobamate. The significance of

this shortage is apparent when it is recalled that these

audits covered approximately a 1-year period in but 99

retail pharmacies in this country.

Of these unaccounted for drugs, 54,128 meprobamate

tablets were purchased by agents of the Food and Drug

Administration, posing as ordinary drugstore customers,

either without any prescription or by having a prescrip-

tion illegally refilled. (TR. 1180-1333; G. Ex. 202.)

19. There is substantial evidence of record that some

pharmacists have dispensed meprobamate on the basis of

invalid prescriptions, or without any prescription at all.

(TR. 510-511, 515, 525-564, 823-841, 1127-1161; G. Ex. 54,

135, 137, 138, 165, 180, 181.)

90. Thera is substantial evidence of record that there

are so-called black market sources for meprobamate. These

sources, which are not legitimate distributors, are utilized

by individuals who have become dependent upon meproba-

mate to obtain supplies adequate to satisfy their needs.

Individuals who report obtaining this drug from these

sources are vague and indefinite about these sources and

no detailed information is available as to the extent or

number of such sources. There is also evidence that

meprobamate has been stolen from hospital supplies for

purposes of resale, and is bought and sold, illegitimately,

by the inmates in penal institutions. (TR. 332-333, 347-

349, 993, 996; G. Ex. 49, 131, 132.)

54a

Findings of Fact and Conclusions of Law

21. The substantial evidence of record shows that a

significant number of individuals have obtained mepro-

bamate in amounts in excess of the amounts prescribed for

them or without the advice of their physician or in amounts

in excess of recommended doses, in the following ways:

a. Through the lax prescribing practices of some phy-

sicians in issuing prescriptions which may be refilled for

indefinite time periods at the option of the patient and be-

cause of the lack of supervision of patients by some physi-

cians. (TR. 509-518, 525-549, 794, 904-907, 994, 1334-1350,

1364-1384, 1404-1421; G. Ex. 44, 55, 71, 83, 165.)

b. By having refilled prescriptions marked “Ad Lib.”

(Ad Libitum—the amount desired) and “p.r.n.” (pro re

nata—as circumstances may require) with greater fre-

quency than is consistent with the use of the drug at ree-

ommended dosages. (TR. 197-202, 518, 525-549, 904, 1407-

1408, 1416; G. Ex. 180, 181.)

ce. By establishing a chain or series of drugstores which

will sell them the drug. This is accomplished by taking

a prescription to one drugstore, having it filled at this store,

and then going to a series of other drugstores and asking

each successive store to sell meprobamate to them. These

additional drugstores are referred to the original store to

verify that a prescription has -been filed at that store.

These successive stores then sell the drug based on the

prescription filed at the original store. (TR. 525-549; G.

Ex. 21, 29, 55, 180, 181.)

d. By obtaining a number of concurrent prescriptions

for meprobamate from several physicians. (TR. 190-194,

245, 514, 518, 766, 875-881, 943, 967; G. Ex. 29, 77, 79.)

55a

Findings of Fact and Conclusions of Law

e. By obtaining meprobamate from friends or relatives

for whom it had been prescribed. (TR. 190-194, 942-943,

1528-1530; G. Ex. 54.)

f. Through theft of the drug and by forging prescrip-

tions for it. (TR. 511, 3006-3007; G. Ex. 58, 67, 68.)

22. The substantial evidence shows that meprobamate

has been found in human subjects at autopsy by reliable

toxicological examination and that routine, official in-

vestigation could not establish that the drug was taken

upon the recommendation of a medical practitioner. The

evidence further shows that pharmacists are frequently

requested to sell meprobamate without any prescription,

and indiviuals have offered to pay physicians for prescrip-

tions for meprobamate without any bona fide doctor-patient

relationship being established. Patients admitted to hos-

pitals with meprobamate in their possession have refused

to reveal their source for this drug. (TR. 661-710, 716-732,

965-967, 1409-1410, 1416, 1419; G, Ex. 84, 182.)

23. The substantial evidence of record conclusively es-

tablishes that a significant number of individuals have

taken meprobamate on their own initiative rather than on

the basis of medical advice from a practitioner licensed by

law to administer this drug in the course of his professional

practice. Thus, the evidence of record complies with the

third criterion set forth in the regulations promulgated

under the Amendments (see Finding No. 7). Although the

exact number of individuals who have abused meprobamate

is not known, nor can this number be reasonably ascertained

with any degree of reliability for the reasons more fully

set forth in Finding No. 27, the number of suicides, at-

tempted suicides, and overdoses of meprobamate reflected

in the reliable evidence of record is significant.

|

ROT MP Ee ep ee

CPR

A

ee ae

CR ORRIN THOME RA Yr torn

a ee ee ae - ae ewes ee ~ « a me

56a

Findings of Fact and Conclusions of Law

An official of the Food and Drug Administration ap-

peared and testified concerning Government Exhibit No.

87. This exhibit is a compilation of data contained in tie

official files of the Administration. This data includes

photographic reproductions of death certificates submitted

by the Departments of Health for 34 States, plus reports

from approximately 350 of the 500 Poison Control Centers

in the United States. The data summarized in Government

Exhibit No. 87 shows that for a period of approximately

2 years (1964-65), meprobamate was found to be the exclu- )

sive or contributing cause of death in 92 suicides and 784

attempted suicides or accidental overdosages.

In addition, the testimony of the chief toxicologist for

only one major city in the United States, Philadelphia,

when studied in relation to Government Exhibit No. 182,

a compilation of data contained in the official files of that

city’s Department of Health, reflects that for approxi-

mately a 4-year period meprobamate contributed to or was

the exclusive cause of death in 37 suicides, plus 4 additional

deaths that apparently were suicides but which may have

been accidental deaths due to overdosage of drugs includ-

ing meprobamate. Further, Government Exhibits Nos. 31-

42, consisting of copies of the coroner’s verdict for Cuya-

hoga County in Ohio for a 4-year period, reflect an addi-

tional 12 cases of suicides caused by the acute intoxica-

tion of the deceased by meprobamate alone or in combina-

tion with other drugs.

The testimony of these witnesses, together with the

exhibits referred to above, when coupled with the testimony

of individuals who have become physically dependent upon

meprobamate, and the expert opinions and factual testi-

mony of the Government’s medical witnesses, establishes

beyond any doubt that meprobamate has been abused in the

ee Oe EF ARP EE FOL,

BLEED THROUGH POOR COPY

—_—

57a

Findings of Fact and Conclusions of Law

past by a significant number of individuals in that they

have taken this drug on their own initiative and contrary

to medical advice, to their own detriment to the point of

death. (TR. 661-732, 1162-1178, 1334-1389, 1390-1402, 3950-

4102, 4256-4444, 4449-4595; G. Ex. 87, 182 (see also G. Ex.

30-42, 44-47, 8, 55, 68, 71, 86, 88, 89-91, 104, 106, 108, 112,

117, 119, 122, 126, 129, 163, 164.)

24. The evidence of record reflects the testimony of

medical experts that drugs which depress the activity of

the central nervous system when administered over long

periods of time may cause certain neuronal systems to

adapt their activity to the effect of the drug so that upon

abrupt withdrawal of the drug, clinically observable signs

and symptoms may result that are associated with acute

psychological and physical discomfort or death. This

phenomenon, known as an abstinence reaction or with-

drawal syndrome, is a sign of a tolerance being established

in the body to the drug and is indicative of physical de-

pendence upon the drug. Individuals are motivated to in-

gest drugs in increasingly larger amounts, upon their own

initiative or without medical supervision, in order to avoid

experiencing this withdrawal syndrome.

Physical dependence is the result of the chronic inges-

tion of a drug at sufficiently high dosage levels, and in the

case of meprobamate, does not generally manifest itself

until after prolonged ingestion in man of daily dosages

exceeding eight 400-milligram tablets, although occurrences

of withdrawal symptoms at lesser dose levels have been

observed. Due to individual variation in convulsion thresh-

old levels, differences in personality structures, metabolic

rates and capacities, and other physiological differences,

no physically dependent person may display the entire spec-

58a

Findings of Fact and Conclusions of Law

trum of withdrawal symptoms upon the abrupt withdrawal

of meprobamate. However, the sudden withdrawal of this

drug after chronic ingestion at the dosages noted above

is generally characterized in cases of mild physical depend-

ence by insomnia, vomiting, tremors, muscle twitching,

anxiety, weakness, nausea, headache, hyperpyrexia, ano-

rexia, and ataxia. In cases of moderate physical depend-

ence, the withdrawal symptoms include also hallucinations,

delusions, and severe depression. The severe form of

withdrawal symptoms additionally include convulsions and

in rare instances death. (TR. 34-51, 312, 314, 478-482, 585-

605, 796, 917-918, 3370, 3379, 3380, 4690, 4696-4698, 4701-

4702, 4704-4706; G. Ex. 12, 19, 20, 24, 28, 29, 131, 133, 150,

162, 200, 201.)

25. The substantial evidence of record shows that in-

dividuals who have ingested meprobamate over prolonged

periods of time upon their own initiative, or who have

on their own initiative increased their dosage of meproba-

mate to levels in excess of those normally prescribed and

recommended, have upon abstinence from the drug suf-

fered the following withdrawal symptoms: Electro-

encephalographic changes similar to those observed in

barbiturate withdrawal, headaches, insomnia, nervousness

and anxiety, agitation and restlessness, sweating, ataxia,

nausea, excess salivation and confusion, delirium, delu-

sions and hallucinations, hyperpyrexia, convulsions, and

death. (TR. 186-187, 493-494, 508-519, 525-549, 575-587,

823-841, 875-881, 1127-1138, 1334-1350, 1390-1398, 1426, 2397,

4758; G. Ex. 16, 17, 21, 23, 28, 29, 63, 81, 82, 84, 94, 150, 166,

171, 185, 186, 193, 204.)

26. The substantial evidence of record shows that some

individuals who are abusing barbiturates or alcohol also

59a

Findings of Fact and Conclusions of Law

concurrently abuse meprobamate, or if their drug of choice

becomes unavailable, will turn to meprobamate. The

abusive use of meprobamate results from the interaction

of two factors, the pharmacological action of the drug and

the psychologica] makeup of the individual. Dependency-

prone individuals having immature, neurotic, or inadequate,

dependent-type personalities, especially those with a his-

tory of dependency upon other drugs, are particularly liable

to become dependent upon meprobamate. Thus, alcoholics

are particularly susceptible to dependency upon and abusive

use of meprobamate.

The likelihood of the cross-substitution of drugs having

similar clinical and pharmacological effects may be deter-

mined with a reasonable degree of accuracy on the basis

of similarity of withdrawal symptoms and the ability of

one drug to suppress the withdrawal symptoms caused by

the abrupt withdrawal of another. The substantial evi-

dence of record shows that intoxication caused by meproba-

mate is clinically and, except for minor differences, neuro-

physiologically indistinguishable from intoxication caused

by alcohol or barbiturates.

The withdrawal symptoms associated with meproba-

mate are similar to those associated with drugs causing

a barbiturate and alcohol-type physical dependence; such

as, the barbiturates, ethyl alcohol, chloralhydrate, paral-

dehyde, and glutethimide.

It has been demonstrated that barbiturates, if iia

istered in appropriate doses, will completely relieve the

withdrawal symptoms caused by the abrupt cessation of

meprobamate ingestion and that meprobamate will suppress

the withdrawal symptoms caused by the cessation of ex-

cessive alcohol ingestion.

OLLI IIEE LE SLE CELL E, PLE LILLARD RL SE ERS RL NRRL S PAB EH a

* SNSIN IE BES Ta PRUE FAP PP es od

oe |

60a

Findings of Fact and Conclusions of Law

There is, therefore, the reasonable likelihood that when

drugs of the barbiturate-alcohol type become less accessible

because of more strict control of their distribution under the

Amendments, individuals who have abused this type of drug

will substitute meprobamate in their nontherapeutic, abu.

sive drug practices. (TR. 38, 47, 49, 79-81, 86-87, 195-197,

210, 238-243, 312-313, 330-331, 461-465, 467-468, 473-475,

478-482, 508, 515, 583, 585-586, 590-595, 599-605, 796, 851,

854-855, 918-921, 933-947, 989, 1527-1548, 4690-4695, 4697,

4703-4705, 4724-4725, 4758; G. Ex. 1, 16, 23, 28, 29, 65, 78,

84, 131, 132, 133, 145, 150, 162, 171.)

27. There are at the present time no reliable statistics

which indicate with certainty the precise extent to which

meprobamate has been or is currently being abused. Hos-

pital records are customarily coded, for purposes of index-

ing and information retrieval, by discharge diagnoses,

not admission diagnoses. In many cases of admission for

drug overdose or drug dependence, the discharge diagnosis

will show the underlying psychiatric disorder that gave rise

to the individual’s suicide attempt or chronic use of drugs,

but not the drug abuse which led to admission. There are

no accurate statistics showing the extent to which meproba-

mate is used in suicidal attempts, successful or unsuccessful,

on either the local, State, or national level. Death certif-

cates, one possible source of such statistics, are issued in

many cases immediately after death in order to permit

burial of the deceased, but prior to toxicological examina-

tion that would reveal the presence of exogenous agents

in the vital organs of the deceased. No consistent practice

is followed in amending such records where exogenous

agents are found upon examination. Thus, the statistics

of State bureaus of vital statistics, based upon such death

BLEED THROUGH POOR COPY

6la

Findings of Fact and Conclusions of Law

certificates, do not reveal the presence of such agents in a

large number of cases. National vitei statistics, having as

their source the State statistics, are equally inadequate.

The lack of trained and experienced personnel, adequate

funds, and adequate coding and indexing systems, in the

nation’s hospitals, bureaus of vital statistics, health depart-

ments, and other public and private institutions all con-

tribute to the lack of accurate statistics concerning me-

probamate abuse. The statistics that are available grossly

understate the frequency with which meprobamate has actu-

ally been abused. (TR. 360-369, 383-388, 404-409, 434-435,

608-610, 632-633, 777, 797, 941-942, 958-959, 1428-1430, 1709,

1711-1712, 2771, 2972-2973, 3661-3665, 3671, 3683, 3696,

3709, 3718-3720, 3733, 3744-3747, 3942-3953, 3958-3959, 3968,

3989, 3991, 4059, 4272, 4294-4297, 4367-4375, 4398-4399, 4425-

4429, 4441, 4450, 4459; G. Ex. 62 pp. 54-56.)

98. The substantial evidence of record establishes that

meprobamate has a potential for abuse, as manifested in

the ways set forth in findings 8 through 27 above, because

of its depressant effect on the central nervous system.

Many of these abuses of meprobamate result from the

phenomenon of tolerance to the drug and the phenomenon

of withdrawal reactions upon discontinuance after long-

continued or excess use. These phenomena of tolerance and

withdrawal reactions are a result of meprobamate’s cen-

tral nervous system depressant effect. Other abuses of

meprobamate stem from its euphoric effect which is a

function of meprobamate’s central nervous system de-

pressant effect. In short, meprobamate’s potential for

abuse results from its effect of depression on the central

nervous system. (TR. 21, 49, 81, 98, 334, 402-463, 478,

3359-3360, 3425-3426, 4698-4709.)

PESe LRA ORT A Pat nie al iid _ |

ALTRI IIS DER OLN PSOE AE I: TO

62a

Findings of Fact and Conclusions of Law

29. A large part of the evidence adduced by the re.

spondent consisted of the testimony of various physicians

to the effect that they had prescribed meprobamate for

their patients over varying periods of time and had seen

no cases or at most only an occasional case of individuals

abusing meprobamate. This evidence does not rebut the

evidence introduced by the Government proving the abuse

potential of meprobamate within the meaning of the amend-

ments. The doctors appearing on behalf of the respondent

were administering meprobamate generally at therapeutic

dosage levels not in excess of recommended doses and

were closely supervising the drug therapy of their patients,

Patients under such close medical supervision do not usu-

ally abuse meprobamate. In addition, some physicians ap-

pearing as witnesses for the respondent were involved

in various specialties of medicine in which meprobamate

abuse is rarely if ever seen; such as, cardiology, general

surgery, obstetrics, gynecology, endocrinology, gerontology,

gastroenterology, otorhinolaryngology, and allergy.

Such evidence tends to confirm the following estimation

set forth in the Final Report of the President’s Advisory

Commission on Narcotic and Drug Abuse of 1963: “Drug

abuse is not a uniform problem throughout the country, and

even in the areas of the highest incidence few medical

practitioners come into contact with the afflicted. It is

estimated that most medical practitioners never see a

habitual drug abuser” (G. Ex. 1, p. 57). (TR. 1934-1944,

1960-1970, 2339-2346, 3182-3187, 3361, 3429-3433, 3515-3523,

3606-3620.)

30. The legislative history of the amendments reflects

the expectation of Congress, in enacting this legislation,

that meprobamate and similar tranquilizing drugs would be

BLEED THROUGH POOR COPY

eel, in saint — ee

oo

63a

Findings of Fact and Conclusions of Law |

expeditiously brought under the control of the amendments

because of their potential for abuse. Testimony taken be-

fore the House Committee on Interstate and Foreign Com-

merce demonstrated the need for bringing meprobamate

under these controls. This Committee considered the ad-

visability of listing meprobamate, among others, by name,

but decided not to single out this or any other drug. The

Committee, however, stated that it expected the Secretary

of Health, Education, and Welfare to take early action with

respect to the consideration of bringing meprobamate and

other drugs within the controls of the amendments. A simi-

lar expectation was expressed by the Senate Committee on

Labor and Public Welfare. (G. Ex. 62, pp. 24, 26, 33-36, 49-

51, 54, 93, 102-103; 115; G. Ex. 2, p. 13; G. Ex. 3, pp. 2 and 3.)

Conclusions. 1. The Drug Abuse Control Amendments of

1965 are intended to protect the public health and safety by

establishing special controls for depressant and stimulant

drugs. This protection is to be accomplished through in-

creased recordkeeping and inspection requirements, through

providing for control over intrastate traffic in these drugs

because of its effect on interstate traffic, and through mak-

ing possession of these drugs (other than by the user) il-

legal outside the legitimate channels of commerce. The

authority of the Department of Health, Education, and

Welfare over counterfeit drugs also is increased by the

amendments. ;

2. Meprobamate is a drug with a depressant effect on

the central nervous system and may be legitimately dis-

pensed only upon the prescription of a practitioner licensed

by law to administer such drugs, and in full conformity

with section 503(b) of the Federal Food, Drug, and Cos-

metic Act (21 U.S.C. 353(b)).

RE DIY Rare TA

64a

Findings of Fact and Conclusions of Law

3. The substantial, probative, and reliable evidence of

record establishes that meprobamate, in the past, due to

its depressant effect on the central nervous system, has

been abused in the following ways:

a. There has been significant use of meprobamate in

amounts sufficient to create a hazard to the health of the

individual and to the safety of other individuals and the

community.

b. There has been significant diversion of meprobamate

from legitimate drug channels.

ce. There has been significant use of meprobamate by

individuals on their own initiative rather than on the basis

of medical advice from a practitioner licensed by law

to administer such drugs in the course of his professional

practice.

4. Due to the history of the abuse of meprobamate and

because meprobamate has the capacity to substitute for

other drugs known to be abused, which are now subject to

the increased controls of the amendments, it is reasonable

to conclude that the abuse of meprobamate will continue

and increase unless this drug is similarly brought under

the controls of the amendments.

5. Meprobamate is a drug which because of its de.

pressant effect on the central nervous system has a substan-

tial potential for significant abuse within the meaning of

the amendments (21 U.S.C. 321(v)(3)).

6. Meprobamate is a “depressant or stimulant drug”

as defined in the amendments (21 U.S.C. 321(v)), and is

therefore subject to control under the amendments (21

ee

—~

65a

Findings of Fact and Conclusions of Law

U.S.C. (360a). Any drug which contains any quantity of

meprobamate is a “depressant or stimulant drug” as

defined in the amendments (21 U.S.C. 321(v)(3)) and is

also subject to control under the amendments (21 US.C.

360a).

Therefore, It is ordered, That the stay of effectiveness

announced May 17, 1966 (31 F.R. 7174), on the listing

of meprobamate in §166.3(c) (1) as a drug subject to control

under the amendments by the order of March 19, 1966

(31 F.R. 4679), be ended.

Effective date. This order shall become effective 90

days from its date of publication in the Feprrat REGISTER.

(Secs. 201(v), 511, 701, 52 Stat. 1055, as amended, 79

Stat. 227 et seq.; 21 U.S.C. 321(v), 360a, 371)

Dated: November 28, 1967.

James L. Goppagp,

Commissioner of Food and Drugs.

2,

CRE eee eo Tae

ee Gut

SENT REPO Mrs Ream ca gaumtaener cs

RTE FRR TREN WDE SE SAN _

%

66a

APPENDIX D

Decree of the Court of Appeals

(Filed November 25, 1969)

UNITED STATES COURT OF APPEALS

For tHE Fourts Circuit

No. 12,200

CarTer-Wa1ace, Inc.,

Petitioner,

vs.

Joun W. Garpner, Secretary of Health, Education and

Welfare, and James L. Gopparp, Commissioner of Food

and Drugs,

Respondents,

On Petition to Review and Set Aside an Order of the

Commissioner of Food and Drugs.

Tuts Cause came on to be heard on the transcript of the

record from The Commissioner of Food and Drugs, and

was argued by counsel.

On ConsmeraTion WuHEREOF, It is now here ordered,

adjudged and decreed by this Court that the order of the

said The Commissioner of Food and Drugs, in this cause,

be, and the same is hereby, affirmed.

SaMvuet W. PHIurs

SPR =

Ne

)

67a

Decree of the Court of Appeals

FILep

Nov 25 1969

SamMvueEL W. PHILLIPS

CLERK

A True Copy, Teste:

Samuei W. Pururpes, Clerk

By /s/ Jo ANN C. KirKPaTRICK

Deputy Clerk

APPENDIX E

Relevant Statutes and Regulations

The Administrative Procedure Act, 60 Stat. 243 (1946),

5 U.S.C. §551, et seq. (Public Law 89-554, 80 Stat. 378),

provides in pertinent part:

§556. Hearings; presiding employees; powers and duties;

burden of proof; evidence; record as basis of de.

cision

(d) Except as otherwise provided by statute, the pro-

ponent of a rule or order has the burden of proof. Any

oral or documentary evidence may be received, but the

agency as a matter of policy shall provide for the ex-

clusion of irrelevant, immaterial, or unduly repetitious

evidence. A sanction may not be imposed or rule or order

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. A party is entitled to present his case or defense

by oral or documentary evidence, to submit rebuttal evi-

dence, and to conduct such cross-examination as may be

required for a full and true disclosure of the facts.

§702. Right of review

A person suffering legal wrong because of agency action,

or adversely affected or aggrieved by agency action within

the meaning of a relevant statute, is entitled to judicial re-

view thereof, * * *

BLEED THROUGH POOR COPY

Relevant Statutes and Regulations

§704. Actions reviewable

Agency action made reviewable by statute and final

agency action for which there is no other adequate remedy

in a court are subject to judicial review.

§706. Scope of review

To the extent necessary to decision and when presented,

the reviewing court shall decide all relevant questions of

law, interpret constitutional and statutory provisions, and

determine the meaning or applicability of the terms of an

agency action. The reviewing court shall—

(2) hold unlawful and set aside agency action, find-

ings, and conclusions found to be—

(A) arbitrary, capricious, an abuse of discretion,

or otherwise not in accordance with law;

(C) in excess of statutory jurisdiction, author-

ity, or limitations, or short of statutory right;

(D) without observance of procedure required by

law;

(E) unsupported by substantial evidence in a case

subject to sections 556 and 557 of this title or other-

wise reviewed on the record of an agency hearing

provided by statute;

In making the foregoing determinations, the court shall

review the whole record or those parts of it cited by a party,

70a

Relevant Statutes and Kegulations

and due account shall be taken of the rule of prejudicial

aon, ***

The Federal Food, Drug and Cosmetic Act, 52 Stat. 1040

(1938), as amended, 21 U.S.C. $301, et seq., provides in

pertinent part:

Section 201(v), 21 U.S.C. §321(v):

(v) The term “depressant or stimulant drug” means—

(1) any drug which contains any quantity of (A)

barbituric acid or any of the salts of barbituric acid;

or (B) any derivative of barbituric acid which has

been designated by the Secretary under section 352 (d)

of this title as habit forming;

(2) any drug which contains any quantity of (A)

amphetamine or any of its optical isomers; (B) any

salt of amphetamine or any salt of any optical isomer of

amphetamine; or (C) any substance which the Secre-

tary, after investigation, has found to be, and by regu-

lation designated as, habit forming because of its stim-

ulant effect on the central nervous system; or

(3) any drug which contains any quantity of a sub-

stance which the Secretary, after investigation, has

found to have, and by regulation designates as having,

a potential for abuse because of its depressant or

stimulant effect on the central nervous system or its

hallucinogenic effect; except that the Secretary shall

not designate under this paragraph, or under clause

(C) of subparagraph (2), any substance that is now

included, or is hereafter included, within the classifi-

cations stated in section 4731, and marijuana as de-

fined in section 4761, of Title 26.

BLEED THROUGH POOR COPY

ee See ce eS eer er ee et SENN ETOP AR a 2 — a

“hs ala ia BE RAI INE TLRS BEAL EM RS PCOS SMEARS Te LO RTD

Tla

Relevant Statutes and Regulations

The provisions of subsections (e), (f), and (g) of section

371 of this title shall apply to and govern proceedings for

the issuance, amendment, or repeal of regulations under

subparagraph (2) (C) or (3) of this paragraph. * * *

Section 511a, 21 U.S.C. §360a:

Records; inspection: right of agents to enter,

notice, scope, inventory, receipt for samples

taken; exemption of practitioners

(d) (1) Every person engaged in manufacturing, com-

pounding, processing, selling, delivering, or otherwise dis-

posing of any depressant or stimulant drug shall, upon the

effective date of this section, prepare a complete and accu-

rate record of all stocks of each such drug on hand and

shall keep such record for three years. On and after the

effective date of this section, every person manufacturing,

compounding, or processing any depressant or stimulant

drug shall prepare and keep, for not less than three years,

a complete and accurate record of the kind and quantity of

each such drug manufactured, compounded, or processed

and the date of such manufacture, compounding, or process-

ing; and every person selling, delivering, or otherwise

disposing of any depressant or stimulant drug shall prepare

or obtain, and keep for not less than three years, a complete

and accurate record of the kind and quantity of each such

drug received, sold, delivered, or otherwise disposed of,

the name and address of the person, and the registration

number, if any, assigned to such person by the Secretary

pursuant to section 360(e) of this title, from whom it was

received and to whom it was sold, delivered, or otherwise

disposed of, and the date of such transaction. No separate

72a

Relevant Statutes and Regulations

records, nor set form or forms for any of the foreroing

records, shall be required as long as records containing the

required information are available.

(3) The provisions of paragraphs (1) and (2) of this

subsection shall not apply to a licensed practitioner de-

scribed in subsection (a) (4) of this section with respect to

any depressant or stimulant drug received, prepared, proc-

essed, administered, or dispensed by him in the course of

his professional practice, unless such practitioner regularly

engages in dispensing any such drug or drugs to his pa-

tients for which they are charged, either separately or

together with charges for other professional services.

Prescriptions; limitation or refills; renewals

(e) No prescription (issued before or after the effective

date of this section) for any depressant or stimulant drug

may be filled or refilled more than six months after the date

on which such prescription was issued and no such prescrip-

tion which is authorized to be refilled may be refilled more

than five times, except that any prescription for such a drug

after six months after the date of issue or after being re-

filled five times may be renewed by the practitioner issuing

it either in writing, or orally (if promptly reduced to writ-

ing and filed by the pharmacist filling it).

Exemption of certain drugs

(f) (1) The Secretary may by regulation exempt any

depressant or stimulant drug from the application of all or

part of this section when he finds that regulation of its

manufacture, compounding, processing, possession, and dis-

position, as provided in this section or in such part thereof,

is not necessary for the protection of the public health.

=<

Se SERED RINE: OPORTO TLL SRT EDS

BLEED THROUGH POOR COPY ~~

73a

Relevant Statutes and Regulations

(2) The Secretary shall by regulation exempt any de-

pressant or stimulant drug from the application of this

section, if—

* * a

(B) he finds that such drug includes one or more

substances not having a depressant or stimulant effect

on the central nervous system or a hallucinogenic effect

and such substance or substances are present therein

in such combination, quantity, proportion, or concentra-

tion as to prevent the substance or substances therein

which do have such an effect from being ingested or

absorbed in sufficient amounts or concentrations as,

within the meaning of section 321(v) of this title, to—

(i) be habit forming because of their stimulant

effect on the central nervous system, or

(ii) have a potential for abuse because of their

depressant or stimulant effect on the central nervous

system or their hallucinogenic effect.

(g) (1) The Secretary may, from time to time, appoint

a committee of experts to advise him with regard to any of

the following matters involved in determining whether a

regulation under subparagraph (2) (C) or (3) of section

321(v) of this title should be proposed, issued, amended, or

repealed: (A) whether or not the substance involved has a

depressant or stimulant effect on the central nervous system

or a hallucinogenic effect, (B) whether the substance in-

volved has a potential for abuse because of its depressant

or stimulant effect on the central nervous system, and (C)

any other scientifie question (as determined by the Secre-

tary) which is pertinent to the determination of whether

such substance should be designated by the Secretary pur-

74a

Relevant Statutes and Regulations

suant to subparagraph (2) (C) or (3) of section 321(v)

of this title. * * *

Section 701(e), 21 U.S.C. §371(e):

Procedure for establishment

(e) (1) Any action for the issuance, amendment, or

repeal of any regulation under section 341, .343(j), 344(a),

346, 351(b), or 352(d) or (h), of this title shall be begun

by a proposal made (A) by the Secretary on his own initia-

tive, or (B) by petition of any interested person, showing

reasonable grounds therefor, filed with the Secretary. The

Secretary shall publish such proposal and shall afford all

interested persons an opportunity to present their views

thereon, orally or in writing. As soon as practicable there-

after, the Secretary shall by order act upon such proposal

and shali make such order public. Except as provided in

paragraph (2) of this subsection, the order shall become

effective at such time as may be specified therein, but not

prior to the day following the last day on which objections

may be filed under such paragraph.

(2) On or before the thirtieth day after the date on

which an order entered under paragraph (1) of this sub-

section is made public, any person who will be adversely

affected by such order if placed in effect may file objections

thereto with the Secretary, specifying with particularity

the provisions of the order deemed objectionable, stating

the grounds therefor, and requesting a public hearing upon

such objections, * * *

(3) As soon as practicable after such request for a pub-

lic hearing, the Secretary, after due notice, shall hold such

a public hearing for the purpose of receiving evidence rele-

BLEED THROUGH POOR COPY

eee REELS LEO IIV ENN DCA ONE OSE SD CPLA EPO lS YA i TEINS LIED REI AS RCE MEN ED EAA § BLOG EIB P EARNERS OCR AOE

75a

Relevant Statutes and Regulations

vant and material to the issues raised by such objections.

At the hearing, any interested person may be heard in

person or by representative. As soon as practicable after

completion of the hearing, the Secretary shall by order act

upon such objections and make such order public. Such

order shall be based only on substantial evidence of record

at such hearing and shall set forth, as part of the order,

detailed findings of fact on which the order is based. The

Secretary shall specify in the order the date on which it

shall take effect, except that it shall not be made to take

effect prior to the ninetieth day after its publication unless

the Secretary finds that emergency conditions exist neces-

sitating an earlier effective date, in which event the Secre-

tary shall specify in the order his findings as to such con-

ditions. * * *

Section 701(f), 21 U.S.C. §371(f):

Review of order

(f) (1) In a case of actual controversy as to the validity

of any order under subsection (e) of this section, any per-

son who will be adversely affected by such order if placed

in effect may at any time prior to the ninetieth day after

such order is issued file a petition with the United States

court of appeal for the circuit wherein such person resides

or has his principal place of business, for a judicial review

of such order. A copy of the petition shall be forthwith

transmitted by the clerk of the court to the Secretary or

other officer designated by him for that purpose. The

Secretary thereupon shall file in the court the record of the

proceedings on which the Secretary based his order, as

provided in section 2112 of Title 28. * * *

(3) Upon the filing of the petition referred to in para-

graph (1) of this subsection, the court shall have jurisdic-

6

ARG IT NSS PUA BR,

76a

Relevant Statutes and Regulations

tion to affirm the order, or to set it aside in whole’ or in

part, temporarily or permanently. If the order of the

Secretary refuses to issue, amend, or repeal a regulation

and such order is not in accordance with law the court shall

by its judgment order the Secretary to take action, with

respect to such regulation, in accordance with law. The

findings of the Secretary as to the facts, if supported by

substantial evidence, shall be conclusive.

(4) The judgment of the court affirming or setting aside,

in whole or in part, any such order of the Secretary shall

be final, subject to review by the Supreme Court of the

United States upon certiorari or certification as provided

in sections 346 and 347 of Title 28.

(5) Any action instituted under this subsection shall

survive notwithstanding any change in the person occupy-

ing the office of Secretary or any vacancy in such office.

Part 166—Depressant anD St1imuLant Drugs; DEFINITIONS,

ProcepuRAL AND INTERPRETATIVE Recuuations (31 F.R.

1071)

Regulations Implementing Drug Abuse Control Amend-

ments of 1965

In the matter of promulgating regulations to implement

the provisions of the Drug Abuse Control Amendments of

1965:

Having considered the comments and suggestions filed

in response to the notice of proposed rule making in the

above-identified matter published in the FrprraL RecIsTer

of December 18, 1965 (30 F.R. 15667), the Commissioner of

Food and Drugs has concluded that the regulations should

BLEED THROUGH POOR COPY

7"

77a

Relevant Statutes and Regulations

be issued as set forth below incorporating suggestions in

whole or in part. Changes have been made in §§166.1(i),

166.2(e), 166.3, 166.5, 166.16(b), and 166.17.

Therefore, pursuant to the provisions of the Federal

Food, Drug, and Cosmetic Act (secs. 201(v), 511, 701, 52

Stat. 1055, as amended, 79 Stat. 227 et seq.; 21 U.S.C. 321

(v), 360a, 371), and under the authority delegated to the

Commissioner by the Secretary of Health, Education, and

Welfare (21 CFR 2.90), Part 166 is amended by adding

thereto new sections as follows:

(e) The Commissioner may determine that a substance

has a potential for abuse because of its depressant or stimu-

lant effect on the central nervous system or its hallucino-

genic effect if:

(1) There is evidence that individuals are taking the

drug or drugs containing such a substance in amounts suffi-

cient to create a hazard to their health or to the safety of

other individuals or of the community; or

(2) There is significant diversion of the drug or drugs

containing such a substance from legitimate drug channels ; f

or

3

:

(3) Individuals are taking the drug or drugs containing

such a substance on their own initiative rather than on the

basis of medical advice from a practitioner licensed by law

to administer such drugs in the course of his professional

practice ; Y

e x *