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Aguidelines for the clinical
evaluation of.
Antiepileptic Drugs
(Adults and Children),

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

> Public Health Service
US. DEPosxToa? Food and Drug Administration

FEB 4l98l

FMGL_

FDA BUREAU OF DRUGS CLINICAL GUIDELINES

(This list is incomplete. Additional Guidelines
' will be published in 1981)

Guidelines May Be Ordered From: Superintendent of Documents, U.S. Government Printing Office,
Washington, D.C. 20402.

FDA 77-3040
FDA 77-3041
FDA 77-3042
FDA 77-3043
FDA 77-3044
FDA 77-3046
FDA 78-3047
FDA 78-3048
FDA 78-3049
FDA 78-3050

FDA 78—3051
FDA 78—3052

FDA 78-3053
FDA 78-3054

FDA 78-3065
FDA 78-3066

FDA 78-3067
FDA 79-3055

FDA 79-3073
FDA 79-3074
FDA 79—3075

FDA 80-3093

FDA 80-30941

FDA 80-3103

FDA 81-3110

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General Considerations for the Clinical Evaluation of Drugs in Infants and Children
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HHS (FDA) 81-31 IO

GUIDELINES FOR THE <SLINICAI. EVALUATION

NTIEPILEPTIC Dimes)
DULTS AND CHILDRE

PRINTED September 1977
REVISED January 1981

This publication may be reproduced and distributed without permission of the Food and
Drug Administration

Comments on the contents of this publication are invited and should be addressed to the
following office:

Group Leader For Neuropharmacologlcal Drugs
Division of Neuropharmacological Drug Products
Bureau of Drugs
Food and Drug Administration
5600 Fishers lane
Rockville, Maryland 20857

 

For sale by the Superintendent oi Documents. 11.8. Government Printing once. Washington. D.C. 20102

ABSTRACT

The Food and Drug Administration, with the assistance of its scientific Advisory
Committees and other outside consultants, the American Academy of Pediatrics'
Committee on Drugs, and consultants to the Pharmaceutical Manufacturers' Association
has developed guidelines for the clinical evaluation of new drugs. These guidelines
present acceptable current approaches to the study of investigational drugs in man, and
pertain to Phases 1 through 111 of the investigation. They represent generally acceptable
principles for arriving at valid conclusions concerning safety and effectiveness of new
drugs, as well as the views of outstanding experts concerning appropriate methods of
study of specific classes of drugs.

The FDA welcomes comments on the guidelines, and expects to keep them current by
review and update at approximately two-year intervals.

 

K 4;; /~".¥’x '17
Asséss

FOREWORD /431
PMBL

The purpose of these guidelines is to present acceptable current approaches to the study
of investigational drugs in man. These guidelines contain both generalities and specifics
and were developed from experience with available drugs. It is anticipated that with the
passage of time these guidelines will require revision. In order to keep them current a
re-review will be performed approximately every 18 to 24 months.

These guidelines are not to be interpreted as mandatory requirements by the FDA to allow
continuation of clinical trials with investigational drugs or to obtain approval of a new
drug for marketing. These guidelines, in part, contain recommendations for clinical
studies which are recognized as desirable approaches to be used in arriving at conclusions
concerning safety and effectiveness of new drugs; and in the other part they consist of the
views of outstanding experts in the field as to what constitutes appropriate methods of
study of specific classes of drugs. In some cases other methods may be equally applicable
or newer methods may be preferable, and for certain entirely new entities it is possible
that the guidelines may be only minimally applicable.

Under FDA regulations (21 CFR 10.90(b)) all clinical guidelines constitute advisory
opinions on an acceptable approach to meeting regulatory requirements, and research
begun in good faith under such guidelines will be acceptable by the Agency for review
purposes unless this guideline (or the relevant portion of it) has been formally rescinded
for valid health reasons. This does not imply that results obtained in studies conducted
under these guidelines will necessarily result in the approval of an application or that the
studies suggested will produce the total clinical information required for approval of a
particular drug.

Many of the clinical guidelines have been developed largely, or entirely, by FDA's
Advisory Committees and consultants. Others were originally developed by intramural
committees and consultants of FDA and of the Pharmaceutical Manufacturers
Association; in these cases the guidelines were reviewed and revised, as appropriate, by
FDA's Advisory Committees.

The general guidelines for the evaluation of drugs in infants and children and most of
those for study of various drug classes in children were developed by the Committee on
Drugs of the American Academy of Pediatrics (AAP). Some of the pediatric guidelines
for specific classes were written by FDA's Advisory Committees. There was cross review
and comment on the pediatric guidelines by both the Committee on Drugs of the AAP and
FDA's Advisory Committees.

The Bureau of Drugs of the FDA wishes to thank the many individuals who devoted so
much time and effort to the development of these guidelines.

3. Richard Crout, M.D. Marion J. Finkel, MD.
Director Associate Director for
Bureau of Drugs New Drug Evaluation

Bureau of Drugs

-fii-

219021

 

 

GUIDELINES FOR THE CLINICAL EVALUATION OF ANTIEPILEPTIC DRUGS
(ADULTS AND CHILDREN)

"General Considerations for the Clinical Evaluation of Drugs" is an important companion
piece and should be reviewed prior to reading these guidelines. It contains suggestions
applicable to most investigational drug studies and enables elimination of repetitious
material in each of the specific guidelines.

ADULT SECTION

I. INTRODUCTION

These guidelines are concerned with drugs used in long-term therapy of seizure disorders.
Evaluation of drugs used in acute situations (e.g., status epilepticus, withdrawal
convulsions, febrile convulsions, etc.) may require modification of these suggestions.

II. EARLY-PHASE I STUDIES

(See "General Considerations for the Clinical Evaluation of Drugs")

A. Investigators

Phase i studies should be performed by investigators skilled in safety evaluations of
new compounds.

B. Subjects and Setting

"Normal" adult male volunteers are suitable subjects. Pretreatment physical,
neurological and laboratory examinations are necessary to ascertain "normality".

Subjects should preferably be in closed environments permitting close observation.
Abstinence from alcohol must be observed for at least two weeks and from other
drugs for a period necessary to prevent carry-over effects. No alcohol or other
drugs should be permitted during the test period.

Subjects with known seizure disorders generally should not be included in
early-Phase I studies. However, if a promising drug with significant potential for
adverse effects is developed, it may be necessary to use highly refractory patients
with frequent seizures and poor prognosis.

C. Observations

Neurological examinations should be performed in addition to the usual clinical and
laboratory observations during the test period.

D. Duration of Treatment
Test drug administration should eventually be extended to a minimum of four weeks.

E. Study Design

Multiple-dose studies should be single-blind and may be double-blind. Placebo
controls are highly desirable to eliminate bias in the reporting of subjective
phenomena.

F. Drug Dynamics

Evidence that the drug is biologically available at the administered dosage must be
presented during Phase I. This may be accomplished by absorption and excretion
studies. (See "General Considerations for Clinical Evaluation of Drugs" for a
detailed discussion.)

(3. Pilot Efficacy Studies

None are recommended.

[11. LATE-PHASE I AND PHASE II STUDIES

A. Objectives

Objectives of the study should be stated clearly.

B. Investigators

Investigators should be physicians experienced in the medical evaluation and
management of epilepsy. They should have appropriate support facilities.

C. Setting

Subjects in late-Phase I and initial-Phase II studies should be hospitalized for a
pretrial period of observation adequate for pharmacological and clinical
stabilization. Further inpatient observation may be necessary for certain patient
populations, drugs or study designs.

In later-Phase Il, outpatient epileptics may be included, allowing observation in
more natural settings and inclusion of patients with varying severities of epilepsy.

D. Patients

Patients with incomplete control of seizure disorders are suitable subjects for
late-Phase I and Phase II testing. Patients failing to respond satisfactorily to
adequate dosages of standard therapy, in whom compliance seemslikely and for
whom adequate plasma drug concentrations of standard therapy have been
documented should be chosen.

Patients well-controlled on current therapy are not suitable subjects for late-Phase I
or Phase II unless experiencing excessive side effects from current medication.

Factors to be considered in patient selection :

1. Classification of seizures according to the International Classification of
Epileptic Seizures (including electroencephalography). Types of seizures to be
studied should be chosen with consideration of animal seizure models in order to
facilitate selection of fairly homogeneous patient populations. Seizures of a
given type may progress to generalized tonic-clonic seizures* and patients with
such seizures may be included.

2. Number of seizure types. Preferably, patients should have only one seizure
type. Those with more than one type generally should be reserved for later
studies. If different seizure types are likely to occur in the studied population,
measurable endpoints should be decided upon prospectively to distinguish
efficacy.

3. Current therapy. Existing therapy preferably should consist of only one drug
(but not more than two) which has remained at constant dosage for several
months. Previously untreated patients with absence seizures may be utilized in
Phase II.

4. Age. Adult subjects are preferable in late-Phase I and early-Phase II testing
unless the seizure type is restricted to the young-age period, e.g., absences,
infantile spasms or atonic seizures (drop attacks, akinetic seizures). Children
with other forms of epilepsy must be selected on the basis of extreme
refractoriness to current medicine or with control obtained only at the cost of
unsatisfactory levels of side effects, with full evaluation of the legal and
ethical implications of such testing.

5. Presence or absence of cerebral lesions. If lesions are present, the type and
natural history should be considered.

*This term is used interchangeably with grand mal seizures throughout these guidelines.

E. Exclusions .

1. Use of drugs (other than concomitant antiepileptic drugs) which would
interfere with safety or efficacy evaluations of the drug under study.

2. Presence of associated disease. Before the drug trial begins, patients should
be examined to rule out treatable causes of seizures. Laboratory tests should
be performed to document the pretreatment status of the subjects. It must be
recognized that in chronically treated seizure patients some of the results may
deviate from accepted normal standards.

F. Observations

Measurements of efficacy should be documented objectively. These may include :
1. Reduced seizure frequency.
2. Increased seizure-free intervals, e.g., time between seizure clusters.

3. Decreased total seizure time. (This parameter has been successfully
determined only in absence.)

4. Improved functional capacity.

5. Decreased incidence of adverse reactions. In patients experiencing adverse
reactions to previous medication, effectiveness of the new agent may be
demonstrated by decreased adverse reactions, even if no improvement in
seizure activity is manifested.

6. Decreased generalization of focal seizures. This parameter has not yet been
used in a quantified fashion, however, such qualitative measures are desirable
supplements to quantitative data.

Particular attention should be given to the method of recording these measures of
efficacy. Pretrial observation of seizure frequency is usually obtained. Length of
this observation depends upon the seizure frequency and the study design. Ideally,
patients with frequent seizures which can be monitored objectively should be
selected. .

In seizure types other than generalized tonic-clonic seizures, newer methods of
quantitation are highly recommended. Telemetry, for example, has revealed
drug-related changes in the frequency of absence seizures far more precisely than
clinical observations or patient reports, permitting more efficient study designs.

Electroencephalography and psychological testing are desirable but not mandatory
unless there are specific indications for performing these tests.

Serum level determinations of the subject's pretest antiepileptic medications are
highly recommended. If the subject continues on pretest antiepileptics, serum level
determinations of these drugs, as well as the test drug, are recommended at least
twice weekly.

The usual "safety" laboratory tests should be performed, viz., hematopoietic
(including platelet estimation), renal, hepatic and any others that may be indicated.
Careful clinical observations should be made, with particular regard to disturbances
of thought processes, gait, speech, coordination, nystagmus and lethargy.

Patients should be evaluated at least weekly during the first four weeks and at least
biweekly for the next eight weeks.

G. Duration of Treatment

After initial Phase II studies have demonstrated relative safety and efficacy, studies
may be extended to a duration of three to six months. Patients need not be
hospitalized, provided close control can be maintained.

H. Study Design

Late-Phase I and initial-Phase II study designs are more rigid than those of
later-Phase II studies.

Pilot or preliminary studies on small numbers of patients need not be blind.
Objectives of preliminary studies must be stated clearly.

Crossover or substitution designs should be reserved for later-Phase II studies by
which time some evidence of drug efficacy in human seizures will have been
obtained. Late-Phase l and initial-Phase II studies generally should consist of
addition of the new drug to existing therapy. Existing therapy should consist of one
drug and not more than two drugs, as noted before, although more flexibility may be
considered in later-Phase II studies.

Later-Phase 11 studies may include withdrawal of existing therapy if satisfactory
control is achieved through addition of the new agent. With crossover or
substitution studies, careful monitoring of serum drug levels and hospitalization or
institutionalization with careful observation are indicated. Adequate safety
precautions must be taken to prevent and immediately treat status epilepticus
should it occur.

in later-Phase II trials, when there is reasonable evidence of efficacy, new patients
may be started on the test drug as the sole medication to determine the effects
when given alone.

If possible, objective evidence of seizure control should be determined in the
presence of estimated therapeutic serum levels. For patients failing to show
evidence of objective improvement in the estimated therapeutic range, dosage may
be increased until the first signs of limiting side effects appear.

If the methods of efficacy evaluation are not subjective or not subject to error in
observation, the test design may be single-blind. Placebo control is usually desirable.

Biostatistical consultation should be obtained from experts familiar with the state
of the art of trial designs for antiepileptic drugs for help in formulation of study
design, determination of adequate sample size, proper grouping of subjects and
analysis of data.

I. Enzyme Induction and Drug Interaction Studies

It is recognized that during late-Phase I and initial-Phase II studies the
investigational drug may be given in combination with other drugs, such as
barbiturates, with the attendant possibilities of enzyme induction, altered
metabolism and antagonism, inhibition or synergism between drugs. The ability to
determine serum levels of the currently utilized antiepileptic drugs makes it
possible to observe potential drug interactions during Phase 11. Therefore, serum
level measurements of the test drug are highly recommended.

IV. PHASE III STUDIES

A. Objectives
Objectives of the study should be stated clearly.

B. Investigators

The investigators should be qualified by training and experience to evaluate
antiepileptic drugs.

C. Setting and Subjects

Ambulatory patients are the usual subjects of Phase III studies, although
institutionalized patients must also be included at some time during this phase.
Hospitalization or adequate observation in institutionalized patients may be required
in withdrawal or substitution studies.

A varied patient population is desirable for Phase III studies for the following
reasons: (I) there are many different types of seizures, 2) many patients have more
than one type of seizure, 3) seizures of a given type may occur in patients of widely
varying demographic and clinical characteristics and 4) a drug may not alleviate all
forms of epilepsy. The investigational drug should be tried in patients with
appropriate seizure types and in patients with more than one seizure type. The drug
should be tested in sufficient numbers of patients with widely varying
characteristics to warrant generalization of results to the population in which the
drug may eventually be used.

Patients well-controlled on current medication should not be subject for Phase III
trials unless experiencing excessive side effects from current medication.

Clinical studies of the test drug's safety and efficacy should ordinarily be
undertaken in children since it is likely that the drug, once marketed, will be used in
children.

Before the drug trial begins, patients must be examined to rule out treatable causes
of seizures. Patients should be classified by all identifiable variables and assigned
randomly, according to the study design. Three important variables should be
considered:

1. Classification of seizure types according to the International Classification
of Epileptic Seizures.

2. Age of patient.

3. Presence or absence of cerebral lesions. If present, type and natural history
of lesion should be considered.

D. Observations

Accuracy of data collection is essential. Every effort should be made to quantify
observations. In, other than generalized tonic-clonic seizures, newer methods of
quantitation are highly recommended. Telemetry, for example, has revealed
drug-related changes in the frequency of absence seizures far more precisely than
clinical observations or patient reports, permitting more efficient study designs.

Serum level determinations of both the investigational and concomitant
antiepileptic drugs are highly recommended at appropriate intervals. Further
information on the therapeutic and toxic ranges of the investigatonal drug should be
obtained. Interactions with commonly used antiepileptic drugs should be studied to
approximate actual conditions of use.

Electroencephalography and psychological testing before and during test drug
administration are suggested if prior studies indicate that EEG's and emotional
factors may be affected by the drug (e.g., psychotropic effects of the drug).

The usual "safety" laboratory tests (hematopoietic, renal and hepatic) and any others
indicated should be performed at appropriate intervals.

E. Duration of Treatment

Some studies may be extended to six months and longer (one year or more) to
evaluate long-term efficacy and safety.

F'. Study Design

A variety of studies should be performed in Phase III, ranging from small,
well-controlled, blinded studies comparing drug efficacies to large, open-label
studies in situations similar to clinical use of antiepileptic drugs.

Evaluation of efficacy in less common seizure patterns may require collaborative
studies in order to obtain significant data.

A variety of experimental designs may be used in Phase III. The following is an
example of a potential study design :

The minimum effective dose of the test drug, as established in Phase II, is
added to existing medications and the dosage is increased sequentially to the
desired seizure-control point or to the point of limitation due to side effects.
The effective dose is continued for the period of the trial. Once the subject is
stabilized, the frequency of seizures during treatment is compared to that of
the pretrial period. After stabilization, withdrawal of pre-existing medication
is attempted and further comparison of seizure frequency control is made.

An adequate number of studies should be controlled. A variety of controls are
available, some of which are described below:

1. Historical control. The results of the new drug are compared with
adequately documented histories of the untreated disease or with previous drug
treatments. Because of the tendency of some patients to respond favorably to
new drugs, the trial period should extend for at least six months and preferably
for one year.

2. Active drug control. For shorter studies, an active drug control may be
used. The effects of the new drug are compared to the effects of another
known drug. The patient should not be able to distinguish between the drugs.
Double-blind methodology should be used. Provisions should be made for
breaking the blind in case of emergencies in which the test drug may play a role.

3. Placebo control. Placebo control is recommended when the test drug is
added to existing therapy.

A well—controlled Phase III study of absence epilepsy or generalized seizures in
institutionalized, brain-damaged patients, uncontrolled by present medication, could
involve crossover or substitution from marketed antiepileptic drugs to the test
drug. Such studies need adequate safeguards to prevent and treat status epilepticus.

Study designs which use placebos as the only medication in patients with a known
seizure disorder are not recommended. Firm justification with specific indications
is required to deprive a subject of all therapy in generalized tonic—clonic seizures.
In some other forms of epilepsy (e.g., massive infantile spasms or absence), placebo
may be justified as the sole source of therapy. Hospitalization is indicated in these
situations.

PEDIATRIC SECTION

("General Considerations for the Clinical Evaluation of Drugs in Infants and Children"
should be reviewed prior to reading this section.)

I. INTRODUCTION

Seizure disorders have certain age-specific phenomena and some types occur exclusively
in children. In addition, an estimated 75 percent of seizure disorders have their onset in
childhood. Since virtually all antiepileptic medications are eventually given to children,
postmarketing studies designed to evaluate effects of the drug on growth and development
of the brain and its cognitive functions should be considered.

II. CLINICAL STUDIES

Children should not be included in clinical trials until late-Phase II or Phase III unless the
seizure type under study is restricted to the young-age period, e.g., absences, infantile
spasmas or akinetic seizures. Even in these cases, safety studies should be performed
first in adults. Children with other forms of epilepsy, considered for inclusion prior to
late-Phase II or Phase III, should be selected on the basis of poor control on current
medication or control obtained only at the cost of unsatisfactory levels of side effects. In
such drug tests, full evaluation of the legal and ethical implications must be made. In
cases where children are to be included in Phase I and early Phase II studies
hospitalization or institutionalization with close and expert supervision is mandatory.

For study designs see the Adult Section of these guidelines. Studies should involve
children and infants of varying ages and seizure types. In addition to safety and efficacy
studies, pharmacokinetic studies should be performed. ’

Studies designed to test rates of learning and performance should also be included. Tests
similar to those indicated in "Guidelines for the Clinical Evaluation of Psychoactive Drugs
in Children" should be used.

Biostatistical consultation is recommended for help in designing efficient studies which
maximize the amount of information obtained from the minimum number of subjects.

a U. S. GOVERNMENT PRINTWG OFFICE: 1981 334-826/7021

 

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HHS Publication No. (FDA) 81-3110

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