Evaluating Drug Effects 
on the Ability to 
Operate a Motor Vehicle 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2017 
Clinical/Medical 
   
Evaluating Drug Effects 
on the Ability to 
Operate a Motor Vehicle 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2017 
Clinical/Medical 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  THE NEED TO EVALUATE DRIVING IMPAIRMENT ........................................... 2 
IV.  TIERED APPROACH TO EVALUATING DRUG EFFECTS ON DRIVING 
ABILITY ............................................................................................................................ 3 
A.  Pharmacology/Toxicology ..............................................................................................................4 
B.  Use of Epidemiological Data ..........................................................................................................4 
C.  Clinical/Behavioral Asessment ......................................................................................................5 
1. Phase 1 Drug Development Trials ...................................................................................................5 
2. Phase 2 and 3 Trials .........................................................................................................................6 
3. Driving Studies .................................................................................................................................7 
4. Randomization ..................................................................................................................................8 
5. Endpoint Analysis .............................................................................................................................9 
6. Exposure-Response Modeling ..........................................................................................................9 
V.  LABELING ....................................................................................................................... 9 
 
 
  Contains Nonbinding Recommendations 
Evaluating Drug Effects on the  
Ability to Operate a Motor Vehicle 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to assist pharmaceutical sponsors in the evaluation of the effects 
of psychoactive drugs on the ability to operate a motor vehicle.  Specifically, this guidance 
addresses the FDAs current thinking regarding FDA-regulated drugs for which such evaluation 
may be needed2 and the types of studies that such an evaluation entails during clinical trials.   
 
This guidance does not address the specific methods or instruments used to collect data on 
driving ability; rather, this guidance outlines the general principles and goals of such studies.  
Experience suggests that a number of methods may be suitable for providing the necessary data.  
For specific drug development programs, sponsors should discuss with the appropriate review 
division the study methods to be used.  
 
This guidance also does not address the effects on driving ability from underlying disease, 
normal aging, or other factors unrelated to regulated drugs (e.g., distracted driving, aggressive 
driving).  Although psychoactive drugs are the focus of this guidance, nonpsychoactive drugs 
may affect driving ability through effects on function, including intended effects and secondary 
effects (e.g., impaired consciousness from a hypoglycemic reaction to a glucose-lowering drug, 
impaired vision from a mydriatic drug).  Therefore, the need to consider possible effects on 
driving ability is not limited to psychoactive drugs, and the approach to evaluating risk for 
nonpsychoactive drugs, which may differ substantially from the approaches described in this 
guidance, should be guided by drug-specific effects.  
 
                                                 
1 This guidance has been prepared by the Division of Neurology Products in the Center for Drug Evaluation and 
Research at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
1  Contains Nonbinding Recommendations 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
Driving is a complex activity involving a wide range of cognitive, perceptual, and motor 
activities.  Reducing the incidence of motor vehicle accidents (MVAs) that occur because of 
drug-impaired driving is a public health priority.  A systematic effort to identify drugs that 
increase the risk of MVAs is a critical component of assessing drug risk and designing strategies 
to reduce this risk.  
 
Drugs that impair driving ability may also impair an individuals ability to judge the extent of his 
or her impairment.  Therefore, in general, patient self-perception is not adequate for evaluating 
the presence or degree of driving impairment or for mitigating risk.  Instead, objective 
information about how a drug affects driving ability may be needed to enable safe use.   
 
 
III.  THE NEED TO EVALUATE DRIVING IMPAIRMENT 
 
When determining whether to evaluate the effect of a drug on driving ability, sponsors should 
first consider the conditions for use of the drug and the intended patient populations.  Drugs 
intended for chronic (including chronic-intermittent) outpatient use by adults are most likely to 
need evaluation of effects on driving ability.  In contrast, drugs limited to use in young children 
or to use in hospital inpatient settings would not need such evaluation.  FDA recommends that 
sponsors engage in early discussions with the appropriate review division to determine whether 
studies are needed in any given development program to evaluate drug effects on driving ability.  
 
Drugs that have pronounced central nervous system (CNS) impairing effects and are intended to 
be administered primarily at night (e.g., drugs for insomnia and other sleep disorders) are of 
concern because residual daytime effects can impair driving ability.  
 
In some cases, psychoactive drugs may appear to have the potential to improve driving 
performance, for example by decreasing somnolence (an established risk factor in MVAs).  
However, such drugs can have additional effects that increase the likelihood of driving 
impairment; for example, CNS stimulants may increase risk-taking (e.g., aggressive driving).  
Consequently, sponsors of psychoactive drugs should consider additional data on other functions 
important for safe driving.   
 
Sponsors also may need to conduct driving studies if an active moiety approved for a particular 
use is proposed for a different indication, at a different dose or dosing schedule, or in a new 
patient population in which there is insufficient information about how the drug may affect 
driving ability.  For example, drugs with well-known CNS depressant activity, such as 
2  Contains Nonbinding Recommendations 
barbiturates and benzodiazepines, have been used in wide ranges of doses and schedules for a 
number of indications, from anxiety to insomnia to general anesthesia.  Potential effects on 
driving ability may differ among the various uses and patient populations.   
 
The driving impairment studies described in this guidance may be impossible to conduct in the 
intended patient population or may need modification for drugs associated with serious safety 
risks that prevent enrollment of healthy subjects.  Depending on the specific circumstances, the 
risk of driving impairment might be adequately addressed using data that were feasible to collect 
combined with labeling that addresses remaining uncertainty.  Sponsors should discuss such 
approaches with the relevant review division during drug development. 
 
 
IV.  TIERED APPROACH TO EVALUATING DRUG EFFECTS ON DRIVING 
ABILITY 
 
A drugs effect on driving ability cannot be assessed using the risk of actual MVAs because 
using MVAs as endpoints in randomized controlled trials would be unethical.  Instead, sponsors 
should use studies that assess the effects of a drug on CNS functions necessary for safe driving 
and, if necessary, driving tests to determine the potential for causing MVAs.  
 
The FDA recommends evaluating impaired driving using a tiered assessment3 consisting of 
pharmacology/toxicology, epidemiology, and clinical/standardized behavioral assessments.  
With this approach, sponsors can use drug information obtained early in development to guide 
the need to collect data later in development related to driving impairment potential.  This can 
ensure that resources are not unnecessarily expended on evaluating drugs with little to no 
potential for impairment or on tests of drugs that are so clearly impairing when used as indicated 
that a detailed study is unnecessary (e.g., drugs used for surgical anesthesia).  Early in drug 
development, assessments should have high sensitivity for detecting impairment.  Later in 
development, studies should be designed to characterize the clinical relevance of earlier findings.  
The following broad functional domains are important for driving ability and should be assessed 
with increasingly focused studies if accumulating data suggest a risk of clinically meaningful 
driving impairment: 
 
  Alertness/arousal/wakefulness  
  Attention and processing speed 
  Reaction time/psychomotor functions 
  Sensory-perceptual functioning 
  Executive functions 
 
                                                 
3 Kay, GG and BK Logan, 2011, Drugged Driving Expert Panel Report:  A Consensus Protocol for Assessing the 
Potential of Drugs to Impair Driving, DOT HS 811 438, Washington, DC:  National Highway Traffic Safety 
Administration. 
3  Contains Nonbinding Recommendations 
A.  Pharmacology/Toxicology 
 
The chemical structure or receptor binding profile of a drug can suggest the potential to affect 
driving ability.  For example, drugs with a benzodiazepine structure or that promote binding of 
gamma-aminobutyric acid to the drugs receptors are likely to have CNS depressant effects and 
will need close attention to depressant effects in clinical trials.  However, structure and receptor 
binding alone may not be sufficient to conclude that a drug does not impair driving ability 
because cortical functions such as judgment are not well assessed in structure/binding studies.  
Similarly, the primary mechanism of action may not be adequate to provide reassurance about 
safety because unanticipated off-target actions can cause adverse effects.  
 
The pharmacokinetic properties of a drug can be critical for evaluating the driving impairment 
risk that a drug may cause.  Plasma or, if more relevant, brain tissue half-life is particularly 
important for drugs when the patient is expected  to be active at night or at other times when the 
patient is typically not expected to be driving.  Another important factor may be the extent of 
blood-brain barrier penetration, as illustrated by differences in somnolence caused by first- 
versus second-generation H  antihistamines related in part to differences in blood-brain barrier 
1
penetration.  
 
Nonclinical studies may provide data useful for anticipating the potential for a drug to impair 
driving ability.  In general, nonclinical studies for evaluating potential for impaired behavior 
should include an in vitro binding panel to assess on- or off-target pharmacologic targets of the 
drug, assays to assess the pharmacologic activity at the targets, and an in vivo CNS safety 
pharmacology study with careful assessment of signs potentially indicative of impaired CNS 
function.  Sponsors should consider the pharmacological activity and pharmacokinetics of major 
circulating metabolites in humans, as well as the effect of the parent compound. 
 
B.  Use of Epidemiological Data 
 
Evidence from drugs of the same or similar class, or with similar activity profiles, may raise 
concern about the effects of a drug on driving ability.  Epidemiological data can also be useful 
for understanding how various factors related to actual clinical use (e.g., drug-disease 
interactions, drug-drug interactions, dosing errors) may impact the effect of a new drug on 
driving ability.   
 
Epidemiological data may show an association between a specific illness (e.g., narcolepsy, 
obstructive sleep apnea) or a driver subset (e.g., young men) and an increased risk for MVA.4  
Although the focus of this guidance is limited to drug effects on driving ability, taking 
epidemiological information about possible vulnerability to drug problems into consideration 
may be important when designing or interpreting driving studies.  
 
Epidemiological data, however, are generally poorly suited to provide convincing evidence that a 
drug or drug class does or does not increase the risk of MVAs.  MVAs are common, and even in 
                                                 
4 LeRoy, AA and ML Morse, 2008, Multiple Medications and Vehicle Crashes:  Analysis of Databases, DOT HS 
810-858, Washington, DC: National Highway Traffic Safety Administration. 
4  Contains Nonbinding Recommendations 
patients with clinically meaningful impairment, many other factors contribute to the occurrence 
of a collision, decreasing the power of epidemiological studies to reliably identify increased risk 
from drug use, which is at worst only one factor among many increasing risks.  Patient 
population and other disease-specific factors can also have a large effect on MVA risk.   
 
Similarly, postmarketing adverse event reports are of limited use for identifying drugs that do or 
do not impair driving ability.  First, there is limited ability to verify critical circumstances of use 
such as dose, timing, and concomitant use of other drugs or alcohol.  In addition, the high 
background rate of MVAs and the recognized relation of MVAs to age, sex, driving experience, 
and many other factors are poorly documented in spontaneous reports.  Finally, underreporting 
may occur if patients and providers are not aware that impairment from a drug may have 
contributed to an MVA.  
 
C.  Clinical/Behavioral Asessment 
 
1.  Phase 1 Drug Development Trials 
 
Beginning with first-in-human trials, all drugs, including drugs intended for non-CNS 
indications, should be evaluated for adverse effects on the CNS (e.g., somnolence, agitation, 
dizziness).  The occurrence of concerning adverse CNS events at clinically relevant exposures in 
even a small number of phase 1 subjects might indicate the need for more focused studies of 
CNS-impairing effects. However, if few adverse events are observed for a drug with no biologic 
plausibility of CNS effects, additional studies may not be warranted. 
 
Early testing for CNS-impairing effects should generally emphasize sensitivity over specificity.  
Psychomotor and neuropsychological tests, including measures of reaction time, divided 
attention, selective attention, and memory may be appropriate.  Early trials often include higher 
doses than will be used in later efficacy trials, which provides an opportunity to explore CNS-
impairing effects at higher exposures.  For drugs designed to affect sleep and wakefulness, 
directed studies such as the multiple sleep latency test or maintenance of wakefulness test may 
help to inform about both drug safety and efficacy.  Subjective evaluation of CNS-impairing 
effects (e.g., by visual analogue scale) can contribute important information with respect to the 
strength of the correlation between subjective and objective impairment. 
 
If there is initial evidence of impairing effects, additional studies should examine CNS 
impairment over the full range of drug exposures that may occur in phase 2 and 3 trials.  Studies 
should include consideration of active metabolites and increased exposure in subpopulations 
such as those with genetic polymorphisms that lead to decreased levels of metabolizing enzymes 
or those with renal or hepatic insufficiency.  
 
In studies primarily intended to examine CNS impairment, a positive control is critical for study 
interpretability.  In general, negative studies in the absence of demonstrated assay sensitivity are 
not interpretable.  Even for studies that show impairment, a positive control is useful to 
understand the magnitude and duration of impairment.  Commonly used positive controls include 
ethanol, sedating antihistamines, and benzodiazepine-like drugs.  Other positive controls may be 
appropriate and should be discussed with the FDA. 
5  Contains Nonbinding Recommendations 
 
2.  Phase 2 and 3 Trials 
 
For drugs with potential effects on driving ability (e.g., drugs with sedating properties, drugs in 
early testing suspected of impairing CNS functions necessary for driving), it is particularly 
important that drug blood levels, including major active metabolites, should be measured during 
phase 2 and 3 trials.  Sponsors should document factors that affect blood levels, such as time of 
dosing, food effects, and concomitant treatments (see IV. C.1., Phase I Drug Development 
Trials).  The number and timing of blood concentration measurements should be adequate to 
support examination of exposure-response relationships.  We recommend that sponsors share and 
discuss with the appropriate review division analysis plans to explore relationships between drug 
and active metabolite concentrations and potential effects on driving ability to confirm the 
adequacy of the analyses. 
 
For drugs identified in early development as having a high potential to cause impairment, 
patients should be monitored at appropriate intervals during phase 2 and 3 trials for signs and 
symptoms that could place individuals at unacceptable risk.  While this monitoring should be 
guided by adverse effects elicited in earlier-phase testing (e.g., somnolence, dizziness, depressed 
level of consciousness, disturbance in attention, hypersomnia, lethargy, mental impairment, 
stupor, altered state of consciousness, and drugged feeling), monitoring should be broad enough, 
as discussed below, to detect effects that might not have been previously identified, such as 
impaired executive function or memory (e.g., amnesia, memory impairment, retrograde amnesia, 
amnestic disorder, global amnesia).   
 
Investigators should use both open-ended and targeted questions regarding adverse effects.  
Specific patient-reported outcomes that measure relevant symptoms, such as sleepiness scales, 
can help to quantify severity.  Investigators should ask patients (and family members when 
appropriate) about their perceived driving ability; negative responses provide limited reassurance 
of safety, but positive reports of difficulty staying awake while driving or collision near misses 
are informative.  Sponsors should specifically query patients about the occurrence of  CNS 
symptoms such as inattention, sleepiness, and impaired judgement experienced while driving.  In 
studies during phase 2 and 3 trials, sponsors should document to the degree possible the time of 
day and duration of adverse effects on the CNS because this information can characterize 
temporal effects on the risk of driving impairment. 
 
Objective tests of psychomotor function, as described in section IV.C.1., Phase 1 Drug 
Development Trials, may also be needed to protect patient safety adequately.  During phase 2 
and 3 trials, sponsors should document to the degree possible the time of day and duration of 
adverse effects on the CNS because this information can characterize temporal effects on the risk 
of driving impairment.  Sponsors should specifically query patients about the occurrence of 
adverse drug effects experienced while driving.  The FDA encourages sponsors to collect data on 
actual MVAs and traffic violations in phase 3 trials, although such events are generally 
infrequent.  
 
6  Contains Nonbinding Recommendations 
3.  Driving Studies 
 
If accumulating data suggest a potential for driving impairment, dedicated driving studies with 
higher specificity than more general tests of CNS function may be needed to refine assessment of 
the clinical effect of impairment.  Sponsors can conduct such studies with either actual motor 
vehicles or driving simulators.  Sponsors should consider the advantages and disadvantages of 
selected approaches and discuss any relevant issues with the appropriate review division.  For 
instance, if the sponsor is conducting a driving study with a simulator, the sponsor should 
consider whether thresholds for impairment have been established and, if not, how to approach 
the establishment of a meaningful threshold.  
 
Driving is a multifaceted activity and any given test of driving ability may not be capable of 
characterizing all of the different types of drug effects that can impair driving ability.  For 
example, sustained ability to maintain driving lane position in a monotonous driving 
environment has been used to assess drug-related somnolence but may be substantially less 
informative with respect to executive functions, which may be better tested in driving scenarios 
presenting new or more demanding situations, such as those that might call for anticipatory 
adaptation of vehicle speed or go/no-go decisions.  Sponsors should explain the rationale to 
support their selections of administered tests.    
 
Sponsors should include positive control and placebo groups in dedicated driving studies.  The 
positive control should be selected based on its ability to confirm assay sensitivity at the 
threshold of concern for clinically meaningful driving impairment.  An important, but not the 
only, benchmark for sponsors to consider when selecting a positive control is the impairment 
caused by ethanol at various blood levels, including levels that are per se illegal for driving.  An 
example of a positive control may be a drug that the FDA approved with detailed labeling 
regarding driving impairment.  
 
Enrolling subjects in driving studies who are from the population likely to use the drug, 
including the elderly, is important for providing information about disease-drug interactions.  In 
some cases, however, it might be possible to conclude that differences between healthy subjects 
and patients are sufficiently small to allow healthy subjects to be studied.   
 
Generally, sponsors should conduct driving studies to evaluate both the effects of initial drug 
exposure and effects after chronic exposure.  Drugs or active metabolites with a long half-life 
can result in markedly higher blood levels after multiple doses than occur after a single dose 
causing greater impairment with chronic, as compared to initial, use.  Conversely, initial 
exposure to a drug may be more impairing than chronic exposure because there may be 
development of pharmacological tolerance or habituation over time.  Testing of driving ability 
should take place when maximal levels of parent and/or active metabolite(s) are achieved.  Even 
if tolerance develops, it is often incomplete and may only develop after an extended duration of 
exposure.  Therefore, determining the time course and extent of any tolerance that develops can 
be important for instructing patients adequately about safe use.  
 
Studies of driving impairment should include an assessment of drug effects at the highest 
relevant exposures expected to be encountered in clinical use.  Therefore, sponsors should study 
7  Contains Nonbinding Recommendations 
drug exposures at the highest therapeutic doses and possibly at doses above the intended 
therapeutic dose to account for increased levels in subsets of patients, such as patients taking 
concomitant medications that cause drug-drug interactions leading to higher blood levels or 
increased pharmacodynamic effects or patients with specific genetic traits or other characteristics 
(e.g., renal hepatic disease) that could lead to higher exposures. 
 
For certain drugs intended to be dosed at night, including drugs for sleep disorders, effects on the 
CNS, which have an intended effect at night, cannot be assumed to be absent at the lower blood 
levels expected during the following day, especially in the morning.  Focused studies of residual 
CNS-impairing effects may be needed to characterize the risk of driving impairment.   
 
4.  Randomization 
 
A randomization scheme is described below for testing both the acute (1 dose) and later (1 week 
in this example) effects of a drug on driving ability.  
 
The example design is a randomized, double-blind, double-dummy, placebo and active-
controlled multiple oral dose, four-period crossover study.  In treatment periods 1 through 4, 
subjects are randomized to receive the following treatments in a double-dummy fashion (with a 
well-matched placebo): 
 
A.  High dose test drug for 8 days  
B.  Low dose test drug for 8 days 
C.  Positive control, day 1 and day 8  
D.  Placebo 
 
The investigational drug is given for 8 consecutive days to determine whether 
tolerance/desensitization develops; the finding of less impairment on day 8 than day 1 would 
indicate the development of tolerance.  The positive control is given only on days 1 and 8 so that 
there is no opportunity for the development of tolerance that could confound interpretation of the 
study. 
 
A minimum 5 half-life washout period occurs between each treatment dosing period for any 
given subject.  Driving tests are conducted at both the beginning of each study period (after the 
first dose or few doses) and at the end of the study period. 
 
Table 1 shows the treatment assignments for each period. 
 
Table 1.  Treatment Assignments 
N  Period 1  Period 2  Period 3  Period 4 
Washout  Washout  Washout 
(8 Days)  (8 Days)  (8 Days)  (8 Days) 
  A    C    D    B 
  B    D    C    A 
  C    B    A    D 
  D    A    B    C 
 
8  Contains Nonbinding Recommendations 
For drugs that have considerably long half-lives, parallel study design may need to be 
considered.  Otherwise, if less than a 5 half-life washout period is proposed, sponsors should 
provide justification with discussion of whether a carry-over effect exists. 
 
5.  Endpoint Analysis 
 
Although analysis of safety endpoints based on mean effect can be informative, exposure (e.g., 
maximum plasma concentration, area under the curve, tissue levels) from many drugs varies 
among subjects by an order of magnitude or more.  Thus, clinically meaningful impairment in 
subjects at the high end of drug exposure may not be predicted by mean changes.  Differences in 
pharmacodynamic sensitivity among subjects may also result in meaningful impairment in 
individual subjects that may not be predicted by aggregate measurements.  Therefore, sponsors 
should examine the entire distribution of a measure of impairment, rather than just its mean, 
paying special attention to values that indicate clinically meaningful impairment. 
 
6.  Exposure-Response Modeling 
 
Establishing the relationship of drug concentrations (exposure) to driving ability test endpoints 
(response) may be useful in interpreting driving studies.  The exposure-response relationship 
may provide insight into dosing regimens not studied directly, predict the effect of various 
intrinsic/extrinsic factors on driving study endpoints, suggest dose adjustments in 
subpopulations, and inform labeling.  Therefore, sponsors should collect time-matched data on 
appropriate drug and metabolite exposure and driving ability test endpoints.  Sponsors should use 
regression techniques to analyze the relationship between drug or metabolite concentrations and 
changes in the endpoints.  General considerations for exposure-response analysis can be found in 
the guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and 
Regulatory Applications.5  
 
 
V.  LABELING  
 
Studies to evaluate an important safety endpoint such as driving impairment should be described 
in the CLINICAL STUDIES section of labeling, including a brief description of the design (e.g., 
population studied, endpoints, statistical analysis methods) and pertinent results.6  Safety 
information from driving studies should be included in other sections of labeling as appropriate, 
including but not limited to, WARNINGS AND PRECAUTIONS, PATIENT COUNSELING 
INFORMATION, and FDA-approved patient labeling (e.g., patient information, Medication 
Guide).  
 
                                                 
5 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
 
6 See the guidance for industry Clinical Studies Section of Labeling for Human Prescription Drug and Biological 
Products  Content and Format. 
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