Sample Case A
Case A
FSD-204
• Concept:
– Novel mechanism for sexual dysfunction indication.
• Case study:
– FSD-204 targets a novel mechanism for the oral treatment of female
sexual dysfunction
– Aim is to provide sufficient pre-clinical and clinical data to allow a
regulatory decision to be made on the level of abuse potential of
FSD-204
Case A
Case Overview
Preclinical
•
•
•
•
•
Phase I
• Phase I
FIH
Receptor binding
Microdialysis
Animal Pharmacology
Animal PK
CNS Safety
Pharmacology
• Phase I
MDT
Drug
Discrimination
Phase II
Early Preclinical Assessment
• Are there any early “signals” of
concern for Abuse?
• Any additional data helpful?
Behavioral Pharmacology
• Design features of DD and
PD&W studies
Study in drugabusing patients
Note: company strategy
requires early “de-risking”
of target
Development Program
Questions
Rat SelfAdministration
Behavioral Pharmacology
• Assessment of results of SA
• Overall conclusion from
preclinical assessment
• Is there a need for a formal
clinical assessment of abuse?
Behavioral Pharmacology
• Assessment of results of DD
and PD&W
• Design of Self-administration
• Phase III Pivotal Efficacy Studies
• Phase II POC/Dose-Ranging
Study (n=100)
Phys. Dependence
and Withdrawal
• 2 week rat toxicology
• 2 week dog toxicology
Phase III
Clinical Assessment
• Review results of Clinical
Abuse study
• Any further work needed?
Clinical Assessment
• Review of AE profile from FIH
study
• How to design Clinical study in
drug abusing patients to
maximize value?
Pharmacology & Pharmacokinetics
•
•
•
•
•
•
•
Case A
FSD-204 is a CNS penetrant compound with a novel MOA
– FSD204 is a Receptor X agonist increasing intracellular levels of
cAMP
Receptor X has a distribution restricted to DA-ergic areas in the CNS:
– Nucleus Accumbens (NAcc)
Binding Profile
– Dorsal Striatum
Receptor Affinity
Novel X 1 nM
– Cortex
Melatonin M1/2 65nM
FSD-204 binds to no other receptors,
5HT1A 80nM
ion channel or transporter targets typically
Dopamine D2 350nM
associated with abuse at 10µM
(68 affinities tested)
Functional activation of receptor X in both
rat and human tissue, EC50 = 3nM
From in vivo models of sexual behaviour, predicted Ceff = 30nM
Half-life in rats = 4hrs, no active metabolites identified in any species
evaluated
Microdialysis experiments showed increase in DA in pre-frontal cortex
only and no effect on other neurotransmitters investigated
FDA
Comment
FDA
Comment
Pharmacology & Pharmacokinetics
What do we know about the drug so far?
• FSD-204 :
– Binds to a novel receptor which has a dopaminergic distribution (reward
areas)
– Binds to D2 receptors with low affinity (Ki :350 nM) - This interaction
may be relevant, depending on the therapeutic dose
– It does not bind to other receptors associated with abuse at high
concentration
• Increase in DA seen only in the PFC with microdialysis may be relevant to
the overall activity
• Preliminary effective dose and limited PK in rats
What else do we need to know at this point?
– Knowledge of the structure activity relationship (SAR) of the drug. What
do we know about the drug and other analogs?
– Binding profile of the main metabolites
– How the interaction of FSD-204 at the receptor level translates into the
overall activity of the drug
Preclinical safety studies
Case A
• Rat neurofunctional assessment (FOB): small, but significant,
increase in spontaneous locomotor activity/rearing at 100 and
300nM
• No effect in other safety pharmacology studies
•
Toxicology studies:
– Dog: seizures observed following multiple dosing (at free plasma
levels of 200nM)
– Rodent: lethality at free concentrations of 400nM.
– No other organ toxicities observed
Case A
Questions on preclinical pharmacology
1.
From the preclinical data provided what, if any, concerns would be
raised on the possible abuse potential of FSD204?
2.
Are any further preclinical data required for interpretation?
3.
Would a change in spontaneous locomotor activity alter the
subsequent preclinical strategy for abuse potential assessment, and
if so, how?
4.
Are hypoactivity and hyperactivity viewed differently in terms of
requirements for a subsequent preclinical AP assessment?
FDA
Comment
Q1: From the preclinical data provided, what, if any,
concerns would be raised on the possible abuse potential
of FSD-204?
• Functional Observation Battery (FOB)
– More than one observation time point is recommended including
that of maximum plasma concentration (Tmax)
– Information on all parameters evaluated and methods used
should be submitted (rearing, crouched posture, arousal, hind
limb splay, handling reactivity, rotarod test, etc)
• Toxicology
– Seizures in dogs at 200 nM. Safety concern associated with the
intake of high doses for abuse purposes
FSD-204 seems to produce behaviors consistent
with the actions of a stimulant.
FDA
Comment
Q2: Are any further preclinical data required for interpretation?
• Drug discrimination and self administration studies are
recommended
FDA
Comment
Q3: Would a change in spontaneous locomotor activity
alter the subsequent preclinical strategy for abuse
potential assessment, and if so, how?
• An increase in spontaneous locomotor activity suggests a stimulant
profile and the possibility of abuse potential
• A decrease in spontaneous locomotor activity suggests a sedative
profile and the possibility of abuse potential
• Thus, a change in locomotion would suggest the necessity for
animal abuse studies (such as drug discrimination or selfadministration)
FDA
Comment
Q4: Are hypoactivity and hyperactivity viewed differently in
terms of requirements for a subsequent preclinical AP
assessment?
• Both behavioral responses indicate the need for abuse potential
assessments in animals
• Hypoactivity suggests activation of receptors associated with
depressant drugs (GABA, opioid, etc.)
• Hyperactivity suggests activation of receptors associated with
stimulant drugs (dopamine reuptake inhibition, dopamine release,
etc.)
Preclinical Pharmacology –
Drug Discrimination
5.
•
Case A
What does the Agency see as the role of DD in AP assessments?
Does it have a use beyond selecting the training drug for SA studies?
Drug discrimination studies performed in Morphine, Cocaine and Diazepam
trained rats
–
–
•
3 doses of FSD204 and vehicle (n≥8), with maximum dose targeting 3xCeff
Route of administration chosen based solely on achieving target exposures
Results
–
Partial generalization (30-40%) to cocaine and morphine
6.
In designing the study, should other factors be considered in
choosing the route of administration?
7.
Is the multiple of 3xCeff sufficient? If not what criteria should be
used to set the dose range?
8.
From these results how should the SA training drug be chosen?
FDA
Comment
Q5: What does the Agency see as the role of drug
discrimination in abuse potential assessments? Does it have a
use beyond selecting the training dose for self-administration
studies?
Hmm?
• Drug discrimination determines whether Drug X produces an
interoceptive cue in an animal that is similar to the training drug.
Thus, generalization by Drug X to training drug is only predictive of
abuse potential if the training drug is a known drug of abuse
• A negative signal in drug discrimination (even against a range of
training drugs known to have abuse potential) does not inherently
mean Drug X has no abuse potential. A unique mechanism of
action in the brain may mean a unique abuse potential profile
dissimilar to those of other drugs of abuse
• Doses used in drug discrimination typically produce plasma levels
similar to those produced by the therapeutic dose
• Choice of training drug is difficult when Drug X acts by a novel
mechanism
FDA
Comment
Q6: In designing the study, should other factors be
considered in choosing the route of administration?
• Typically, the route of administration for drug discrimination
studies is intraperitoneal
• The route of administration should simulate the pharmacokinetic
exposure in humans
FDA
Comment
Q7: Is the multiple of 3xCeff sufficient? If not what criteria
should be used to set the dose range?
• The clinically effective dose is unknown at Phase 1
• Frequently, the clinically effective dose is found to be much
higher (and sometimes much lower) than initially predicted by
the preclinical studies
• Ideally abuse potential studies should not be conducted until
Phase 2 studies are completed
Animal abuse potential studies may need to be repeated if the
doses used are not representative of final human therapeutic
doses
FDA
Comment
Q8: From these results how should the self-administration
training drug be chosen?
• Doses are typically lower than therapeutic doses to prevent overdose
in animals when the drug is self-administered repeatedly
• However, a range of doses should be tested in self-administration to
ensure that potentially rewarding plasma levels are achieved during
the trial
Case A
Preclinical Pharmacology Physical Dependence & Withdrawal
•
Design
– Male rats (n=8) dosed once daily (p.o., clinical route) for two weeks
– Dose at Cmax of 3xCeff in humans
• Plasma levels measured at 24 hr post-dose are below predicted Ceff but
above Ki for Receptor X
– Cocaine as positive control (FSD shows mild stimulant profile) and vehicle
group
– Endpoints measured before, during and up to 4 days following drug
discontinuation (8, 24, 32, 48, 72 and 96 hr):
• Body weight and food consumption
• Behavioral scoring of discontinuation signs and symptoms, including
presence/absence of: salivation, jumping, wet dog shakes, head shakes,
paw shakes, abnormal posture, abdominal constriction, teeth chattering,
tremors, genital licking, rearing, hyperactivity, retropulsion, sniffing,
stretching, scratching, burying, grooming, pilo-erection
Case A
Preclinical Pharmacology Physical Dependence & Withdrawal
• Result
– No tolerance or withdrawal signs observed after discontinuation of
FSD204
– Cocaine showed tolerance to behavioural effects and significant
weight loss following discontinuation
FDA
Comment
Preclinical Pharmacology Physical Dependence & Withdrawal
FDA
Comment
• Animals
– If the indication is for females only, studies should include female
animals
• Observation times
– Observation times should be based on the PK parameters of the
drug for the species used and should be of a long enough
duration to detect behaviors
– All behaviors should be noted and not limited to a set list of
behaviors of interest. Unexpected results may alter the
understanding of the drug’s actions
– Video recording of animals during the study might be helpful
More frequent observations within the first 8 hours following drug
discontinuation are recommended
• Tolerance is not directly related to physical dependence
Case A
Questions on PD&W study design
9.
10.
11.
12.
13.
14.
Is cocaine the appropriate positive control?
Are the endpoints sufficient to assess PD&W? If not,
how should appropriate endpoints be selected?
Should both a positive and negative control group be
included if in-house data is available to show validation of the
cocaine PD&W model?
Is dosing for 14 days by the clinical route adequate
for the non-clinical assessment of PD&W?
What other factors should be considered when selecting the
route of drug administration for a PD&W study?
Is there a need to target sustained pharmacological
exposures, or is it sufficient to achieve this transiently?
FDA
Comment
Q9: Is cocaine the appropriate positive control?
• FSD-204 is reported to be a “mild stimulant”, so methylphenidate
may have been a better positive control than cocaine in dependence
and withdrawal studies
• The Sponsor can propose any drug as a positive control, but must
justify the selection
FDA
Comment
Q10: Are the endpoints sufficient to assess physical
dependence and withdrawal? If not, how should appropriate
endpoints be selected?
• Withdrawal behaviors known to be associated with the drug class
should be observed during discontinuation
• For a drug with novel mechanism of action, a number of withdrawal
behavior checklists derived for various classes of drugs may be
useful in establishing which behaviors to look for during Drug X
discontinuation
• The presence of physical dependence (withdrawal behaviors
following drug discontinuation) is not sufficient to indicate abuse
potential
• However, full characterization of a drug’s abuse potential does
require assessment of physical dependence
FDA
Comment
Q11: Should both a positive control and a negative control
group be included if in-house data is available to show
validation of the cocaine physical dependence and
withdrawal model?
• The data reported for cocaine did not show any weight loss during
the drug administration phase. Given that stimulants are known to
reduce feeding and to reduce body weight, this suggests that the
dose of cocaine used was not high enough
• A positive control is used to validate the study. A placebo is the only
necessary negative control
FDA
Comment
Q12: Is dosing for 14 days by clinical route adequate for the
non-clinical assessment of physical dependence and
withdrawal?
• Duration of exposure needed depends on the PK of the drug
• Appropriate duration of drug administration prior to assessing
withdrawal is based on elimination half-life
• For most drugs, a 14-day duration of drug administration should be
sufficient. However, for drugs with half-lives that are relatively long,
additional drug dosing may be necessary prior to discontinuation
FDA
Comment
Q13: What other factors should be considered when
selection of the route of drug administration for a physical
dependence and withdrawal study?
• Half-life determines duration of the drug discontinuation
observation period
• The observation period should extend to at least 3-7 days, or
longer if the drug is known to be eliminated slowly
FDA
Comment
Q14: Is there a need to target sustained pharmacological
exposures, or is it sufficient to achieve this transiently?
• Drug exposure should parallel exposure in clinical populations
• This may depend on the intended use of the drug and the PK
parameters of a drug. For instance, a drug may be intended for
chronic use if steady state levels of drug are needed for optimal
clinical benefit
• If the drug product is controlled- or sustained-release, then a minipump may be an appropriate method for delivering drug to an
animal in the physical dependence study
• If the drug produces pharmacokinetics that peak and trough across
the day, then the animal drug administration should attempt to
produce a PK profile that is as similar as possible
Preclinical Pharmacology –
I.V. Self-administration
Case A
• Rats (n≥8) trained to respond for cocaine under FR3
• Responding extinguished until stable and <50% of cocaine infusion
rates
• Test FSD-204 (3 doses & vehicle with highest dose targeting 3xCeff)
– Each dose available for minimum of 3 days until responding stable
– Randomized order within animal design
Case A
Preclinical Pharmacology –
I.V. Self-administration
• Data:
Across repeated days of testing
40
30
30
Infusions/hr
40
20
hi
gh
id
m
V
lo
w
0
eh
0
Co
Ve
FS
**
20
10
FSD-204
(mg/kg/inf)
**
**
10
C
oc
E ain
xt
e
in
ct
io
n
Infusions/hr
Summary (stable responding)
**p<0.01
1
2
Cocaine
Vehicle
FSD-204 high dose
3
4
5
6
7
8
day of access
**p<0.01 compared to vehicle
FDA
Comment
FDA
Preclinical Self-Administration
Comment
• Animal self-administration studies measure two related aspects of
abuse potential:
– Reward: If the drug produces a positive measured effect in a selfadministration study for a limited time period, this may suggest that
the drug can be abused by a human on a single occasion
– Reinforcement over time: If the drug maintains a positive measured
effect in a self-administration over extended periods of time, this may
suggest a drug can be abused by a human on multiple, closelyspaced occasions
• If a drug produces self-administration in early trials (showing that it has
rewarding properties), this may suggest that the drug can be used
successfully by humans on an acute basis to produce a “high” and that
the drug may have human abuse potential
FDA
Preclinical Self-Administration
Comment
• The inability of a drug to produce reinforcement following initial
indication of reward does not negate the abuse potential signal. In
terms of public health, non-chronic use of an abusable drug might be
relevant
• Typically a FR10 schedule of reinforcement is used
• Doses should proceed from low to high. If animals are exposed to
high doses first, they may not self-administer the low doses as readily
A negative result in self-administration studies does not always
indicate lack of abuse potential
Animals typically do not self-administer 5-HT2 agonist
hallucinogens, cannabinoids, NMDA antagonists, and other
drugs that produce effects broadly characterized as
“psychedelic”
Preclinical Pharmacology –
Self-administration
Case A
 Design
15.
16.
Are rats an appropriate species for self administration
studies?
Are there specific criteria which must be met to justify the
use of the rat for abuse potential assessments?
 Data
17.
18.
19.
When rats are given the opportunity to self-administer
FSD-204, they respond for 2-3 days in a burst extinction
pattern for the high dose only. How is this viewed? Is
there a minimum number of sessions that each dose of the
test drug should be available for?
When responding stabilizes, no increase in infusion rates
above vehicle is observed. Does this change the
interpretation?
It is normal practice to present rat data as grouped
means. Does the Agency agree that this is sufficient for
such data?
FDA
Comment
Q15: Are rats an appropriate species for self-administration
studies?
• Rats are an appropriate species for self-administration studies. Rats
might be advantageous when a large number of animals are
required, or in studies where drug naïve animals are necessary
• Some researchers may justify conducting self-administration studies
in non-human primates, based on their scientific expertise and the
type of drug being studied (examples : ethylketazocine, modafinil)
FDA
Comment
Q16: Are there specific criteria which must be met to justify
the use of the rat for abuse potential assessments?
• The drug must cross the blood-brain barrier of the rat
• If the drug produces a high degree of vomiting in humans, rodents
may be an inappropriate species because they do not have an
emetic response
FDA
Comment
Q17: When rats are given the opportunity to self-administer
FSD-204, they respond for 2-3 days in a burst-extinction
pattern for the high dose only. How is this viewed? Is there
a minimum number of sessions that each dose of the test
drug should be available for?
• If animals fail to maintain initially high levels of self-administration for
a drug despite continued access, this can be interpreted in a variety
of ways:
– development of tolerance
– the drug has long-lasting effects and the preferred level of effect
does not require further self-administration
– inhibition of metabolism, which can also lead to prolongation of
the rewarding effects
– development of negative effects
• A “burst-extinction pattern” may indicate that the drug has rewarding
properties on an acute basis, which is suggestive of human abuse
potential
• Duration of exposure should be at least 3-5 days
FDA
Comment
Q18: When responding stabilizes, no increase in the
infusion rates above vehicle is observed. Does this
change the interpretation?
• The drug appears to have rewarding properties on an acute basis
FDA
Comment
Q19: It is normal practice to present rat data as grouped
means? Does the Agency agree that this is sufficient for
such data?
• Group means with SEM bars is adequate. However, data may also
be presented as scattergrams or other methods of representing
individual data in conjunction with the overall mean
Case A
Preclinical summary
•
Overall, no positive signals were observed in the drug
discrimination, physical dependence and withdrawal, or
self-administration studies.
20.
Does the Agency agree with this assessment given the nonclinical data supplied?
FDA
Comment
Q20: Does the Agency agree with the assessment
[that no positive signals were observed in the drug
discrimination, physical dependence and withdrawal
or self-administration studies] given the non-clinical
data supplied?
• Under the conditions of the study, self-administration data show that
the drug may produce rewarding effects on an acute basis, which is
suggestive of human abuse potential
• Interpretation of data from animal abuse potential studies requires
review of full protocols and full individual and mean datasets
Proposed Safety Monitoring
in Clinical Program
•
Case A
All clinical trials will include routine collection of AEs, with special
attention to CNS effects
FDA
Comment
FDA
Proposed Safety Monitoring
in Clinical Program
• Proactive collection of CNS AEs is necessary
• Points to consider for collecting AE data of specific interest:
– Correlate AEs with known or suspected mechanism of action
– Thoroughly review the literature for drugs with similar
mechanisms of action or targets
– Probing questions should be considered when evaluating
adverse events that are spontaneously reported (The terms on
the following slides should be considered)
– More frequent/longer evaluations of AEs should be included
until the PK is more fully characterized
– Prospective questionnaires should be used in later phases of
development
Comment
FDA
Abuse-Related Adverse Event Terms
Comment
• This compilation of terms is based on our experience to date and is
not intended to be inclusive of all possible abuse-related MedDRA
terms. Also, not all groups of terms will apply to every drug under
development
• Most terms are listed under General, Neurological, and Psychiatric
Disorders High Level Groupings
• The list includes:
– Specific terms that are in the MedDRA dictionary
– Frequently used verbatim terms, words or phrases
FDA
Euphoria-related terms:
Comment
• Euphoric mood: euphoria, euphoric, exaggerated well-being,
excitement excessive, feeling high, felt high **, high** , high **
feeling, laughter
• Elevated mood: mood elevated, elation
• Feeling abnormal: cotton wool in head, feeling dazed, feeling
floating, feeling strange, feeling weightless, felt like a zombie,
floating feeling, foggy feeling in head, funny episode, fuzzy, fuzzy
head, muzzy head, spaced out, unstable feeling, weird feeling,
spacey
• Feeling drunk: drunkenness feeling of, drunk-like effect, intoxicated,
stoned, drugged
** Exclude terms that clearly are not pertinent or relevant such as “high
blood pressure,” “respiratory depression,” etc.
FDA
Euphoria-related terms (cont.)
• Feeling of relaxation: Feeling of relaxation, feeling relaxed,
relaxation, relaxed, increased well-being, excessive happiness
• Dizziness: dizziness and giddiness, felt giddy, giddiness, light
headedness, light-headed, light-headed feeling, lightheadedness,
swaying feeling, wooziness, woozy
• Thinking abnormal: abnormal thinking, thinking irrational,
wandering thoughts
• Hallucination: (auditory, visual, and all hallucination types),
illusions, flashbacks, floating, rush, and feeling addicted
Comment
FDA
Terms associated with drugs of abuse
related to mood, impaired attention,
psychomotor events cognition:
Comment
• Somnolence: groggy, groggy and sluggish, groggy on awakening, stupor
• Mood disorders and disturbances: mental disturbance,
depersonalization, psychomotor stimulation, mood disorders, emotional
and mood disturbances, deliria, delirious, mood altered, mood
alterations, mood instability, mood swings, emotional lability, emotional
disorder, emotional distress, personality disorder, impatience, abnormal
behavior, delusional disorder, irritability
• Mental impairment disorders: memory loss (exclude dementia),
amnesia, memory impairment, decreased memory, cognition and
attention disorders and disturbances, decreased concentration, cognitive
disorder, disturbance in attention, mental impairment, mental slowing,
mental disorders
• Drug tolerance, Habituation, Drug withdrawal syndrome, Substancerelated disorders
FDA
Dissociative/Psychotic Terms
• Psychosis: psychotic episode or disorder
• Aggressive: hostility, anger, paranoia
• Confusion and disorientation: confusional state, disoriented,
disorientation, confusion, disconnected, derealization, dissociation,
detached, fear symptoms, depersonalization, perceptual
disturbances, thinking disturbances, thought blocking, sensation of
distance from one's environment, blank stare, muscle rigidity, noncommunicative, sensory distortions, slow slurred speech, agitation,
excitement, increased pain threshold, loss of a sense of personal
identity
Comment
Clinical Evaluation
21.
22.
Case A
If there is agreement that FSD-204 is not self-administered by rats
and no withdrawal signs have been observed, are there
circumstances under which a Clinical Abuse Potential study in drug
abusing subjects would not be required?
Are there thresholds for requiring a Clinical Abuse Potential study?
FDA
Comment
Q21: If there is agreement that FSD-204 is not selfadministered by rats and no withdrawal signs have
been observed, are there circumstances under which
a Clinical Abuse Potential study in drug abusing
subjects would not be required?
• The self-administration data show that the drug may produce
rewarding effects on an acute basis, suggestive of human abuse
potential
• Data regarding behaviors observed during the drug
discontinuation period is needed to conclude that no withdrawal
signs have been observed
• A clinical abuse potential study would not be necessary if:
– The NME is not CNS active
– A narrow safety margin is determined
– No signals suggestive of abuse potential are identified in
Phase I and II studies
FDA
Comment
Q22: Are there thresholds for requiring a Clinical
Abuse Potential study?
• NMEs that are CNS-acting require a human abuse potential study if
there are positive signals from the preclinical data or the clinical AE
profile in Phase 1 and 2 signals abuse potential
• For known drugs of abuse that are already scheduled under the
CSA, a novel formulation may require additional abuse potential
studies, depending on the adverse event profile observed during
clinical efficacy trials
• Sponsors may plan to conduct clinical abuse potential studies when
moving into Phase 3 studies. This approach will allow for selection
of appropriate comparator drug(s), subject population, dose
selection, and timing/duration of assessments
Case A
AE Profile of FSD-204 following FIH study
Escalating doses (3, 10, 25, 50, 100mg)
• Treatment emergent Adverse Events (8 subjects/FSD group)
Event
NME (n=40)
Placebo (n=20)
20%
5%
Dizziness
12.5%
5%
Headache
10%
10%
Vomiting
5%
0%
Insomnia
5%
5%
Somnolence
5%
0%
Upper resp. tract
Inf.
2.5%
0%
Diarrhea
2.5%
5%
2.5% (n=1)
0%
Nausea
Hallucinations
FDA
Comment
FDA
AE Profile of FSD-204 following FIH
Study
Comment
• Given the non-existence of hallucinations in the placebo group, the
rate of hallucination (n=1 of 40) in FSD-204 treated subjects is
concerning when extrapolated to the clinical population or to a drugabusing population who may use supratherapeutic doses
• Hallucinations should be actively monitored in all further clinical
studies to determine whether this AE has clinical relevance
• Terms such as dizziness and somnolence are somewhat vague and
do not always capture the ‘true experience’ of the adverse event.
Occasionally the verbatim term does not directly map to a preferred
term. Attempts should be made to accurately capture all adverse
events
Case A
If Clinical Abuse Potential Study is needed…
•
•
23.
Company strategy necessitates early “de-risking” of program prior to
initiating large studies (Phase 2 and 3)
Should a Clinical Abuse Potential study be needed, it will be
conducted prior to Phase 2 (dose ranging) -before effective dose is
fully identified.
Can the Agency offer any advice regarding dose selection or other
study design features to maximize chances of this study being an
adequate evaluation in drug abusing population for registration?
FDA
Comment
Q23: Can the Agency offer any advice regarding dose
selection or other study design features to maximize
chances of this study being an adequate evaluation in
drug abusing population for registration?
• Individuals enrolled into abuse potential studies are healthy subjects
• Phase 1 studies can provide signals suggestive of abuse potential,
depending on doses studied, subject population, and AE evaluation
• Phase 2 dose-ranging studies will provide the best estimate of the
therapeutic dose but only Phase 3 studies will provide the final data
• All study phases contribute to the AE data base. The greater the
number of subjects/patients exposed to different doses, the greater
the ability to construct an accurate AE profile related to abuse
potential. This profile allows the identification of the appropriate drug
history for subjects in abuse potential studies, comparator drugs, and
safety issues for the proposed doses
FDA
Comment
Q23: Can the Agency offer any advice regarding dose
selection or other study design features to maximize
chances of this study being an adequate evaluation in
drug abusing population for registration? (cont)
• Prospective assessments such as subjective questionnaires may be
included in Phase 1 study design to obtain additional information
that should be monitored in Phase 2/3 studies
• Since human abuse potential studies typically use doses that are 23 times the highest proposed therapeutic dose for any indication, it
is not advisable to conduct a human abuse potential study until
Phase 2 clinical trials have been initiated with the proposed
therapeutic doses
• Communication is encouraged between the preclinical and clinical
scientific staff of a company so that each group is aware of abuse
potential studies being conducted and results that are observed
Study Design Issues
•
Case A
FSD-204 has a novel mechanism of action – how to select the
appropriate comparator
– Potential drivers for selection include:
• Mechanism and/or receptor profile
• Adverse event profile (stimulant vs. sedative)
• Indication (compare to predominant class used to treat
disorder)
24. Can
the Agency comment on the relative importance of these
criteria in selecting a comparator?
25. How
should patients be selected for FSD-204? (i.e. should they
be stimulant preferring patients?)
FDA
Comment
Q24: Can the Agency comment on the relative
importance of these criteria [mechanism, AE profile,
indication] in selecting a comparator?
• The choice of a positive control for an NME, especially a first-inclass NME, with a novel mechanism of action can be challenging.
• All available data (receptor profile, AEs, and similar drugs if
available) should be used to determine a comparator
• The AE profile observed in Phase 1 and Phase 2 studies provides
some of the best information on which to design a study and select a
comparator
• A drug administered via different routes (insufflated vs oral) may
have a greater risk of abuse. These comparisons (the drug against
itself in different dosage forms) pose a much greater challenge for
which we do not have an answer
FDA
Comment
Q25: How should patients be selected for FSD-204?
(i.e., should they be stimulant preferring patients)?
• The drug history of the individuals recruited should include use of
drugs that produce effects that most closely parallel those produced
by Drug X
• Individuals should have used the drug class of interest in the past
year and state a preference for that drug class. It may be advisable
that the study design include a pre-qualification phase
Additional Background
Case A
•
Projected top dose to test in FIH based upon toxicology
results in most-sensitive species: 100mg
– established based upon acceptable margins to seizures
in dogs and death in rodents.
– Sponsor and FDA reviewing Division agree that
escalation beyond 100mg is not acceptable in healthy
volunteers or FSD patients.
•
FIH study completed with top dose of 100mg: Linear PK up
to 100mg established in multiple dose study
– AE profile from FIH and multiple dose tolerance were
similar and dose-related
– 100mg was not an MTD, but dose escalation stopped
due to exposure limits
Additional Background
•
•
•
Case A
Need to de-risk development program early (during Phase 1)
Clinical abuse potential study:
– Doses tested: 40mg, 90mg
– Results: Small but non-significant group mean increase in
“Liking” and “Good Drug Effects” at top dose of FSD-204
(2/20 subjects vs. 1/20 in placebo control drove group mean
effect)
– At top dose (90mg) there were not many subjective effects in
drug abusing patients
Subsequent Phase 2 dose ranging indicates that “effective
dose” is 80mg. We expect this to be the marketed dose. No
hallucinations were reported in phase II study (n=200 FSD-204
exposures).
26. Is
there a need to do any additional abuse potential testing in
drug abusing patients – given the exposure limit and findings
in the subjective effects study and given that a dose 2-3x
higher than the likely therapeutic dose has not been tested, ?
(i.e. would there be a need to explore higher dose range in
drug abusing patients in an additional study, despite the
exposure ceiling?)
FDA
Comment
Q26: Is there a need to do any additional abuse potential
testing in drug abusing patients – given the exposure limit
and findings in the subjective effects study and given that a
dose 2-3x higher than the likely therapeutic dose has not
been tested? (i.e. would there be a need to explore a
higher dose range in drug abusing patients in an additional
study, despite the exposure ceiling?)
• The phrase ‘not many subjective effects in drug abusing patients’
cannot be evaluated. Subjective effects in even 1 or 2 subjects may
be a sufficient signal, given the relatively low number of subjects
enrolled in these studies
A narrow therapeutic window represents a great risk
for patients who inadvertently might increase the
dose, and for those who take the drug for abuse
purposes
Identified areas in need of further
research
• Validation of questionnaires to capture subjective effects in early
phases of development
• Development of criteria for the identification, coding and reporting of
AEs that may signal abuse potential, abuse, misuse, addiction
• The design of studies that would allow the systematic evaluation of
the abuse potential of novel formulations of drugs with known abuse
potential
• Development of a standardized battery of tests to assess the
physicochemical properties of abuse-deterrent formulations (ADF)
of known drugs of abuse