Sample Case A

1
Sample Case A
2
FSD-204
Case A

• 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

3
Case Overview
Case A
Preclinical
Phase I
Phase II
Phase III

• Phase I FIH

• Phase II POC/Dose-Ranging Study (n100)

• Phase III Pivotal Efficacy Studies

• Phase I MDT

• Receptor binding
• Microdialysis
• Animal Pharmacology
• Animal PK
• CNS Safety Pharmacology

Note company strategy requires early
de-risking of target
Development Program

• 2 week rat toxicology
• 2 week dog toxicology

Questions

• Early Preclinical Assessment
• Are there any early signals of concern for
  Abuse?
• Any additional data helpful?

• Clinical Assessment
• Review results of Clinical Abuse study
• Any further work needed?

• 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
• Design features of DD and PDW studies

• Clinical Assessment
• Review of AE profile from FIH study
• How to design Clinical study in drug abusing
  patients to maximize value?

• Behavioral Pharmacology
• Assessment of results of DD and PDW
• Design of Self-administration

4
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)
• Dorsal Striatum
• Cortex
• FSD-204 binds to no other receptors,ion channel
  or transporter targets typicallyassociated with
  abuse at 10µM(68 affinities tested)
• Functional activation of receptor X in bothrat
  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

Binding Profile
Receptor Affinity Novel X 1 nM Melatonin M1/2
65nM 5HT1A 80nM Dopamine D2 350nM
FDA Comment
5
Pharmacology Pharmacokinetics
FDA Comment

• 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

• Stimulant?

6
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

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Questions on preclinical pharmacology
Case A

• From the preclinical data provided what, if any,
  concerns would be raised on the possible abuse
  potential of FSD204?
• Are any further preclinical data required for
  interpretation?
• Would a change in spontaneous locomotor activity
  alter the subsequent preclinical strategy for
  abuse potential assessment, and if so, how?
• Are hypoactivity and hyperactivity viewed
  differently in terms of requirements for a
  subsequent preclinical AP assessment?

8
Q1 From the preclinical data provided, what,
if any, concerns would be raised on the possible
abuse potential of FSD-204?
FDA Comment

• 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.

9
FDA Comment
Q2 Are any further preclinical data required for
interpretation?

• Drug discrimination and self administration
  studies are recommended

10
Q3 Would a change in spontaneous locomotor
activity alter the subsequent preclinical
strategy for abuse potential assessment, and if
so, how?
FDA Comment

• 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 self-administration)

11
Q4 Are hypoactivity and hyperactivity viewed
differently in terms of requirements for a
subsequent preclinical AP assessment?
FDA Comment

• 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.)

12
Preclinical Pharmacology Drug Discrimination
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 (n8), with maximum
  dose targeting 3xCeff
• Route of administration chosen based solely on
  achieving target exposures
• Results
• Partial generalization (30-40) to cocaine and
  morphine

• In designing the study, should other factors be
  considered in choosing the route of
  administration?
• Is the multiple of 3xCeff sufficient? If not
  what criteria should be used to set the dose
  range?

• From these results how should the SA training
  drug be chosen?

13
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?
FDA Comment

• 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

Hmm?
14
Q6 In designing the study, should other factors
be considered in choosing the route of
administration?
FDA Comment

• Typically, the route of administration for drug
  discrimination studies is intraperitoneal
• The route of administration should simulate the
  pharmacokinetic exposure in humans

15
Q7 Is the multiple of 3xCeff sufficient? If not
what criteria should be used to set the dose
range?
FDA Comment

• 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

16
Q8 From these results how should the
self-administration training drug be chosen?
FDA Comment

• 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

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Preclinical Pharmacology - Physical Dependence
Withdrawal
Case A

• Design
• Male rats (n8) 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

18
Preclinical Pharmacology - Physical Dependence
Withdrawal
Case A

• 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
19
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 drugs
  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

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Questions on PDW study design
Case A

• Is cocaine the appropriate positive control?
• Are the endpoints sufficient to assess PDW? If
  not,how should appropriate endpoints be
  selected?
• Should both a positive and negative control group
  beincluded if in-house data is available to show
  validation of the cocaine PDW model?
• Is dosing for 14 days by the clinical route
  adequatefor the non-clinical assessment of PDW?
• What other factors should be considered when
  selecting the route of drug administration for a
  PDW study?
• Is there a need to target sustained
  pharmacologicalexposures, or is it sufficient to
  achieve this transiently?

21
Q9 Is cocaine the appropriate positive control?
FDA Comment

• 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

22
Q10 Are the endpoints sufficient to assess
physical dependence and withdrawal? If not, how
should appropriate endpoints be selected?
FDA Comment

• 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 drugs abuse
  potential does require assessment of physical
  dependence

23
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?
FDA Comment

• 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
  

24
Q12 Is dosing for 14 days by clinical route
adequate for the non-clinical assessment of
physical dependence and withdrawal?
FDA Comment

• 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

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Q13 What other factors should be
considered when selection of the route of drug
administration for a physical dependence and
withdrawal study?
FDA Comment

• 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

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Q14 Is there a need to target sustained
pharmacological exposures, or is it sufficient to
achieve this transiently?
FDA Comment

• 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 mini-pump 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

27
Preclinical Pharmacology I.V.
Self-administration
Case A

• Rats (n8) trained to respond for cocaine under
  FR3
• Responding extinguished until stable and lt50 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

28
Preclinical Pharmacology I.V.
Self-administration
Case A

• Data

FDA Comment
29
Preclinical Self-Administration
FDA Comment

• Animal self-administration studies measure two
  related aspects of abuse potential
• Reward If the drug produces a positive measured
  effect in a self-administration 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,
  closely-spaced 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

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FDA Comment
Preclinical Self-Administration

• 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

31
Preclinical Pharmacology Self-administration
Case A

• Design
• 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
• 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?

32
Q15 Are rats an appropriate species for
self-administration studies?
FDA Comment

• 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)

33
Q16 Are there specific criteria which must be
met to justify the use of the rat for abuse
potential assessments?
FDA Comment

• 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

34
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
testdrug should be available for?
FDA Comment

• 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

35
Q18 When responding stabilizes, no
increase in the infusion rates above vehicle is
observed. Does this change the interpretation?
FDA Comment

• The drug appears to have rewarding properties on
  an acute basis

36
Q19 It is normal practice to present rat data as
grouped means? Does the Agency agree that this is
sufficient for such data?
FDA Comment

• 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

37
Preclinical summary
Case A

• Overall, no positive signals were observed in the
  drug discrimination, physical dependence and
  withdrawal, or self-administration studies.
• Does the Agency agree with this assessment given
  the non-clinical data supplied?

38
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?
FDA Comment

• 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

39
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
40
FDA Comment
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

41
Abuse-Related Adverse Event Terms
FDA 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

42
Euphoria-related terms
FDA 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.

43
Euphoria-related terms (cont.)
FDA Comment

• 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

44
Terms associated with drugs of abuse related to
mood, impaired attention, psychomotor events
cognition
FDA 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, Substance-related disorders

45
Dissociative/Psychotic Terms
FDA Comment

• 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,
  non-communicative, sensory distortions, slow
  slurred speech, agitation, excitement, increased
  pain threshold, loss of a sense of personal
  identity

46
Clinical Evaluation
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?

47
Q21 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?
FDA Comment

• 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

48
Q22 Are there thresholds for requiring a
Clinical Abuse Potential study?
FDA Comment

• 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

49
AE Profile of FSD-204 following FIH
studyEscalating doses (3, 10, 25, 50, 100mg)
Case A

• Treatment emergent Adverse Events  (8
  subjects/FSD group)

FDA Comment
50
AE Profile of FSD-204 following FIH Study
FDA Comment

• Given the non-existence of hallucinations in the
  placebo group, the rate of hallucination (n1 of
  40) in FSD-204 treated subjects is concerning
  when extrapolated to the clinical population or
  to a drug-abusing 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

51
If Clinical Abuse Potential Study is needed
Case A

• 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?

52
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?
FDA Comment

• 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

53
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)
FDA Comment

• 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 2-3 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

54
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)

• Can the Agency comment on the relative importance
  of these criteria in selecting a comparator?
• How should patients be selected for FSD-204?
  (i.e. should they be stimulant preferring
  patients?)

55
Q24 Can the Agency comment on the relative
importance of these criteria mechanism, AE
profile, indication in selecting a comparator?
FDA Comment

• The choice of a positive control for an NME,
  especially a first-in-class 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

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Q25 How should patients be selected for
FSD-204? (i.e., should they be stimulant
preferring patients)?
FDA Comment

• 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

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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

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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 (n200 FSD-204
  exposures).
• 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?)

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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?)
FDA Comment

• 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

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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