This presentation provides a high-level review of FDA’s guidance, offers strategies for analgesic product development and shares experiences with PROs and paper vs. tablet collection.

1. Strategies for Analgesic
Development and the FDA
Guidance for Analgesic Indications

2. Brett Gordon
• Project Director
Ben Vaughn
• Senior Statistical
Scientist

3. Topics
• Context
• New guidance
• Patient Reported Outcomes: Paper vs. Device
• Case Study
 Note: Case studies were developed from publicly available information
and do not include information about Rho’s clients or studies.

4. Context
• Prior analgesic guidance was from 1992
• For context, OxyContin was approved in 1995
• 1998 Effectiveness Guidance clarified agency’s
expectations for establishing efficacy and
extrapolating to a new population, dose,
regimen or form
• Broad indications have lead to historic
inconsistencies in labeling

5. Context
The new draft guidance:
• Addresses specific requirements for both
narrow and broad indications, and acute and
chronic pain indications
• Falls in line with agency’s recent approvals
• Reflects understanding gained over the past
decade in where extrapolation of narrow
indication trials to broad claims may not be
appropriate

6. New Guidance
Guidelines for establishing indications and
Claims are organized into:
• New Molecular Entities
• Reformulations of approved products
• Add-on or Adjunctive Indications
• Additional claims

7. New Molecular Entities (NMEs)
• Requirements build in a logical manner
• Must meet requirements for narrower
indications to achieve broad claims (Think
Monopoly: you need houses before hotels)
• All requirements are a minimum; additional
trials may be needed
• Typical product development will probably
focus on getting approval a specific indication
and slowly expand broader claims

8. New Molecular Entities (NMEs)
Specific/ Narrow indications:
• Typically two trials are sufficient
• Relatively narrow indications may be granted as a
result of efficacy being shown in limited settings
or substantial safety concerns exist
Breakthrough pain:
• Typically two trials
• Population should be on around the clock opioid
therapy of at least 60mg ME with persistent pain

9. New Molecular Entities (NMEs)
General acute pain:
• Typically two trials, one visceral, one non-visceral;
at least one in the intended setting (in-
patient/outpatient)
• Visceral pain
– Acute pancreatitis, renal colic, postoperative visceral
surgery
• Non-visceral
– Postoperative orthopedic surgery, fractures, and other
acute musculoskeletal pain

10. New Molecular Entities (NMEs)
Peripheral Neuropathic Pain (diabetic; post-herpetic
neuralgia; HIV-associated; post-traumatic
/postoperative; chemotherapy-associated):
• Two trials in specific condition for claim on that
condition
• May add an additional condition with one
additional trial in that condition
• At least one trial each in three conditions
required for general claim of treatment of
peripheral neuropathic pain

11. New Molecular Entities (NMEs)
Central Neuropathic Pain:
• Two trials in different conditions (pain of
spinal cord injury, post-stroke neuropathic
pain, or the pain of multiple sclerosis)
General Neuropathic Pain:
• Must meet requirements for general
Peripheral Neuropathic Pain and complete
one central Neuropathic Pain trial (four trials
total)

12. New Molecular Entities (NMEs)
Chronic Musculoskeletal Pain:
• Two trials in one indication for labeling in the
condition; one additional trial in a separate
condition for claim of Chronic Musculoskeletal
Pain

13. New Molecular Entities (NMEs)
Chronic Pain:
• Meet General Neuropathic Pain requirements
(four trials)
• Non-neuropathic Pain:
– Two trials in one condition
– Two trials in TWO other conditions
– Suitable conditions include osteoarthritis, chronic low
back pain, chronic visceral pain, cancer pain, and
fibromyalgia
• Eight trials in 7 conditions, total

14. Other Scenarios
Reformulations of approved products
• One trial may be sufficient for reformulation
– Includes modifications to release from IR products
• Two trials needed for new routes, new
populations, new indications
– Exceptions are made with adequate justification
Add-On or Adjunctive Indications
• Indication match the setting under which the
product was studied

15. Additional Claims
• Review the Patient Reported Outcome
Measures Guidance
• Assess whether reliable instruments exist and
whether it is feasible to create and validation
measures where they do not
• Discuss with agency intended claims
• Pre-specify and include statistical plans for
multiplicity

16. Efficacy Considerations
• Again, try to use established and reliable
instruments; Discuss with the agency EARLY in
development if a novel instrument is to be used
• Minimize recall:
– Avoid “pain relief” since it requires recall of prior state
– No more than 24h recall for worst pain intensity is
recommended
• Observer reported outcomes should be limited to
events, behaviors and signs that can be detected;
an observer can report wincing or crying, but not
intensity

17. Efficacy Considerations
• Avoid composite scales that span multiple
domains for primary outcome
• Multiple items within a domain are acceptable
• Responder definitions that incorporate pain
intensity, rescue and study completion may be
acceptable for primary
• Pain intensity outcomes must take rescue
medication use into account

18. Safety
• No major surprises in the guidance
• Analgesics are likely to be sedating and cause
respiratory depression; special monitoring
required while risk is assessed
• Naltrexone blocking should be used in early
phase testing for opioids, especially at higher
doses
• Follow-up periods for safety are likely to
extend past the time of the efficacy endpoint

19. Safety
• Abuse liability should be assessed as part of
development
• REMS requirements will expand to more
analgesic products where the risks are similar to
ER/LA opioids
• Post-marketing studies will be required to assess
risk of misuse, abuse, addiction, hyperalgesia,
overdose, tolerance and death
• NSAIDs should discuss with agency assessment of
CV risk including myocardial infarction, sudden
cardiac death, and cerebrovascular accident

20. Trial Considerations
Drop outs are a major challenge
• Allow use of rescue meds; take assessment prior to
issuing RM
• Use Add-on design (but might only support adjunctive
therapy indication)
• Allow for sufficient titration periods; opioids especially
can be challenge starting and stopping
• Titrate to effect to tailor to individuals needs and
tolerance
• Enrichment design: Removes subjects that are not
candidates for the product prior to randomization

21. Trial Considerations
• Time to onset of pain relief and time to rescue
or re-medication should be characterized; this
can be in a single- or multi-dose setting
• Acute pain, multi-dose trials
– Parenteral drugs should be followed a minimum of
24h; 48h in second trial if required
– Oral drugs should have longer follow up that
parallels the planned usage; assessments can be
pain right now and primary is time-weighted
average over follow-up (SPID24/SPID48)

22. Trial Considerations
Chronic pain
• Typically 12 week minimum duration (an
exception might be terminal cancer)
• Missing data strategies must be carefully
considered
• Primary efficacy should be change from
baseline to end of DB period
• Products should enter phase III with adequate
information to determine best trial design

23. Trial Considerations
Population
• Should mirror market population
• Narrow entry criteria=Narrow label; second trial
with broader criteria may support generalizability
• Try to keep any underlying disease and other
treatments stable
• If including subjects with prior substance abuse
history, specific monitoring should be included

24. Trial Considerations
Concomitant medications
• PK/PD studies may be needed to characterize
interactions between IP and likely conmeds
• Narrow entry criteria=Narrow label; second trial with
broader criteria may support generalizability
• Continuing usage of previous analgesic meds =
adjunctive indication
• Consider stratification when subjects continue existing
varying regimens for underlying disease
• Be certain to consider all therapies including non-drug

25. Trial Considerations
Pediatrics
• Unmet need, sponsors are encouraged to
perform trials to support pediatric indication
• See guidance
• Discuss with review division

26. Trial Considerations
Should be superiority trials, thus comparators
include:
• Placebo
• Lower dose of investigational drug
• Approved drug where the investigational drug
is expected to be superior
Even when primary is placebo, consider
including active comparator.

27. Outcomes
Pain intensity
• Must be a PRO
• NRS, VAS or categorical; each has advantages
and disadvantages that must be considered
• Disease-specific instruments may be
preferable (WOMAC for OA pain, for example)

28. Outcomes
Function
• Pain may impact physical and emotion
function; also, drug related AEs may impact
function
• Important to collect for informing risk/benefit
• Again, use established instruments where
available

29. Outcomes
Health Related Quality of Life
• Multi-domain
• Not appropriate as primary endpoint
• Unlikely to gain label claims as a secondary
• “welcome as an exploratory endpoint”

30. Outcomes
Rescue Medication
• If allowed, MUST be recorded and analyzed
• Specify drugs allowed
• Specify scenarios under which their usage is
triggered
• Specify timing of pain measures with respect
to RM usage

31. Outcomes
Global Single-Item Assessment
• Highly problematic: attempt to measure overall
experience, but contributing factors from subject
to subject vary wildly
• Not to be used for claims of treatment benefit
Opioid Sparing
• May provide evidence of efficacy
• If product is intended only for concomitant use
with opioids, must show additional benefit

32. Outcomes
Sleep
• Any claim must be clinically and statistically
meaningful beyond the analgesic effect
• Single-item assessments will not support label
claims
• Use established instruments that measure
specific domains: difficulty falling asleep,
staying asleep, and waking up refreshed

33. Statistical Considerations
• Should always have a single, primary analysis on
which to claim trial success
• Analyses should fully describe the drug’s efficacy:
Effect size, variability, onset, duration
• Responder analyses are easy to interpret, but
may be lower-powered
• Including a cumulative distribution function plot
in the package insert is suggested to better
inform prescribers of the trial outcome (!)

34. Statistical Considerations
• Include descriptive statistics for all clinically
relevant outcomes
• Always present some means for assessing
variability (CDFs, Boxplots, SDs)
• If there is not an established clinical
significance for your primary outcome, use
conservative estimates wherever possible to
maximize power [personal recommendation]

35. Statistical Considerations
Missing data
• Single Imputation (LOCF, BOCF, etc) is no
longer acceptable by default but may be used
as sensitivity analysis
• See “The Prevention and Treatment of Missing
Data in Clinical Trials” for recommendations;
final method will be specific to the protocol
• Method must be pre-specified

36. Tablets (and other e-devices)
vs. Paper
An assortment of new technology is available for
collecting patient reported outcomes
Examples:
• IVRS
• IWRS
• Tablets
• Smartphones

37. Key advantages of Electronic
Collection
• Data are available much faster (sometimes
instantly)
• Devices can trigger alarms to prompt patients (or
an IVRS may call at a specific time), giving
consistency in time of collection and minimizing
missing data
• Instructions may be programmed into the device
to guide subjects for more consistent answers
• Site staff does not have to key data or manually
measure VAS scores
• Elimination of digit bias

38. Disadvantages of Electronic Collection
• Staff training, staff re-training
• Validation of the device
• Population level of comfort with device
• Cost
• Accuracy (?) Finger size vs. pen mark
• If your pen breaks, you don’t have to call tech
support

39. Digit Bias
• Can generally be ignored but interesting to
observe in action
• On a 100 point VAS, there should be roughly
equal numbers of multiples of 5 and multiples
of 5 +/- 1 (i.e. 44, 45 and 46 should appear
roughly equally: 33% for each)
• Very consistently, hand-measured VAS
outcomes return 40% for multiples of 5

40. Digit Bias
• On an 11 point NRS, it’s not uncommon for
subjects to use just 2 or three numbers
repeatedly
• Hand held devices can eliminate the issue by
presenting a slider with no numbers
associated

41. Key Considerations for Electronic vs.
Paper PRO collection
• Is the site comfortable and experienced with
the device?
• Is the subject population comfortable with the
device?
• Will you be collecting daily measures or in-
clinic?
• How many outcomes will be collected?

42. Case Study- Cymbalta (duloxetine)
• 1994- Originally approved for Major
Depressive Disorder
• 2006- Approved for Diabetic Painful
Neuropathy
– Peripheral Neuropathic Pain
– Two trials in specific condition for claim on that
condition
• 2007- Approved for Generalized Anxiety
Disorder

43. Case Study- Cymbalta (duloxetine)
• 2009- Approved for Fibromyalgia
– Specific/ Narrow indications
– Two trials in specific condition for claim on that
condition
• 2010- Approved for Chronic Musculoskeletal
Pain
– Chronic Low Back Pain- two trials
– Osteoarthritis
• Needed minimum of one trial
• Conducted two trials

44. Case Study- Cymbalta (duloxetine)
• What about a Treatment of Chronic Pain
indication?
– Meets Non-Neuropathic criteria (At least four
trials in three conditions)- Fibromyalgia, LBP, OA
– Need General Neuropathic Pain
• Need one trial in one central neuropathic condition
• Need Peripheral Neuropathic Pain
» Meets two trials in any one condition- DPN
» Need one additional trial in each of two conditions
– Would still need to conduct minimum of 3 trials

45. Pain
Acute Chronic
Narrow
2 trials in
1 condition
Breakthrough
2 trials in
1 condition
General
2 trials in nociceptive
- 1 visceral
- 1 non-visceral
Musculoskeletal Neuropathic
General
8 trials
- General Neuropathic Indication (4 trials)
- 2 trials in 1 non-neuropathic condition
- 1 trial in each of 2 other non-
neuropathic conditions
Narrow
2 trials in
1 condition
General
3 trials
- 2 condition A
- 1 condition B
Peripheral Central
General
4 trials
- Peripheral
Indication
(3 trials)
- 1 central trial
Narrow
1st Condition
- 2 trials
2nd Condition
- 1 trial
General
3 trials
- 1 condition A
- 1 condition B
- 1 condition C
Narrow
2 trials in
1 condition
General
2 trials
- 1 condition A
- 1 condition B

46. Case Study- CDRH Comparison
• MONOVISC- Approved February 25, 2014
– Hyaluronic acid(HA) visco-supplementation
– Indication- treatment of pain in osteoarthritis (OA)
of the knee
– Trials completed for initial PMA submission: 1
– Trials demonstrating superiority for the primary
effectiveness endpoint: 0
– New trials completed: 0

47. Case Study- CDRH Comparison
• MONOVISC- How?
– Post-hoc non-inferiority analysis
• Historical comparison to data used for ORTHOVISC
approval in 2004
• ORTHOVISC (3 syringes) vs MONOVISC (1 syringe)
• Closer look at ORTHOVISC approval
– Trials completed: 3
– Trials demonstrating superiority for the primary effectiveness
endpoint: 0
– Approval granted on combined effectiveness subgroup
population from 2 of 3 trials
– What would CDER do?

48. References
• Guidance for Industry Analgesic Indications: Developing Drug
and Biological Products(Feb 2014).
• Guidance for Industry Providing Clinical Evidence of
Effectiveness for Human Drug and Biological Products (May
1998)
• Guideline for the Clinical Evaluation of Analgesic Drugs (Dec
1992)
• Analgesic Indications A Historical and Regulatory Perspective
(Cymbalta Ad Com, Aug 2010)
• MONOVISC Summary of Safety and Effectiveness Data (Feb
2014)
• ORTHOVISC Summary of Safety and Effectiveness Data (Feb
2004)