strategies for analgesic development and the fda guidance for analgesic indications

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Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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Page 1: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Strategies for Analgesic Development and the FDA

Guidance for Analgesic Indications

Page 2: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Brett Gordon• Project Director

Ben Vaughn• Senior Statistical

Scientist

Page 3: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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.

Page 4: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 5: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

ContextThe new draft guidance:• Addresses specific requirements for both narrow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

Page 6: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 7: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 8: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 9: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 10: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 11: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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)

Page 12: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 13: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 14: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Other ScenariosReformulations 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

Page 15: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 16: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 17: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 18: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 19: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 20: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Trial ConsiderationsDrop 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

Page 21: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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)

Page 22: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Trial ConsiderationsChronic 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

Page 23: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Trial ConsiderationsPopulation• 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

Page 24: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Trial ConsiderationsConcomitant 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

Page 25: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Trial ConsiderationsPediatrics• Unmet need, sponsors are encouraged to

perform trials to support pediatric indication• See guidance• Discuss with review division

Page 26: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Trial ConsiderationsShould be superiority trials, thus comparators include:• Placebo• Lower dose of investigational drug• Approved drug where the investigational drug

is expected to be superiorEven when primary is placebo, consider including active comparator.

Page 27: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

OutcomesPain 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)

Page 28: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

OutcomesFunction• 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

Page 29: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 30: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

OutcomesRescue 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

Page 31: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

OutcomesGlobal 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 benefitOpioid Sparing• May provide evidence of efficacy• If product is intended only for concomitant use

with opioids, must show additional benefit

Page 32: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

OutcomesSleep• 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

Page 33: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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 (!)

Page 34: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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]

Page 35: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Statistical ConsiderationsMissing 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

Page 36: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 37: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 38: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 39: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 40: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 41: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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?

Page 42: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 43: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 44: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 45: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

Pain

Acute Chronic

Narrow2 trials in 1 condition

Breakthrough2 trials in 1 condition

General2 trials in nociceptive- 1 visceral- 1 non-visceral

Musculoskeletal Neuropathic

General8 trials- General Neuropathic Indication (4 trials)- 2 trials in 1 non-neuropathic condition- 1 trial in each of 2 other non-

neuropathic conditions

Narrow2 trials in 1 condition

General3 trials - 2 condition A- 1 condition B

Peripheral Central

General4 trials- Peripheral Indication (3 trials)- 1 central trial

Narrow1st Condition- 2 trials

2nd Condition- 1 trial

General3 trials- 1 condition A- 1 condition B- 1 condition C

Narrow2 trials in 1 condition

General2 trials- 1 condition A- 1 condition B

Page 46: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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

Page 47: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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?

Page 48: Strategies for Analgesic Development and the FDA Guidance for Analgesic Indications

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)