# Presentation: 845311

## Outcomes in Randomized Controlled Trials in Pain:A Proposed Responder Analysis

**Vibeke Strand, MD**
**Biopharmaceutical Consultant**
**Clinical Professor, Division of Immunology, Stanford University**

## Responder Analyses have Face and Content Validity

**Allow assessment of multiple domains**
**Could better categorize analgesics**
**Facilitate comparison of efficacy across:**
**Products**
**Heterogeneous populations, and**
**Multiple disease indications**
**May lead to tiered approach to label indications**
**Precedent: ACR Responder Index in RA**

## ACR Response Criteria used in RA RCTs

**Require ≥20% improvement in 5 of 7 measures:**
**Tender Joint Count****	****  and Swollen Joint Count**
**and 3 of the following 5:****	****	****	****	****	****	****	****	****	****MD Global****	****	****	****	****Physical function: HAQ****	****	****	****	****Pain by VAS****	****	****	****	****Patient Global****	****	****	****	****ESR and/or CRP **

## Strength of Rheumatoid Arthritis GuidanceDocument

**Tricenter agreement; Proven track record ******** 6 products!**
**Tiered Label Indications:**
**Improvement in Signs and Symptoms**
**By ACR Response Criteria**
**At 6 or 12 months**
**Inhibition of Radiographic Progression**
**Sharp Scores [erosions + JSN]**
**At 12 months**
**Improvement in physical function and HRQOL**
**HAQ and SF-36**
**Over 2-5 years**
**May be achieved in a single protocol using prespecified ****	****outcome criteria and Hochberg analysis**

## Appropriate Domains for Inclusion in RCTsin Chronic Pain

**Based on a Breakout Session at the Jointly **
**Sponsored FDA / NIH Workshop in May 2002**
**Definition for the Workshop:**
**RCTs of ≥ 3 months duration;**
**In patients with pain of > 3 months duration,**
**regardless of underlying cause**

## Examples of Chronic Pain Indications

**Musculoskeletal**
**RA**
**OA**
**Low Back Pain**
**Fibromyalgia**
**Neuropathic**
**Diabetic Neuropathy**
**Post Herpetic Neuralgia**
**Trigeminal Neuropathy**
**Cancer Pain ****[not necessarily >3 months]**
**Rapidly progressive disease**
**Adjust intervention as disease progresses**

## Proposed Domains for Chronic Pain

**To Be Selected:**
**Regardless of clinical indication**
**Consider available instruments; whether or not**
**Validated in pain or specific clinical indications**
**Previously used in RCTs in Pain**
**Disease specific or generic**** **
**Strength of choices based on multiple available ****	****instruments and prior clinical experience**
**	**

## Proposed Domains for Chronic Pain

**PAIN****: brief, ongoing; allodynia****	****“Need multiple measures of pain”****	****	****Patient global assessment****	****	****Rescue medications****	****	****Time to treatment failure****	**
**Suffering**
**Pain relief**
**Disease specific measure of improvement /**** ****	****physical function**
**Health related quality of life [****HRQOL****]**
**Patient global**** assessment**
**AEs****; and how perceived by the patient**
**Damage****: irreversible due to disease or its Rx**
**Economics**

## Appropriate Domains for Chronic PainFinal Vote

**  ****PAIN****: unanimous: 28**
**  ****Physical function**** / ****disease specific measure****: 27**
**  ****HRQOL****: 24**
**  ****Patient Global****: 15**
**  ****AEs****: 11**
**This represents a “core set” of minimum required outcome domains to be assessed.  Others, specific to the underlying disease process or the clinical indication, may be added as secondary endpoints.....**

## Goal: Define Improvement Multidimensionally

**Separate experience of pain itself, from:**
**Functional Impairments and Disability**
**Which may / may not ensue**
**Separate ‘physical impairment’ from ‘disability’**
**Utilize individual responder analyses**
**Utilize disease ‘specific’ or ‘relevant’, ****	**
**	****as well as generic measures of HRQOL**

## 
      Functional Limitations

		??

   Disability          “In the eyes of the beholder”
       Age, Gender Appropriate
       Work v Family / Social

**      ****Functional Limitations**
**	****                  **
**	****	****??**
**          **
**   ****Disability****   ****       “In the eyes of the beholder”**
**       ****Age, Gender Appropriate**
**       ****Work v Family / Social**

**Limitations Do NOT Necessarily Imply ****Disability**

**	****	****	****	****	**
**IMPAIRMENT****  ****Due to Pain &/or ****  Structural****  Alterations **

## Measures for Chronic Pain: Patient GlobalAssessment of Treatment Intervention

**“****In all the ways your pain affects you, including its treatment,****how are you doing today?”**
**Transition question**
**Utilities:**
**EuroQOL or EQ5D**
**Health Utility Index: ****HUI**

## Minimum Clinically Important Differences[MCID]

**Degree of improvement in various  outcome measures**
**Perceptible to patients**
**Considered clinically important / meaningful**
**Defined by patient query, delphi technique****	****OMERACT: 33-36% improvement; 18% > placebo**
**Demonstrated by statistical correlations with clinical ****	****responses in RCTs;    **_**patient global assessments**_
**Determination of proportion of patients with clinically ****	****important improvement provides a more ****	****interpretable result with direct clinical implications**

## Consistency of MCID Values

**Changes in disease specific or ‘relevant’ measures ****	****of function / HRQOL related to ‘much’ or ‘very ****	****much’ improvement in patient global ****	****assessment **
**Changes in generic measures of HRQOL related to ****	****improvements in patient global assessment**
**Consistent high correlations between disease ****	****specific and generic measures of HRQOL**
**MCID values consistent.  Examples: OA****	****	****	****	****	****	****  RA****	****	****	****	****	****	****  FM**

## Measures of Chronic Pain

## Measures of Chronic Pain: PAIN

**Numeric Pain Intensity Scale**
**VAS or Faces or graphic scales: anchor VAS**
**Verbal rating scales: Likert or VAS**
**Brief Pain Inventory - ****BPI**
**McGill Pain Questionnaire – ****MPQ**
**Chronic Pain Coping Inventory - ****CPCI**
**West Haven-Yale Multidimensional Pain Inventory – ****MPI**
**ASA Nine Outcomes Measures**
**Treatment Outcomes in Pain Survey - ****TOPS**
**	**

## Faces Rating Scale

## MCID: Pain Intensity Numerical Rating Scalev. Patient Global Assessment of Change

**10 placebo RCTs of Pregabalin in:****	****Diabetic neuropathy, ****	****	****Postherpetic neuralgia, ****	****LBP, ****	****	****Fibromyalgia and ****	****OA**
**Relationship of “much”, “very much” improved in ****	****PGIC **[LIkert 5]** to PI-NRS **[10 points]
**Reduction of 30% or 2 points in Pain Intensity ****	****[PI-NRS] = MCID**
**Regardless of Baseline pain or disease state**

**Farrar et al: Pain 2001; 94:149-158**

## Measures of Physical Function &/or HRQOL Chronic PAIN

**Brief Pain Inventory – BPI: ****cancer**** ****HRQOL; ****	****not extensively validated in non malignant pain  **
**McGill Pain Questionnaire – MPQ:****	****intensity and subjective experience of pain**
**Chronic Pain Coping Inventory –**** ****CPCI:****	****coping strategies and level of adjustment**
**Multidimensional Pain Inventory –**** ****MPI: ****HRQOL****	****	****how psychosocial role functioning affected;****	****omits work-related activity**
**Treatment Outcomes in Pain Survey –**** ****TOPS: ****HRQOL ****	****measured longitudinally in individuals **
**	**

## Generic HRQOL Instruments

**Sickness Impact Profile – SIP   ****implies illness**
**Nottingham Health Profile -**** ****NHP**
**Medical Outcomes Survey [MOS] -**** ****SF-12 and SF-36**
- 	**HRQOL in large groups; across disease states**
**	****Limited assessment of UE, facial pain; **
**	****Poor differentiation of LBP v upper body pain**
**WHO Quality of Life Instrument -  WHOQOL-100****    ****Newer instrument**
**EuroQOL or EQ5D    ****widely used**** ****in EU**
**Quality of Well Being - QWB**

## Disease Specific [‘Relevant’]Measures of Physical Function &/or HRQOL

## Disease Specific Measures: Physical Function &/or HRQOL

**Rheumatoid Arthritis:****	****HAQ, MHAQ, MDHAQ**
**	****	****	****	****	****AIMS, AIMS-2**
**	****	****	****	****	****MACTAR, PET**
**Osteoarthritis:**** WOMAC**
**	****	****	****        ****Harris Hip Score**
**	****	****	****        ****HSS Knee Score and Knee Society Score**
**	****	****	****        ****Ankle OA Score**
**	****	****	****        ****AOFAS hind-, mid- and fore-foot scores**
**LBP:****  Roland-Morris****	****   Oswestry Disability Questionnaire**
**Geriatrics:**** Katz Index of Independence in ADLs**
**	****	****	**** ****HAQ**
**Cancer:**** Functional Living Index, Cancer: FLIC**
**	****	****       ****Functional Assessment of Cancer Therapy: FACT**

## EXAMPLE:Rheumatoid Arthritis: Disease Specific Measures of Physical Function &/or HRQOL

## Health Assessment Questionnaire - HAQ

**Widely accepted, validated, rheumatology-specific ****	****instrument to assess ****physical function**** in RA**
**Gold Standard: OMERACT/FDA Guidance**
**20 questions**** covering ****8 types of activities****  ****	****Dressing + Grooming; Arising; Eating; Walking; ****	****Hygiene; Reaching; Gripping, ADLs**
**HAQ Disability Index (HAQ DI)**
**Scores the worst items within each scale**
**Based on use of aids and devices**
**Other, shorter versions equally useful: MHAQ, MDHAQ**

**Notes:**
With regards to the specific instruments included in the Leflunomide trials,

The HAQ is the most widely used validated disease specific instrument to assess physical function and disability over time in rheumatology research and randomized controlled clinical trials.  It is accepted as a Gold Standard 
Likewise it is recommended by both:
	1999 FDA Final Guidance for Industry
	and OMERACT
The self-administered instrument consists of 21 questions with 8 domains (dressing and grooming, rising, eating, walking, hygiene, reach, grip, activities)

The HAQ Disability Index uses scores of the worst items within each of the eight domains with Sores range from 0 to 3.  

__________________________________________
[Note to Joe Doyle:  Collect articles that correlate HAQ DI to progression or Early changes in HAQ DI (over 2yrs) to long-term outcomes (disability, function, work disability)]

## SF-36: Short Form 36 Health Survey

**Validated, widely used generic measure of HRQOL**
**8 Domains scored 0 - 100; age, gender adjusted norms**
**Designed to evaluate health status of large groups**
**Doesn’t separate work limitations v everyday activity **
**Summary Scores: Normative based (Mean: 50, SD: 10)**
**Physical Component: PCS**
**Impact of physical fxn impairment / disability**
**Mental Component: MCS**
**Impact of mental affect, pain symptoms**
**Change evident within 4 weeks**

## SF-36 Two-Component Model

**Physical****component**

**SF-36 Two-Component Model**

## Minimum Clinically Important Differences [MCID]

**2  ****Kosinski et al. *****Arth Rheum.***** 2000; 43:1478-87****3  ****Redelmeier et al. *****Arch Intern***** *****Med*****. 1993; 153:1337-42**
**4  ****Wells et al. *****J Rheumatol.***** 1993; 20:557-60****5  ****Kosinski et al. *****Arth Rheum.***** 2000; 43:S140 **
**6  ****Samsa et al. *****Pharmacoeconomics*****. 1999; 15:141-155 **
**7  ****Thumboo et al. *****J Rheumatol*****. 1999; 26:97-102.**

**Minimum Clinically Important Differences ****[MCID]**

**     ****     ****HAQ DI ****1-4****	****     ****0 - 3****	****  –****	****0.22****	**
**     ****SF-36 ****2, 5-7****	****        ****0 - 100****	****  +****	****5 - 10 points****	**
**     ****PCS/MCS mean ****	****  50 ± 10****	****  +****	****2.5 - 5 points****	**

**	****Score****	****Direction****	****	****	****MCID**
**	****Range****	**** of Scoring****	****	****Literature****	**** ****	**

**Notes:**
This table illustrated the MCID for the HAQ DI, PET Top 5 and the SF-36 as sited in the literature and by recent efforts of the  Outcomes Measures in Rheumatology Clinical Trials (commonly referred to as OMERACT)

## Mean Improvement in HAQ Disability Index Year-2 Cohort at 24 Months

**Improvement**

**Worsening**

**Mean Change from Baseline**

**LEF**

**MTX**

**US301**

**MN302/304**

**SSZ**

**MN301/303/305 **

***LEF vs MTX; p=0.01**

**-1**

**-0.5**

**0**

**-0.22**

**-0.73**

**-0.56**

**-0.6**

**-0.37**

**-0.48**

**-0.56**

*****

**(248)**

**(273)**

**(51)**

**(46)**

**(97)**

**(101)**

## ATTRACT: HAQ Disability IndexMean Improvement through Week 102

**ATTRACT: HAQ Disability Index****Mean Improvement through Week 102**

**MTX + Placebo**

**3 mg/kg**
**q8w**

**3 mg/kg**
**q4w**

**10 mg/kg**
**q8w**

**10 mg/kg**
**q4w**

**< 0.001**

**< 0.001**

**< 0.001**

**< 0.001**

**p-value vs. MTX + Placebo**

**0.2**

**0.4**

**0.5**

**0.5**

**0.4**

**0.45**

**0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**All**
**infliximab**

**Mean improvement**

## ERA: Improvement in HAQ Disability Indexat 24 months 

**Baseline:      ****	****1.44****	****1.49****	**

## US 301: Baseline SF-36 Scores US Norms vs US301 Population

**0**

**Physical****Function**

**Role****Physical**

**Bodily****Pain**

**General****Health****Perception**

**Vitality**

**Social**
**Function**

**Role****Emotion**

**Mental****Health**

**Study US301 Population**

**US Norms (A/S Adjusted)**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

## US301: Mean Improvement in SF-36 DomainsITT Cohort at 12 Months

**PBO (n=101)**

**LEF (n=157)**

**MTX (n=162)**

***LEF vs PBO p<0.05****†****LEF vs MTX p<0.05**

**US301: Mean Improvement in SF-36 Domains****ITT Cohort at 12 Months**

**	****Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****	****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****	****Perception**

**-4**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

*****

*****

*****

*****

*****

- †

- †

**Improvement**

**Worsening**

**Mean Change from Baseline**

## US301: Mean Improvement in SF-36: Year-2 Cohorts Leflunomide and Methotrexate

**US301: Mean Improvement in SF-36: Year-2 Cohorts Leflunomide and Methotrexate**

**Mean Scores**

**Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****	****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****	****Perception**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**US Norms (A/S Adjusted)**

**    ****Baseline Year-2 Cohort**

## US301: Mean Improvement in SF-36: Year-2 Cohorts Leflunomide and Methotrexate

**US301: Mean Improvement in SF-36: Year-2 Cohorts Leflunomide and Methotrexate**

**Mean Scores**

**Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****	****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****	****Perception**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**LEF 24 Months (n = 93)**

**MTX 24 Months (n = 89)**

**US Norms (A/S Adjusted)**

**Baseline Year-2 Cohort**

## ATTRACT: Mean Improvement in SF-36 Week 54: Physical Domains

**MTX**
**Control**

**3 mg/kg**
**q8 Wks**

**3 mg/kg**
**q4 Wks**

**10 mg/kg**
**q8 Wks**

**10 mg/kg**
**q4 Wks**

**0.035**

**<0.001**

**<0.001**

**0.002**

**MTX**
**Control**

**3 mg/kg**
**q8 Wks**

**3 mg/kg**
**q4 Wks**

**10 mg/kg**
**q8 Wks**

**10 mg/kg**
**q4 Wks**

**0.083**

**<0.001**

**<0.001**

**0.002**

**p-value vs. MTX control**

**p-value vs. MTX control**

## US301: Mean Improvement in PCS and MCS Leflunomide Year-2 Cohort at 12 & 24 Months

**Baseline**

**Month 12**

**Month 24**

**(n=93)**

**(n=93)**

**(n=93)**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**PCS**

**MCS**

**30.9**

**42.7**

**41.7**

**48.5**

**52.2**

**53.2**

**US Norm**

**US301: Mean Improvement in PCS and MCS ****Leflunomide Year-2 Cohort at 12 & 24 Months**

**2 SDs ****below ****US Norm**

**PCS= Physical Component Summary Score**
**MCS=Mental Component Summary Score**

## ATTRACT: Median Improvement in SF-36 PCS Week 102

**ATTRACT: Median ****Improvement in SF-36 PCS ****Week 102**

**Baseline:      ****	****23.9 – 30.8******

## ERA: Mean Improvement in SF-36 PCS

**ERA: Mean ****Improvement in SF-36 PCS**
**12 Months **

**MTX**
**(217)**

**10 mg**
**(208)**

**25 mg**
**(207)**

**MTX**
**(204)**

**10 mg**
**(194)**

**25 mg**
**(198)**

**MTX**
**(199)**

**10 mg**
**(188)**

**25 mg**
**(****193****)**

**Baseline**

**6 Months**

**12 Months**

***p < 0.01, 25 mg vs 10 mg**

**Mean Normal Scores**

**US Norm**

*****

**29.20**

**  ****28.01**

## MCID Values Consistent in RCTs in RA

**Improvements in HAQ DI and SF-36 in RA****	****with newly approved therapies are statistically ****	****significant; more importantly, CLINICALLY ****	****MEANINGFUL**
**MCID values are consistent across agents and patient ****	****populations**
**Disease specific [‘relevant’] measure: HAQ**
**Generic measure: SF-36**
**Improvements in disease specific highly correlated ****	****with generic measures**

## EXAMPLEOsteoarthritis: Disease Specific Measures of Physical Function &/or HRQOL

## Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index 

**Self-administered questionnaire**
**Developed querying patients with hip or knee OA**
**Reflects physical activities most affected by symptoms, disease manifestations**
**Composite score based on 24 questions; subscores:**
**Pain (5 questions)**
**Joint stiffness (2 questions)**
**Physical function (17 questions)**
**Scored by 0 - 4 Likert or 0 - 10 cm VAS scales**
**Improvement = negative change**

## WOMAC Scores in Osteoarthritis: MCID

**MCID in WOMAC composite score, Likert scale****:**
**12 wk pivotal OA RCTs with Celecoxib:   ****10.1**** [0 – 89]**
**Pain, Stiffness, Physical Fxn:  2.1, 1.2, 6.5****[0 – 20]  [0 – 8]  [0 – 61]**** **
**MCID in WOMAC VAS****:**
**Anchoring to Patient Response to Rx  [0-4 Likert scale]**
**6 wk RCTs OA hip, knee; Rofecoxib v Ibuprofen v PL:**
**Pain, Stiffness, Physical Fxn: ****9.7, 10, 9.3 mm, VAS**
**11 mm VAS for Patient Global Assessment**** ****	****	****	****	**** **

**Ehrich et al: **** JRheum***** *****2000;27: 2635-2641**

**Zhao et al. Pharmacother 1999;19:1269-78**

## Improvement in WOMAC Composite ScoresWeek 12 from Baseline: Pivotal OA Trials

**Improvement in WOMAC Composite Scores****Week 12 from Baseline: Pivotal OA Trials**

**Improved Scores**

**Zhao et al *****Pharmacother***** 1999;19:1269-78**

## WOMAC Physical Function Subscale12 months: Pivotal RCT, OA knee or hip

**R = randomization**
***P***** < 0.05 for all groups; treatment response compared with baseline **
**Cannon GW, et al. *****Arthritis Rheum*****. 2000;43:978–987.****  **

**Mean Change (mm)**

**-30**

**-35**

**-25**

**-20**

**-15**

**-10**

**-5**

**0**

**R**

**2**

**4**

**8**

**12**

**26**

**39**

**52**

**Week**

**Rofecoxib 12.5 mg**
**Rofecoxib 25 mg**
**Diclofenac 150 mg**

**Mean baseline = 69.6 mm**

## Mean Improvement in SF-36: All Rofecoxib v Normative Data US Population

**	****PF****	****        RP****	****PAIN****	****GHP****	****     VITAL****	****SOC****	****RE****	****          MH**

**Mean Improvement in SF-36: All Rofecoxib ****v Normative Data US Population**

**Difference between ages 45-54 and 55-64**
**US population.  Ware et al 1993**

## Change in  SF-36 Scores at Week 12 from Baseline: Pivotal Trial in OA of knee

*** p < .05 v placebo**

## SF-36 Scores at Week 12 in OA of kneev US Normative Data in 55-65 year olds

## MCID Values Consistent in RCTs in OA

**Improvements in WOMAC and SF-36 in OA****	****with newly approved therapies are statistically ****	****significant; more importantly, CLINICALLY ****	****MEANINGFUL**
**MCID values are consistent across agents and patient ****	****populations**
**Disease specific measure: WOMAC**
**Generic measure: SF-36**
**Improvements in disease specific highly correlated ****	****with generic measures**

## EXAMPLEFibromyalgia: Disease Specific Measures of Physical Function &/or HRQOL

## Fibromyalgia: Pain, Sleep Disturbance and Fatigue Correlated

**Consistent relationships**** between patient reported:**
**Pain Diary – NRS****    Pain by MPQ – VAS****    Sleep Quality Diary – NRS ****    Multidimensional Assessment of Fatigue – MAF**
**Numerical rating [NRS] recorded daily ****	****  visual analog [VAS] scales reported weekly **
**High baseline scores**** = impaired sleep and much fatigue**
**Low scores in SF-36 RP, BP and Vitality**
**Poor sleep quantity and quality: MOS-Sleep **
**High scores in MAF = Fatigue**
**Higher levels of anxiety than depression: HADS**

**Corbin et al: Arth Rheum 2001; 44:S66-67, S212**

## EXAMPLECancer Pain: Disease Specific Measures of Physical Function &/or HRQOL

## Measures of Physical Function &/or HRQOLCANCER

**Functional Assessment of Cancer Therapy: ****FACT**
**Linear Analog Self Assessment: ****LASA**
**Functional Living Index – Cancer: ****FLIC**
**Quality of Life Index: ****QLI**
**European Organization for Research and Treatment ****	****of Cancer Questionnaire: ****EORTC**
**Cancer Rehabilitation Evaluation System: ****CARES**
**Treatment Outcomes in Pain Survey – ****TOPS**
**Missoula-Vitas Quality of Life Index: ****MVQLI**

## Measures of Physical Fxn, HRQOL - CANCER

**Treatment Outcomes in Pain Survey**** ****– TOPS     ****	****Designed as extension of SF-36; HRQOL ****	****Tracks responses in individual patients over time****	****Valid in multiple models of chronic pain / ****	****	****	****	****multidisciplinary treatment of pain**
**Functional Living Index, Cancer – FLIC ****	****Scales for specific patient populations, diseases**
**Functional Assessment of Cancer Therapy – FACT ****	****Scales for specific patient populations, diseases ****	****	****5 subscales generally relevant; Likert scales**
**Linear Analog Self Assessment Scales – LASA**** ****	****Scales for specific patient populations, diseases ****	****VAS scales; readily comprehensible, convenient**

## Appropriate Domains: Responder Analysis for Chronic Pain 

**PAIN:****  ****	****multiple instruments****	****     ****	****	****	****NRS, VAS or Face Scales**
**Disease specific [‘relevant’] physical fxn / HRQOL:****	****Many instruments; specific to disease state****	****or TOPS****	****when relevant, may add measures of sleep, ****	****	****	****depression, etc.**
**Generic measure of HRQOL:  ****	****such as SF-36**** ****facilitate comparisons across ****	****	****treatments, populations, ****	****diseases **
**Patient Global**** ****Assessment of Risk/Benefit****	****Specific Question, or****	****Health Utility Measure: HUI, EQ5D**
**AEs**

## Appropriate Domains: Responder Analysis for Acute Pain: 24-48 hours duration

**PAIN:****  **
**Brief Pain Inventory – BPI**
**VAS or Faces Rating Scale**
**Numerical Rating Scale – NRS**
**Time to Treatment Failure**
**Rescue Medications**
**Patient Global**** ****Assessment of Risk/Benefit**
**AEs**
**? Necessity for HRQOL Measure in Acute Pain ?**

## Appropriate Domains: Responder Analysis for Acute Pain of ≥ 2 Weeks Duration

**PAIN****: Brief Pain Inventory – BPI****	****    VAS or Faces Rating Scale****           Numerical Rating Scale – NRS****	****    Time to Treatment Failure****	****    Rescue Medications**
**Physical function**** ****/**** ****disease “relevant” measure****:****	****According to disease population; indication****	****or TOPS**
**Generic HRQOL****: SF-36 well validated**
**Patient Global**** ****Assessment of Risk/Benefit****:****	****Specific question****	****HUI or EQ5D**
**AEs**

## MCID: Acute Pain Cancer Related Breakthrough Pain

**Titration phase: multiple cross-over RCT of ****	****oral transmucosal fentanyl citrate**
**130 treatment [not opioid] naïve patients; ****	****1268 episodes of pain**
**Differences in pain scores between episodes which ****	****did, did not yield adequate pain relief**
**MCID:****        Pain Intensity Difference [****PID****] 0-10 ****=**** ****33%****Maximum Total Pain Relief [****TOTPAR****] 60 mins ****= 33%**
**Absolute ****PID****, Pain Relief [****PR****], Sum of PID over 60 ****	****mins [****SPID****] ****= 2 of 5 points in Likert scale**

**Farrar et al: Pain 2000; 88:287-94**

## Conclusions: Responder Analyses in Pain RCTs

**Domains consistent for chronic pain and ≥ 2 weeks**
**Minimum number of required domains **
**Assessed by a variety of validated instruments**
**Add other domains as secondary endpoints**
**PAIN: include time to Rx failure; use of rescue meds **
**Chronic Pain [TOPS] or Disease specific [‘relevant’] ****	****HRQOL measures available; validated**
**Addition of generic measure of HRQOL important**

## Conclusions: Responder Analyses in Pain RCTs

**As with other Responder Analyses could require:**
**Improvement in a majority of domains but NOT ALL**
**Without deterioration in the others**
**Degree of improvement required could be based on ****	****MCID values**
**Improvement across multiple domains not closely correlated: **
**Reflects a ROBUST clinical response**
**May add statistical power; decrease sample sizes**

## That these decisions be evidence based!!!

## “Universal Quality of Life Scale“

**“****Universal Quality of Life Scale“**