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Background Analysis: US FDA Advisory Committee to Review Pediatric Trial Outcomes for Purdue’s Butrans – SEP 14, 2017 (AADPAC/DSRM)
The US FDA has scheduled a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the Drug Safety and Risk Management Advisory Committee (DSRM) for Thursday, September 14, 2017. The Committees will discuss supplemental new drug applications (sNDAs) for Butrans (buprenorphine transdermal system, BTDS) submitted by Purdue Pharma L.P. (Purdue), evaluating Butrans in pediatric patients aged 7 through 16 years for management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The Committees will be asked to discuss the findings of the clinical study of Butrans conducted in pediatric patients, and whether they support additional labeling.
Description of Indication
Chronic pain is pain that lasts more than 12 weeks. It can originate from an injury, such as a back sprain, or there may be an ongoing cause, such as illness. Sometimes the cause is unclear.
Chronic pain can lead to limited movement and reduced flexibility and strength. The pain associated with doing important and enjoyable activities for a person with chronic pain can cause emotional despair. Chronic pain can also contribute to other health problems, such as fatigue, sleep disturbance, decreased appetite, and mood changes.
Description of Product
Buprenorphine is a partial opioid agonist/antagonist. Prior to the initial 2010 approval of Butrans (buprenorphine transdermal patch), there was only one parenteral formulation of buprenorphine approved for the management of pain, and there were sublingual formulations of buprenorphine, with and without naloxone, that were approved for the treatment of opioid addiction. The current labeled indication for Butrans states that it is a partial opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. It is available in 5 strengths: 5 microgram/hour (mcg/h0, 7.5 mcg/h, 10 mcg/h, 15 mcg/h, and 20 mcg/h.
Clinical Trials of Proposed Indication
The sNDAs are based on Purdue’s pediatric clinical study of Butrans (ClinicalTrials.Gov ID: NCT01324570), an open-label trial of the safety, pharmacokinetics (PK) and efficacy in children from 7 to 16 years of age who require continuous opioid analgesia for moderate to severe pain. Patients were treated for up to 24 weeks.
The primary outcome measures were as follows:
· safety: the number of adverse events (AEs)
· PK: apparent clearance (CL/F) at various time points
· PK: apparent volume of distribution (Vc/F) at various time points
The secondary outcome measures were as follows:
· efficacy: pain right now assessment in patients 7-11 years of age
· efficacy: pain right now assessment in patients 12-16 years of age
· efficacy: patient/caregiver-assessed global impression of change (PGIC)
A total of 41 patients were enrolled, with 6 patients between the ages of 7 and 11 years, and 35 patients between the ages of 12 and 16 years. Two patients in the lower age group completed the trial, and 21 patients from the older age group completed the trial. Four of the younger patients withdrew due to an AE. Reasons for non-completion in the older age group were due to an AE (7 patients), withdrawal by patient (3 patients), lack of efficacy (1 patient), confirmed or suspected diversion (1 patient) and administrative reasons (2 patients).
The safety population (N=41) was the group of patients who received at least 1 dose of study drug during the study. Five patients in each age group experienced a serious AE (SAE). For the younger group (N=6), the reported SAEs were anemia (16.67%), atrioventricular block first degree (16.67%), Crohn’s disease (16.67%), fatigue (16.67%), appendicitis (16.67%), malnutrition (16.67%), osteonecrosis (16.67%) and hypersomnia (16.67%). For the older group (N=35), the reported SAEs were hereditary angioedema (2.86%), sickle cell anemia with crisis (5.71%), osteomyelitis chronic (2.86%) and migraine (2.86%).
AEs were reported as all other AEs occurring in ≥ 5% of patients. Six were reported for the younger age group and 20 were reported in the older age group. For the younger group, the reported AEs were leukocytosis (16.67%), neutropenia (16.67%), sinus tachycardia (16.67%), constipation (16.67%), nausea (16.67%), vomiting (16.67%), application site irritation (16.67%), fatigue (16.67%), clostridium difficile colitis (16.67), arthralgia (16.67%), juvenile arthritis (16.67%), headache (16.67%), somnolence (16.67%), dizziness (16.67%), sedation (16.67%), and epistaxis (16.67%). For the older group, the reported AEs were sickle cell anemia with crisis (5.71%), constipation (2.86%), nausea (20.00%), vomiting (8.57%), diarrhea (5.71%), application site pruritus (20.00%), application site irritation (11.43%), fatigue (2.86%), electrocardiograph QT prolonged (5.71%), back pain (8.57%), arthralgia (5.71%), pain in extremity (5.71%), migraine (5.71%), headache (14.29%), somnolence (14.29%), dizziness (5.71%), and paresthesia (5.71%).
The full analysis population (FAP) for PK consisted of patients who received the study drug and had at least 1 valid quantifiable PK blood sample (N=41). Three patients had no quantifiable plasma buprenorphine concentration measurements and were not included in the PK analysis. The final buprenorphine pediatric PK analysis dataset comprised 38 patients. Mean CL/F was 293 liters/hour (95% confidence interval (CI), 264-326). Mean Vc/F was 2350 liters (CI 1950-2820).
Pain Right Now in Younger Group
For the younger group, pain right now was assessed using the Faces of Pain Scale-Revised (FPS-R). The FPS-R is a horizontal row of 6 faces representing pain intensity, with “no hurt” at the far left and “hurts worst” at the far right; the intensities are scored as 0, 2, 4, 6, 8, or 10. A score of 0=no pain, and 10=very much pain. For screening to week 4, pain right now was assessed at 30 minutes before initial application on day 1; one hour after initial BTDS application on day 1; thereafter, once daily at approximately 8 PM for the first 4 weeks. Baseline score was the last assessment prior to the first dose. For weeks 1-4, weekly averages of the pain right now scores were calculated using the sum of all available pain right now scores recorded daily during a given week divided by the number of available scores. The study measured pain right now for weeks 6-24 once a week at approximately 8 PM while on treatment; however, no patients in this age group were treated beyond week 12. Five patients who received at least one dose were assessed.
Mean scores were as follows: Baseline=2.8, Week 1=3.49, Week 2=2.98, Week 3=0.29, Weeks 4 through Week 12=0.
Pain Right Now in Older Group
For the older group, pain right now was assessed using a 100-millimeter (mm) visual analogue scale (VAS). The 100-mm VAS is a 100-mm line with 1 end marked as “no pain” and the other marked as “pain as bad as it could be.” The patient was asked to make a mark on that line indicating his or her level of pain. Pain right now score was defined as the distance (in mm) from the “no pain” end to the patient’s mark; 0=no pain, and bigger numbers indicate more pain. For screening to week 4, pain right now was assessed 30 minutes before initial application on day 1; one hour after initial BTDS application on day 1; thereafter, once daily at approximately 8 PM for the first 4 weeks. Baseline was the last assessment prior to the first dose. For weeks 1-4, weekly averages of the pain right now scores were calculated using the sum of all available pain right now scores recorded daily during a given week divided by the number of available scores. For weeks 6-24, pain right now was measured once a week at approximately 8 PM. Thirty-five patients who received at least one dose were assessed.
Mean scores were as follows: Baseline=46.6, Week 1=43.1, Week 2=41.6, Week 3=36.0, Week 4=34.7, Week 5=30.3, Week 6=28.0, Week 7=29.1, Week 8=34.3, Week 9=27.3, Week 10=36.7, Week 11=35.7, Week 12=42.5, Week 13=36.0, Week 14=38.2, Week 15=30.5, Week 16=38.7, Week 17=30.9, Week 18=37.7, Week 19=37.4, Week 20=35.6, Week 21=32.4, Week 22=38.5, Week 23=38.7, and Week 24=36.5.
Patient/Caregiver-Assessed Global Impression of Change
The PGIC rating score variable was collected on a 7-point scale ranging from 1 to 7 (where 1 = very much improved; and 7 = very much worse). The PGIC is designed to assess overall satisfaction with the treatment. The PGIC score was summarized using the number and percent of patients in each of the 7 possible response categories overall and by age group. PGIC was assessed by the parent/caregiver at the end of treatment visit or early discontinuation visit. The full analysis population (FAP) (N=40) was the group of patients who received at least 1 dose of the study drug during the study; however, data was provided for only 38 patients for this outcome measure.
In the younger group (N=4), one patient reported a score of 1 (very much improved), 2 patients reported scores of 4 (No change) and one patient reported a score of 5 (minimally worse).
In the older group (N=34), six patients reported scores of 1 (very much improved), 12 patients reported scores of 2 (much improved), 8 patients reported scores of 3 (minimally improved), 5 patients reported scores of 4 (no change), 2 patients reported scores of 5 (minimally worse), and one patient reported a score of 6 (much worse).
US Regulatory Background
June 30, 2010 –Initial approval date for Butrans.
With the approval, the FDA waived the requirement for pediatric studies in lieu of a PK/safety study. At the time, the Agency stated that efficacy to pediatric patients could be extrapolated from efficacy in adults. The FDA’s Summary Review states as follows.
In keeping with the current approach used with other extended-release opioids indicated for moderate to severe chronic pain for an extended period of time, pediatric studies will be waived for pediatric patients below the age of 7 because the number of patients available for study is too small and studies are impracticable. The remainder of the pediatric population can be deferred because the adult studies are ready for approval. The required studies will be pharmacokinetic and safety studies since the efficacy associated with an opioid analgesics can be extrapolated to pediatric patients as young age 2. This plan was reviewed at the Pediatric Research Committee and approved.
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METADATA: Sponsor: Purdue Pharma L.P., Drug Name: buprenorphine transdermal Drug Class: partial opioid agonist/antagonist Indication: chronic pain
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