Challenges in Conducting Postmarketing Abuse Investigations

Transcription

1 Challenges in Conducting Postmarketing Abuse Investigations Paul Coplan, ScD, MBA Risk Management & Epidemiology Purdue Pharma, L.P. ADF Guidance Meeting Washington DC, October 1,

2 That which we do not bring into consciousness appears in our lives as fate Carl Gustav Jung Disclaimer: Views expressed are those of the speaker and not those of any organization he is affiliated with. 2

3 Key Challenges 1. New molecular entity or product 2. Clinical endpoints 3. Time to see event 4. Novel surveillance measures 5. Public Health Impact 3

4 1. New Product or New Molecular Entity: The Challenge ADF Guidance (page 13): The goal of postmarketingstudies, Category 4, is to determine whether the marketing of the potentially abuse-deterrent formulation results in a significant decrease in population-based and use-based estimates of abuse compared to estimates of abuse if only formulations without abuse-deterrent properties are marketed Challenge Low (initial) uptake No baseline Possible Approach Assess relative rate of abuse Eg, IR Tapentadol (new molecular entity), buprenorphine patch (new formulation of established molecular entity) 4

5 Example: Relative Rates of Nonmedical Use of IR Tapentadol vs. other opioids in RADARS System College Survey Population-adjusted rates Prescription-adjusted rates (URDDS) Source: Dart et al. ClinJ Pain

6 Example: Relative Rates of Abuse Exposures in RADARS System Poison Center Program for Buprenorphine Products Rates per 1,000 Individuals Dispensed Drug from Jan 2011 to Sep 2012 Source: The RADARS System Poison Center Program and IMS LRx 6

7 Example: Relative Rates of Abuse Exposures in RADARS System Poison Center Program for ER Opioids by Opioid Substance Rates per 1,000 Individuals Dispensed Drug from Jan 2011 to Sep 2012 Source: The RADARS System Poison Center Program, IMS LRx 7

8 New Product of Molecular Entity: Summary Can identify relative rates of abuse over time as compared to other comparator opioid groups What level constitutes sufficiently lower level to be considered abuse-deterrent? Need to account for underlying differences between opioid active substances and types of formulations in abuse-related outcomes Cannot compare to pre-reformulation baseline 8

9 2. Clinical Endpoints/Outcomes ADF Guidance: Clinical outcomes should include: Prevalence or rates of overdoses, poisonings, addiction, and death Severity of overdoses, poisonings, and addiction Duration of addiction 9

10 Example: Decrease in Number of Causal Drug-Related Deaths in Florida for Oxycodone after 2010: ADF or Legislation/Policing? Oxycodone Methadone Other prescription opioids Heroin # of occurences in drug related deaths Introduction of ORF Oxycodone Other RX opioids Methadone Heroin State legislation to control pill mills (IR SE oxycodone) +20% -22%* -7% +10% Time period * Statistically significant change (p<.0001) from (2H2009 1H2010) to (1H2011-1H2012) Change in oxycodone deaths per 6 month period increased by 69, then decreased by 88 (p<0.001) Data source: Florida medical Examiner data 10

11 Endpoints that are feasible to measure are not direct clinical outcomes Reported abuse among individuals at substance abuse treatment centers Calls to poison centers reporting abuse or misuse Surveys of reported abuse in general population or students Trends in number/type of prescriptions Street price Number of drug diversion events reported by law officers Doctor shopping By # of doctors/pharmacists and overlapping prescriptions Adverse events reported to manufacturer and AERS, including fatalities, fatal overdoses, tablet manipulation or medication error 11

12 Endpoints for Epidemiology Study Program Physicochemical barriers to crushing and dissolving Intentional Abuse Unintentional errors Rates of abuse Routes of abuse Diversion Patients Non-patients Abuse exposures reported to poison centers Substance abuse treatment patients Cohort of OxyContin abusers Overdose death spontaneous reports National surveys of abuse Substance abuse treatment patients Cohort of OxyContin abusers Internet chat room monitoring National drug diversion surveillance Therapeutic error exposures reported to poison centers Overdose and poisoning events among people prescribed opioids Spontaneous adverse event reports Unintentional general exposures reported to poison centers Spontaneous adverse event reports

13 Example: Fatalities reported to manufacturer are product-specific but rely on spontaneous reports: Example -fatalities associated with OxyContin 366 cases with date of death specified, 3Q2009-2Q2012 Note: Reports received after 2Q2012 with a date of death before 2Q2012 not yet included. Source: Sessler et al., PAINWeek 2013; Purdue Adverse Event Reporting Database (ARGUS) 13

14 3. Time to see change in poison centers: Number of Abuse Exposures continue to decrease after 2 Years Number of Calls to Poison Centers for Abuse Total OxyContin Original OxyContin Reformulated OxyContin Canadian OxyContin Unknown OxyContin Reformulation introduced 0 3Q Q Q Q Q Q Q Q Q Q Q Q Q Q 2012 Source: RADARS System Poison Center Program 14

15 Canadian OxyContin exposures are found in all 50 states (N = 6,061), 1Q 2007 to 2Q 2010 Metropolitan county Micropolitan county Non-core county 1 With identifiable ZIP, of 653 total cases SOURCE: National Poison Data System; McKinsey 15

16 Opana ER Abuse Exposures in RADARS Poison Center Program: Changes after Reformulated OxyContin and ER Opana introduced Rate per 1,000 URDD Introduction of Reformulated OxyContin Introduction of reformulated Opana ER Year/Quarter 16 16

17 Example: Time to see change in NSDUH: Significant reductions in nonmedical use of OxyContin occur only 2 years after reformulation 700 Number of non-medical users in past month (1000s) Source: National Survey on Drug Use and Health, SAMHSA 2012 report; Gfroerer

18 Reduction in Accidental Exposures in National Poison Data System 66% of accidental exposures among children months of age (Baseline is 12 months prior to ORF introduction; number of exposures) Source: Coplan et al. Pharmacoepidemiology Drug Safety, 2013; National Poison Data System. 95% CI shown 18

19 4. Internet Monitoring of Web Fora used by Drug Abusers: Posts reporting Tampering resulting in Injecting or Snorting 3,500 3,000 2, Total Posts about OxyContin Posts about Tampering Methods for Reformulated OxyContin - --Posts about Tampering Methods for ReformulatedOxyContin That Reported Injecting or Snorting OxyContin Post Count 2,000 1,500 1,000 Reformulation of OxyContin Q3* Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q Source: Coplan P. International Conference on Opioids, 2013 NAVIPRRO Web Informed Services 19

20 5. Broader Use of ADFs needed to have Public Health Impact Unique patients in 2012 Opioid Overdose Diagnoses (%) Size of ADF reduction Impact of ADF on All Overdoses Type of Opioid % of Users IR Hydrocodone- Acetaminophen 43,400, % 23.3% 0% 0.00% IR Oxycodone- Acetaminophen 14,800, % 10.7% 0% 0.00% IR Oxycodone single entity 3,600, % 6.8% 0% 0.00% IR hydromorphone 1,100, % 2.9% 0% 0.00% ER Morphine 1,100, % 4.0% 0% 0.00% ER Oxycodone 1,000, % 4.3% 50% 2.15% Fentanyl patches 876, % 4.2% 0% 0.00% IR morphine & Fentanyl 593, % 1.6% Methadone 542, % 2.5% 0% 0.00% ER Oxymorphone 200, % 1.2% 40% 0.48% Buprenorphine patches 127, % 0.3% 0% 0.00% ER tapentadol 80, % 0.0%? 0.00% ER Hydromorphone 40, % 0.1% 0% 0.00% None %?? Total 67,458, % 20 Source: Patient numbers from IMS Health NPA; % of opioid overdoses from MarketScan Commercial database in 2011

21 Summary New formulations or molecular entities: baseline comparators missing, but can be compared to other products Clinical endpoints: Mismatch between feasible-tomeasure endpoints and clinical endpoints defined in Guidance Time to see majority of change in existing surveillance systems: approximately 2 years ADFs will need to be widely used to have a significant public health impact 21

22 Thank You 22

23 BACK-UP SLIDES FOR Q&A 23

24 Evaluating Abuse Deterrence of Low Use Product Calls to Poison Centers related to Abuse of ER Opioid Products Rates per 100,000 Population from January 2011 to September 2012 Source: The RADARS System Poison Center Program 24

25 Calls to Poison Centers related to Abuse of Buprenorphine Products Rates per 100,000 Population from January 2011 to September 2012 Source: The RADARS System Poison Center Program 25

26 Trends for Intentional abuse exposures in Florida for SE ER Oxycodone(OxyContin), other SE oxycodone and Heroin in National Poison data System ( )