1. Bob Bianchi Prescription Drug Research Center Category 1 Focus Group Meeting Washington DC November, 4 2015

2. Introduction The landscape in abuse deterrent product development and evaluation has changed since Purdue Pharma conducted in vitro testing on their reformulated Oxycontin almost ten years ago. More recently the approval of Inspirion’s ER morphine sulfate product (MorphaBond) provides insight into FDA’s thinking. Delivery platforms are different, and the most common forms of abuse for each opioid formulation must be addressed Of great interest is the development of in vitro testing protocols, which is why we are here today. No abuse proof product developed, YET ADF formulations will only discourage the casual, recreational abuser that makes up the majority of abusers.

3. Holy Grail in Pain Killers

4. FDA Thinking Adaptive approach The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving. FDA is taking a flexible, adaptive approach to the evaluation and labeling of potentially abuse-deterrent products. The development of an abuse-deterrent opioid product should be guided by the need to reduce the abuse known or expected to occur with similar products.

5. FDA Thinking Complete characterization First and foremost, any studies designed to evaluate the abuse-deterrent characteristics of an opioid formulation should be scientifically rigorous. Take into consideration the known routes of abuse for the non-abuse-deterrent predecessor or similar products, as well as anticipate the effect that deterring abuse by one route may have on shifting abuse to other, possibly riskier route Testing should provide information sufficient to fully characterize the product’s abuse-deterrent properties, including the degree of effort required to bypass or defeat those properties.

6. FDA Thinking Complete characterization (continued ) The test product should be compared to appropriate comparator products for ease of mechanical manipulation The ability to crush, cut, grate, or grind the product formulation using readily available tools such as spoons, cutters, and coffee grinders should be assessed Particular attention should be given to particle size distribution following each mode of physical manipulation because particle size may influence the rate of opioid extraction from manipulated product.

7. FDA Thinking Experiments must be reproducible and statistically valid Represent real world activities Explore the limits of abuse deterrent properties in heat & cold Evaluate solubility in solvents of various polarity and pH Various time points and temperatures – 30 seconds- 12 hours or until 80% API extracted Evaluate dose dumping in alcohol of various concentrations Evaluate liquid-liquid extraction with pH adjustment

8. Abuser Thinking Product selection Immediate release not as desirable as ER Not ADF Readily available Inexpensive Easy to access to API Method selection Fast, easy and requiring little technical knowledge Few, inexpensive steps – no special equipment

9. Abuser Profile Most have little or no technical training Follows recipe from friend or Internet Limited resources Desperate – needs drug NOW Some hardened/experienced users have chemistry training and accept the intellectual challenge

10. Internet Resources http://www.rhodium.ws/chemistry/ http://www.erowid.org/index.shtml http://www.drugs-forum.com/forum http://www.saferinjecting.net/safer-injecting- drugs.html http://www.saferinjecting.net/safer-injecting- drugs.html http://groups.google.com/groups/dir?sel=usenet%3Dalt. drugs http://forum.opiophile.org/ http://groups.google.com/groups/dir?sel=usenet%3Dalt. drugshttp://forum.opiophile.org/ http://www.bluelight.ru/vb/home.php

11. Scientist’s Thinking This is not traditional analytical chemistry - Alza What would an abuser do? Extraction/manipulation method selection Search Internet Consult expert Determine most prevalent mode of abuse Must be reliable, reproducible and efficient Must be safe for lab & staff Determine resource requirements – equipment, solvents Determine ease of manipulations – subjective assessment Draw conclusion about ease & efficiency of method Take Pictures Every formulation is different

12. Don’t Be Fooled by Appearance

13. Conclusion Each formulation has its own unique properties requiring unique approaches. Experiments must be comprehensive Satisfy FDA recommendations Engage an independent laboratory Think like an abuser Provide regular feedback to sponsor

14. Thank You Bob Bianchi Prescription Drug Research Center 134 N LaSalle Street Suite 2200 Chicago, IL 60602 www.PDRCLLC.Com RBianchi @PDRCLLC.com 571-233-4780