Nathaniel Katz, MD, MS Analgesic Solutions, Natick, MA Tufts University School of Medicine, Boston, MA

Transcription

1 Nathaniel Katz, MD, MS Analgesic Solutions, Natick, MA Tufts University School of Medicine, Boston, MA National Academies of Science, Engineering, and Medicine Workshop November 4, 2016 Washington, DC

2 Neurologist, pain specialist Clinical practice: acute, chronic, and cancer pain Academic research on pain control Benefits and harms of opioids Masters in Biostatics FDA Advisory Committee Chair Founder of consulting and clinical research company (Analgesic Solutions) 2

3 IMMPACT/ACTTION Bob Rappaport, Sharon Hertz Bob Dworkin, Dennis Turk Guidance documents Analgesic drug development Abuse liability assessment Dedication of staff 3

4 PRECLINICAL CLINICAL 4

5 NMDA antagonists Glycine antagonists Opioid-NMDA combinations Ultra-low-dose antagonists Vanilloid-receptor antagonists Vannilloid-receptor agonists NK-1 antagonists N-Ca Channel Blockers GABA agonists Cannabinoids Anti-NGF antibodies

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7 Amgen: 11% Bayer: 25% Begley CG, Nature, 2012; Prinz F, Nature Rev Drug Discov, 2011; Andrews NA Pain,

8 Studies never done Reports cannot be found Report in unacceptable format E.g. copies of pages from lab notebooks Poor quality control in labs (academic & industry) Selective reporting of data No animal accountability Ignorance of basic principles of experimentation Fabrication of data and methods Studies not randomized Studies not blinded 8

9 FDA SHOULD REVIEW PRECLINICAL EFFICACY DATA Begin with an audit of integrity of preclinical efficacy data including site inspections If positive, routinely review data Will require major retooling 9

10 New class, much more effective than any other class of analgesic for chronic pain (including opioids) Dozens of studies, over 15,000 patients Safer than opioids Clinical hold >4 years for rare joint destruction and sympathetic nerve lesions (preclinical) >80,000 opioid overdose deaths in US while class on hold J&J drops fulranumab, leaves pain space 10

11 Companies hiding safety data? FDA not considering societal perspective? FDA judgment of safety data biased? Overemphasis on preclinical toxicology? The reasons for keeping this class on hold are not subject to public scrutiny The stakes are too high for such decisions to be hidden 11

12 THE DECISION TO PUT PROMISING NEW ANALGESICS ON HOLD NEEDS EX-FDA OVERSIGHT Which analgesics are promising? Composition of committee? Protection of process? 12

13 DEVELOP MECHANISM FOR LIMITED APPROVAL WITH RESTRICTIONS TO GATHER ADDITIONAL DATA Restricted distribution perhaps under REMS Further safety and efficacy data gathered Restrictions loosened upon data review 13

14 FDA guidance documents major step forward Further clarity needed on requirements for confirmatory labeling Epidemiology: e.g. OxyContin Randomized controlled trials Requirements for labeling for low abuse potential opioid? 14

15 CLARIFY STANDARDS FOR LABELING ON REDUCED ABUSE Strong epidemiologic data rejected by FDA for reasons unavailable to public No call for RCTs 15

16 Harm reduction models allow estimation of net public health impact of introducing new medication Assumptions include: Medication properties Properties of current treatments Market penetration 16

17 USE HARM REDUCTION MODELS TO CONSIDER SOCIETAL IMPACT OF DRUG APPROVAL DECISIONS FDA can generate models or have sponsors generate them Provides semi-quantitative estimates of consequences of approval decisions 17

18 Revive the NIH Medicines Development Program for analgesics Fund the large prospective study of opioids for chronic pain 18

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20 MANDATORY TRAINING ON OPIOID PRESCRIBING Recommended by 2 advisory committees 200,000 deaths since 1 st recommendation Must be goal oriented and monitored 20

21 FIX THE FDA ADVISORY PROCESS Critical data not shared with advisory committees Right-sized conflict of interest regulations needed to ensure qualified advisors Flexible formats (e.g. closed small group discussion) needed 21

22 RESOURCE THE DIVISION Pain division understaffed Non-timed deliverables delayed Resource allocation does not consider extra demands (e.g. responding to political requests) 22

23 PROACTIVELY IMPLEMENT ADVANCES IN CLINICAL RESEARCH METHODS Adaptive designs Patient and staff training Central statistical surveillance 23

24 MANDATE RESEARCH ON OPIOID NEEDS AFTER ACUTE PAIN EVENTS Opioids are massively overprescribed for acute pain, accounting for billions of excessive dosage units annually Dissemination of guidelines for amount of opioids required postoperatively could dramatically reduce opioid burden 24

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