Analgesic Development
Mark S. Wallace, M.D. Professor Clinical Anesthesiology University of California, San Diego
Disclosure • Consultant/Independent Contractor: Insys, Teva • Speaker's Bureau: Jazz Pharmaceuticals
Learning Objectives • Review the phases of clinical trials • Describe the guiding principles regarding IRB regulations • List the elements of informed consent
Therapeutic Considerations: Setting Priorities • Efficacy – clinical trial data – clinical experience
• Safety/tolerability • Ease of use – frequency – patient acceptability
• Cost
48
Clinical Trials “From Bench to Bedside” • Preclinical – Efficacy, Toxicity
• Phase I – Safety, Tolerability, Efficacy (?)
IND
• Phase IIA – Proof of concept, actual patients, small numbers, placebo controlled
• Phase IIB – Placebo controlled, FDA registered, data used for approval, larger numbers
• Phase III – Placebo controlled, Open label, large numbers
• Phase IV – Post-marketing studies
NDA
Preclinical Models: Do they predict efficacy in humans? • Acute Models – Hot plate, tail flick, paw pressure
• Facilitated – Formalin, carageenan
• Neuropathic – Chung, Bennet, Selzer
• Spontaneous versus Elicited pain
Phase I Studies • Traditionally are designed to assess safety and tolerability • Can efficacy be assessed?
Phase I Studies: Using Healthy Volunteers vs Patients • Studies amendable to healthy volunteers – – – – –
Topical Transdermal Transmucosal Oral Intravenous
Phase I Studies: Using Healthy Volunteers vs Patients • Studies requiring patients – High risk • Genetic studies • Chemotherapuetics
– Invasive delivery method • Intrathecal • Intraparynchymal
Phase I Studies: Risk Assessment • Healthy volunteers – Requires close assessment of risk since there is no benefit to subject – Risks must be minimal. If high, then study would be required to be conducted in patients with poor alternatives and who would benefit.
Phase I Studies: Risk Assessment • Patients – Study should be designed to possibly benefit the subject – Accept a higher level of risk, however, IRB will look closely at risk management procedures
Phase I Studies: Risk Management • i.e. intravenous delivery of agent with chance of allergic reaction. • Intense lab and physiological monitoring must be in place • Often requires inpatient observation • Study stop criteria • DSMB required
Assessing Analgesic Signaling in Phase I Studies
Key Experimental Medicine Candidates • • • • • • • •
Cold Pressor Acute Pain Models Intradermal Capsaicin Topical Capsaicin Heat/Capsaicin Sensitization UVB Brief Thermal Sensitization Intramuscular capsaicin
Primary Hyperalgesia
PRIMARY HYPERALGESIA • Corresponds to injured area • Lowered pain thresholds to noxious thermal and mechanical stimuli • Involves both peripheral and central mechanisms
SECONDARY HYPERALGESIA • Lowered pain thresholds to mechanical stimuli but not thermal stimuli • Involves central mechanism only but requires continued peripheral input
Intradermal Capsaicin Zone of Hyperalgesia
Zone of Heat Hyperalgesia (Flare)
Capsaicin Injection Site
Zone of Allodynia
Heat Capsaicin Sensitization • Heat pretreatment of skin followed by topical capsaicin application • Rekindling of pain and secondary hyperalgesia with heat applied for 5 minutes every hour • Shown to be sensitive to an opioid and gabapentin
Effect of Alfentanil and Ketamine on Intradermal Capsaicin Pain
Effect of Gabapentin (600mg TID) on Intradermal Capsaicin Pain
Effect of Smoked Cannabis on Intradermal Capsaicin Pain
Phase II study of a sublingual cannabinoid spray in Cancer Pain • GW Pharmaceutical announced the results of their phase II study with sativex in cancer pain. Low dose significantly reduced pain, High dose no different from placebo –GW Pharmaceutical, 2010
NOCICEPTIVE PHARMACOLOGY OF FACILITATED AND NEUROPATHIC PAIN ANIMAL Facilitated Neuropath
ID Cap
Human Heat Cap*
Post op
Human Neuropathic
Opioid
+
+ (systemic) 0 (spinal)
+
+
+
+ (systemic) +/0 (spinal)
NMDA antagonim
+
+
+
+
+**
+
Clonidine (spinal)
+
+
+
?
+**
+
Gabapentin
+
+
+/0
+
+**
+
Tricyclic
+ (spinal)
+
0 (systemic)
?
?
+
Sodium Channel Ant.
+
+
0
0
+**
0
Adenosine
+ (arthritis)
+
?
+ (spinal)
+**
+ (spinal)
Cannabinoids
+
+
+
+
+
+
+ (Cap)
+
O
+ (topical cap)
?
O
+
+
+
?
?
?
TRPV1 antag AMPA antagonist
*heat capsaicin model
**in combination with opioid
Phase II/III
Patient Reported Outcomes • Specific to the disease being studied • Must be measurable • Must show response to treatment
Patient Reported Outcomes • Primary Outcome – Must be met before secondary outcomes can be considered – May be multiple
• Secondary Outcomes – Usually consists of multiple outcomes
Determining Level of Evidence: Agency for Healthcare Research and Quality Criteria •
Conclusive: multiple high quality scientific studies or consistent reviews of metanalysis
•
Strong: At least one properly designed randomized, controlled trial of appropriate size OR multiple properly designed studies of smaller size OR at least one randomized trial supplemented by prospective and/or retrospective evidence
•
Moderate: well designed small randomized trial OR well designed trials without randomization OR quasi-randomized studies, single group, pre-post cohort, time series OR matched case-controlled studies OR at least one meta-analysis
•
Limited: well designed non-experimental studies from more than on center or research group
•
Intermediate: opinions of respected authorities, based on clinical evidence, descriptive studies, or reports of expert committees
AHRP Publication No. 02-E016, April, 2002
Where do you lie on the bell curve?
The Powerful Placebo
• Reviewed 15 studies that examined the tx of a variety of disorders from common cold to angina. The placebo response rate ranged from 15-58% (avg 35%) • Necessitates double-blind, placebo-controlled clinical trials
Placebo Response • Wide variation in placebo response rates has since been observed in other settings. • The response rate for the tx of pain probably is the most variable, ranging from 1- 100%. (Wall, The Placebo Effect: An Unpopular Topic. Pain 1992)
• Roberts combined results for tx that were originally believed efficacious but later abandoned: avg 70% excellent or good • Strongest when the symptom is dependent on the central or autonomic nervous system.
General Reasons for Clinical Improvement • • • • • • • •
Specific effects of treatment Regression to the mean Clinician-patient interactions Natural History Social desirability Concomittent therapies Hawthorne Effect True placebo response
Nocebo • Nonspecific influences of tx may produce adverse effects. • The overall incident of adverse events in healthy volunteers during placebo administration was 19% in a review of 109 double-blinded drug trials. • Healthy pts are more likely to report nocebo effects.
Placebo Effects of Surgery • Two double blinded randomized trials of IMA ligation vs skin incision and dissection for pts with angina pectoris. • Both demonstrated equal rates of improvement for up to one yr. (exercise tolerance, ntg use, EKG changes)
Placebo Effects of Surgery • “Surgery can evoke a placebo effect and urged caution in interpreting the benefit of new operations.” Beecher
• “Skeptics have long noted that an operation, particularly a new one, seems to bring benefit for several yrs until it is reevaluated and then often abandoned.” Shipiro
Challenges in applying high levels of evidence to surgical or minimally invasive procedures • Ethical limitations of blinded surgical techniques • Placebo use that prolong suffering and yet expose to surgical risk • Cost prohibition • Difficulties in blinding sham procedures • Ability to recruit adequate numbers
Statistical Analysis of Clinical Trials • Baseline Observation Carried Forward – For subjects that terminate early, the baseline observation is carried to end of study and combined with dataset – Represents drug tolerability
• Last Observation Carried Forward – For subjects that terminate early, the last observation is carried to end of study and combined with dataset – Less representative of drug tolerability
Research Using Scheduled Drugs: Regulatory Issues • The production and distribution of schedule I drugs such as marijuana for clinical research is carefully restricted under a number of Federal laws and international commitments • Marijuana is subject to control under Schedule I of the Controlled Substances Act (CSA) (21 U.S.C. 801 et seq.)
Research Using Scheduled Drugs: Regulatory Issues • Drug Enforcement Agency • Department of Health and Human Services • Food and Drug Administration (IND application) • National Institute of Drug Abuse • State Research Advisory Panel (California)
Research Using Scheduled Drugs: Drug Enforcement Agency • Persons who wish to conduct research using Schedule I substances such as marijuana must obtain a special registration under the CSA from the DEA (21 U.S.C. 823(f))
Research Using Scheduled Drugs: Department of Health and Human Services • To receive a Schedule I license, a researcher must first be determined by HHS to be qualified and competent, and the proposed research must be determined by HHS to have merit. • The scientific merits of the protocol are evaluated through a Public Health Service interdisciplinary review process. – Scientific quality – Quality of organizations peer-review process – Objectives of the proposed research
Research Using Scheduled Drugs: Food and Drug Administration • Proposed protocols must be determined to be acceptable under FDA’s standards for authorizing the clinic study of investigational new drugs • In all phases, assure the safety and rights of subjects • In Phase 2 and 3, assure the quality of study is adequate to permit an evaluation of the drug’s effectiveness and safety
Research Using the Cannabinoids: National Institute of Drug Abuse • NIDA oversees the cultivation of research-grade marijuana on behalf of the United States government • NIDA’s supply of marijuana is subject to a number of constraints associated with the cultivation of a researchgrade crop and that the supply at times may be variable • Concentrations come in high, medium, and low: – High: 7% – Medium: 4% – Low: 1%
Research Using Scheduled Drugs: State Research Advisory Panels • California requires proposed research projects involving certain opioid, stimulant, and hallucinogenic drugs classified as Schedule I and Schedule II controlled substances to be pre-reviewed and authorized by the Research Advisory Panel of California in the Attorney General’s Office • The panel’s primary objective is to ensure the safety and protection of human research subjects and adequate security of the controlled substances used in the study • The panel also evaluates for scientific validity
Ethical Research with Human Subjects
IRB regs: Historical Background • Nazi war crimes and Nuremburg code • Beecher 1966 NEJM article on “Ethics and Clinical Research” – NIH requires IRB review for NIH funded human subjects research beginning 1966
• 1973 Tuskegee Syphilis study becomes headline news
IRB regs: Historical Background • Nazi war crimes and Nuremburg code
High altitude hypoxia
Cold water immersion
IRB regs: Historical Background • Beecher 1966 NEJM article on “Ethics and Clinical Research” 22 examples of abuses of human rights in biomedical research by US institutions
IRB regs: Historical Background • 1972: 40 year Tuskegee Syphilis study becomes headline news
400 black males with untreated syphilis, 1932 – 1972 Effective treatment available 1947 but not given
Historical Background, cont’d • National Research Act, public law 93-348 – Creates National Commission for Protection of Human Subjects of Biomedical and Behavioral Research – Directs DHHS secretary to create regs for IRBs: 45 CFR 46
• Commission issued “The Belmont Report” in 1979 providing framework of ethical principles for research and its oversight
Guiding principles (Belmont Report) • Respect for Persons • Beneficence • Justice
Guiding principles (Belmont Report) • Respect for Persons – Individuals should be treated as autonomous agents – Persons with diminished autonomy are entitled to protection (‘special populations’) • Children • Mental disabilities • Prisoners
Guiding principles, cont’d (Belmont Report) • Beneficence – Do no harm – Maximize possible benefits and minimize risks – Applied at both an individual level for research participants and a societal level for the effect of the knowledge gained from the research
Guiding principles, cont’d (Belmont Report) • Justice – fair distribution of the burdens and benefits of research – selection of research participants should involve those groups who will benefit from research, not ‘convenience’ populations that are more likely to be disadvantaged
Elements of Federal Regulations • Establish IRBs and specify minimum composition • Require (most) federally funded human subjects to be reviewed & approved by IRB • Mandate ongoing monitoring • Require Informed Consent • Specify elements of informed consent, special cases which require additional protections
IRB review principles • IRB is the volunteer subject’s advocate • IRB answers to federal regs; cannot be overruled by other university committees or offices • Science is reviewed along with risk/benefit to participants: poorly designed studies can never be ethical
What Needs to be Reviewed • All research involving human subjects • Research = “a systematic investigation..designed to develop or contribute to generalizable knowledge” • Common misunderstanding: retrospective reviews of health care practices are research (i.e. chart review studies)
Elements of Informed Consent • • • •
A statement that the study involves research Explanation of the purposes of the research Expected duration of participation Description of the procedures
Elements of Informed Consent, cont’d • • • • • •
Risks and benefits Alternatives to participating Degree of confidentiality of records Compensation or treatment for injury Who to contact with questions Participation is voluntary
Elements of Informed Consent, cont’d • Termination without participant consent • Additional costs to participant • Consequences of and procedures for participant withdrawing • New findings will be communicated • Financial interests of investigator
Informed Consent • General principle is that, if it is practicable to get consent, consent must be obtained and documented (Respect for Persons) • Consent can be waived by IRB for some kinds of minimal risk research e.g., medical records review studies
Exception from Informed Consent • In the 1990s FDA and HHS provided guidelines for exception from informed consent for limited class of projects. • Particularly EMS and Trauma studies
Exception from Informed Consent • Seven criteria must be met: – – – – – – –
Life-threatening Eligible subjects cannot be identified, prospectively Prospect of benefit Not be feasible without the exception Opportunity to agree/disagree Plan for safe discontinuation Community disclosure; DSMB
Special Topics: Subject Recruitment Children Surrogate Consent Prisoners
Screening and Recruiting Questions • When are procedures done to determine research eligibility part of the research? • What can be done prior to obtaining research informed consent? • What are acceptable methods for recruiting?
Screening Prior to Enrollment: Consent not Required • PI and/or study staff may discuss availability of studies with individuals • Results of routine clinical care procedures that would be done with or without study entry may be used to determine eligibility
Screening Prior to Enrollment Requires Consent • Any procedure done solely to determine eligibility for a study is part of the research. • Wash-out done in anticipation or preparation for research is part of the research
Screening Prior to Enrollment Alternatives to Written Consent • IRB may waive requirement for written informed consent for minimal risk procedures to determine eligibility. • PI submits script for oral consent for screening.
Children and Adolescents
Children as Research Subjects • FDA provides the special regulations regarding inclusion of subjects under the age of 18 years designed to protect their welfare • Consent documents must include: – Parent Consent; – Child Assent (ages 7-12) – Adolescent Consent (ages 13-17)
Children and Adolescents • Title 45 CFR part 46, subpart D requires the IRB to determine the risk category: – 46.404 • minimal or no risk to child
– 46.405 • more than minimal risk, but intervention is likely to benefit the child
– 46.406 • more than minimal risk, unlikely to benefit child, but research is likely to yield generalizable knowledge and benefit society
– 46.408 • IRB may grant a waiver of permission
Surrogate Consent
Surrogate Consent • May be considered only in research related to cognitive impairment, lack of capacity, or serious life-threatening diseases • Protocol-specific • If subject expresses resistance or dissent to the use of a surrogate by word or gesture, the subject must be excluded from participation.
Surrogate Consent • Investigator Responsibilities – Attempt to provide informed consent – Assess decisional capacity in all cases involving cognitive disorders – Document this assessment and provide tools to the IRB for review – Obtain surrogate consent if subject is found to lack decisional capacity
Prisoners Wards of the Court and Persons reporting to the Juvenile Justice System
Prisoners as Research Subjects • Studies that include “prisoners” must undergo full committee review • IRB membership must include “prisoner rep” • Federally funded research involving prisoners must be approved by HHS • The process of excluding prisoners could actually increase risk of participating
References •
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Wallace MS, Ridgeway B, Leung A, Schulteis G, Yaksh T. Concentrationeffect relationships for intravenous alfentanil and ketamine infusions in human volunteers: Effects upon acute thresholds and capsaicin-evoked hyperpathia. Journal of Clinical Pharmacology 42:70-80, 2002 Petersen, K.L., et al., Effect of remifentanil on pain and secondary hyperalgesia associated with the heat--capsaicin sensitization model in healthy volunteers. Anesthesiology, 2001. 94(1): p. 15-20. Petersen, K. L.; Maloney, A.; Hoke, F.; Dahl, J. B.; Rowbotham, M. C. A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization. J Pain 2003. 4:400-6 (lamotrigine 400 mg Eisenach, J.C., D.D. Hood, and R. Curry, Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers. Anesth Analg, 1998. 87: p. 591-6. Dirks, J., et al., Gabapentin suppresses cutaneous hyperalgesia following heatcapsaicin sensitization. Anesthesiology, 2002. 97: p. 102-107.
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Gottrup, H., et al., Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology, 2004. 101(6): p. 1400-8. Wallace MS, Schulteis G. Effect of chronic oral gabapentin on capsaicininduced pain and hyperalgesia: a double-blind, placebo-controlled, crossover study. Clin J Pain 24:544-9, 2008. Wang, H.; Bolognese, J.; Calder, N.; Baxendale, J.; Kehler, A.; Cummings, C.; Connell, J.; Herman, G. Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects. J Pain. 2008, 9:1088-95 Wallace, M.S., et al., Concentration-effect relations for intravenous lidocaine infusions in human volunteers: effect on acute sensory thresholds and capsaicin-evoked hyperpathia. Anesthesiology, 1997. 86: p. 1262-72. Wallace, M.S. and D. Grubbs, Effects of oral desipramine on capsaicin induced hyperalgesia. Anesth Analg, 2002. 95: p. 973-978.
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Eisenach JC, Hood DD, Curry R, Tong C. Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans. Anesthesiology 1997; 86:1279-87. Dirks, J., et al., The effect of systemic lidocaine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Anesth Analg, 2000: 91:967-72 Gottrup H., Hansen PO, Arendt-Nielsen L, Jensen TS. Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans. Br J Anaesth 2000, 84:155-162. Ando, K., et al., Neurosensory finding after oral mexiletine in healthy volunteers. Reg Anesth and Pain Med, 2000. 25: p. 468-474. Wallace MS, Quessy S, Schulteis G. Lack of effect of two oral sodium channel antagonists, lamotrigine and 4030W92 on intradermal capsaicininduced hyperalgesia model. Pharmacol Biochem Behav 78:349-355, 2004 Frymoyer, A. R.; Rowbotham, M. C.; Petersen, K. L. Placebo-controlled
References •
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Eisenach JC, Hood DD, Curry R, Tong C. Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans. Anesthesiology 1997; 86:1279-87. Dirks, J., et al., The effect of systemic lidocaine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Anesth Analg, 2000: 91:967-72 Gottrup H., Hansen PO, Arendt-Nielsen L, Jensen TS. Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans. Br J Anaesth 2000, 84:155-162. Ando, K., et al., Neurosensory finding after oral mexiletine in healthy volunteers. Reg Anesth and Pain Med, 2000. 25: p. 468-474. Wallace MS, Quessy S, Schulteis G. Lack of effect of two oral sodium channel antagonists, lamotrigine and 4030W92 on intradermal capsaicin-induced hyperalgesia model. Pharmacol Biochem Behav 78:349-355, 2004
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Frymoyer, A. R.; Rowbotham, M. C.; Petersen, K. L. Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers. J Pain 2007, 8:1925 Dirks, J.; Petersen, K. L.; Rowbotham, M. C.; Dahl, J. B. Effect of systemic adenosine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Reg Anesth Pain Med, 2001. 26:414-9 (65 mcg/kg/min for 85 minutes) Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, Gouaux B, Abramson I. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 107:785-796, 2007. Abrams, D. I.; Jay, C. A.; Shade, S. B.; Vizoso, H.; Reda, H.; Press, S.; Kelly, M. E.; Rowbotham, M. C.; Petersen, K. L. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. 2007. 68:515-21
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Mikkelsen, S.; Dirks, J.; Fabricius, P.; Petersen, K. L.; Rowbotham, M. C.; Dahl, J. B. Effect of intravenous magnesium on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Br J Anaesth 2001. 86:871-3 Wall, The Placebo Effect: An Unpopular Topic. Pain 1992 J Psychosom Res, 62 (2007), pp. 563–570 Curr Opin Anaesthesiol 2007;20:435–9 Ann Rheum Dis 2008;67:1716–23 Lancet 2010;375:686–95 AHRP Publication No. 02-E016, April, 2002 Beecher, NEJM, 1966, vol. 274