JANUARY 30 & 31, 2002

Holiday Inn Gaithersburg


Nathaniel P. Katz, M.D. Chairman

Winston C.V. Parris, M.D., FACPM 

Richard M. Smiley, M.D., Ph.D.

Joseph R. Tobin, M.D.

Janice Bitetti, M.D.

Madelyn Kahana, M.D.

Thomas Vetter, M.D.

Consultant (voting)

Michael A. Ashburn, M.D., M.P.H.

Amanda S. Carlisle, Ph.D., M.D.
Eric S. Holmboe, M.D.

Terese T. Horlocker, M.D

Llyn A. Lloyd, R.Ph.

Edward Lowenstein, M.D.
Mitchell B. Max, M.D.

Laura F. McNicholas, M.D., Ph.D.

Marcus M. Reidenburg, M.D.


Jim Anthony, Ph.D.

Howard Chilcoat, M.D.

Kathleen M. Foley, M.D.

Debra Friedman, M.D.

Bruce Allen Levy, M.D., J.D.

Steven Passik, M.D.

Russell Portenoy, M.D.

Richard G. Roberts, M.D.

Charles Schuster, M.D.

Neil L. Schechter, M.D.

Mark S. Schreiner, M.D.


Kimberly L. Topper, MS



Jeff Bloom


Charles H. McLeskey, M.D.


Maria K. Connolly, D.N.Sc


J. David Haddox, M.D., D.D.S.


Gerald DalPan, M.D.

Sharon Hertz, M.D.

Sandra Kweder, M.D.

Sharon Hertz, M.D.

Deborah Leiderman, M.D.,

Bob Rappaport, M.D

Bill Rodriguez, M.D.


Howard Davis

Judy Ball, Ph.D.








I certify that I attended the January 30 & 31, 2002 meeting of the Anesthetic and Life Support Drugs Advisory Committee and that these minutes accurately reflect what transpired.


/S/ _______ 22 Apr 02 /s/ 22 Apr 02

Kimberly L. Topper, MS Date Nathaniel P. Katz, M.D. Date

Acting Executive Secretary Chairman

A verbatim transcript of this meeting is available for more detailed information.





Anesthetic and Life Support Drugs Advisory Committee

January 30, 2002


The meeting opened at 8:00 with a welcome from the chair and an introduction of all members at the table. Dr. Rappaport introduced the day's topic and provided the format for discussion.

The Open Public Hearing (OPH) was held with the following presenters:

John D. Giglio, M.A., J.D., American Pain Foundation, Chris Mullikin, RNC, CPP, MHS, Pain Management Center, Nancy Kowal MS, NP, American Society of Pain Management Nurses, Lorraine Reeves, Executive Director, Chronic Pain Advocacy League, Cheryll Cusimano RN , Touro Rehabilitation Center / Touro Infirmary, Chronic Pain Unit, Rhonda Garrett, Interstitial Cystitis Association of America, Paul Swerdlow, M.D. , National Institutes of Health, Chair, Sickle Cell Advisory Committee, Dan Handel M.D., National Institutes of Health, Chief of Pain and Palliative Care Service, James W. Broatch, MSW, Reflex Sympathetic Dystrop Syndrome Association, Kathleen Anderson, American Society for RSD/CRPS (ASRSD), Kathryn A. McLaughlin RN, BSN, CHPN, Hospice and Palliative Nurses Association, Michael H. Levy, M.D., Ph.D., Fox Chase Cancer Center, Peter Wilson, M.D., American Society of Anesthesiologists, Jeffrey Ramirez, Pharm.D., Veterans Health Administration, Randolph V. Merrick, M.D., UVA Health Services Foundation, Jeff Stoffler, Patient, Najib Babul, M.D., TheraQuest Biosciences, Art Van Zee, M.D., St. Charles, Virginia, and Glenda Dahlquist, M.D., Pain Management, Ohio. Dr. Katz thanked all the presenters and closed the OPH.

Dr. Rappaport then introduced the morning session on opiate analgesic development and the use of opiate analgesics. He reaffirmed the framework within which the FDA makes its decisions based on scientific evidence from the available data.

Dr. Bruce Allen Levy presented on Pain Treatment Guidelines. He provided proper prescribing definitions for non-therapeutic prescribing and prescribing pharmaceuticals or practicing consistent with the public health and welfare. His definition of intractable pain is a state in which the cause of the pain cannot be removed or otherwise treated and which in the generally accepted course of medical practice no relief or cure of the cause of the pain is possible or none has been found after reasonable efforts. He laid out the proper prescribing for pain guidelines and described practices warranting board scrutiny. He stated the challenge to State Medical Boards is to protect the medical use of controlled substances and simultaneously prevent drug diversion and abuse and ensure public access to effective pain.

Dr. Russell Portenoy presented the Evolving Trends of Opioid Therapy. The evolving consensus shows safe and effective therapy requires knowledge and skills in addiction medicine sufficient to judge risks, monitor treatment, and handle problems and a commitment to documentation and infrastructure. It also requires pain management specialists as consultants educated in both pain management and the principals of addiction medicine. He concluded that the treatment of pain with opioid therapy can probably be effective for any type of pain syndrome but the data are limited, responsiveness varies across individuals and subpopulations and responsiveness cannot be assessed unless therapy is optimized by individualization of the dose. He concluded by stating that opioid therapy is an approach to pain treatment with extraordinary promise and substantial risks and there is a clear obligation upon the prescribers to assess and reassess, be skillful in the drug administration, have knowledge of addiction medicine principals and to provide documentation and communication.

Dr. Gerald Dal Pan discussed the Opiate Analgesic Trials and Drug Development Plans. He stated the choice of the patient population in clinical trials is a crucial element in the development of opiate agents. Considerations for patient populations include the intensity of the underlying pain, the underlying disease that's the cause of the pain, the pathophysiologic mechanisms of the pain and the duration of the treatment needed. He then discussed the drug utilization data from the National Prescription Audit Plus and the National Disease and Therapeutic Index from the IMS Health. He concluded by presenting the two questions to the committee for discussion.





1. Discuss the target population for various opioid formulations and what factors you consider in making this determination?

  1. In the context of clinical trials to support an indication for chronic pain, discuss the need to assess sustained efficacy over the duration of the trial.

Dr. Rappaport introduced the topic of Opiate use in the pediatric population and provided a brief introduction to the topics each of the speakers will address in the afternoon.

Dr. Debra Friedman discussed the use of analgesics in the Pediatric population. She discussed the administration, evaluation, patient and family concerns, and standards and policies related to the administration of opiates within the pediatric population. Dr. Friedman addressed pain assessment in pediatrics and discussed the issues of oral, intramuscular and intravenous pain resolution techniques. She provided a format for discussion of pediatric pain resolution.

Dr. Bill Rodriquez covered the changes in the FD&C Act with regard to the Food and Drug Modernization Act (FADMA). The 1994 Pediatric Rule applied to approved drugs and biologics and the pediatric indication may be based on adequate and well-controlled trials in adults, with other information supporting pediatric use. It also provided for when the course of the disease and the effects if the drug, both beneficial and adverse, are sufficiently similar in the pediatric and adult populations, it may be permissible to extrapolate the adult efficacy data to pediatric patients. The 1998 Final rule requires pediatric studies for certain new and marketed drugs and biological products. The rule became effective April 1, 1999 and the compliance date was December 2, 2000. Effective on this date the FDA could require submission of pediatric studies and all applications being submitted need to comply with the rule. The important parts of the rule are that it will not delay approval for adult indications, it limits requirements to indications under review or in development, and it promotes early consideration of pediatric use and drug development plans. The Best Pharmaceuticals for Children Act was signed into law on January 4, 2002. This Act renewed pediatric exclusivity, required FDA to review pediatric supplements under the 6 month priority review, and required the sponsor to submit with IND a statement about intent to study the pediatric population.

Dr. Bob Rappaport provided three hypothetical situations for opiate analgesic pediatric drug development to assist the committee in the discussion of the following questions.

Opiate Analgesic Use in Pediatric Patients

1. The FDA is aware that there are still significant unmet needs in pediatric pain management. In the context of the Agency's new mandate to require studies of drugs in children, discuss these unmet pharmacotherapeutic needs in current pediatric pain management and how they might be met with regard to opioid drug products.

2. Discuss the significance of barriers to opioid analgesic trials in children (ethical, safety, scientific, practical, etc). What strategies might be used to overcome barriers?

3. Many different opioid formulations, delivery methods, and drug-device combinations are currently available on the market or may be available in the future. Discuss the age appropriateness and limitations of these various methods of administration, as well as any others that may be useful or particularly hazardous in pediatrics. Are there particular delivery systems that have found a useful niche in pediatric pain management that should be encouraged?

  1. It has been historically accepted that the mechanisms of action of opioid analgesics are sufficiently similar between adults and children that large controlled studies demonstrate efficacy, of the nature conducted in adults, have not been required for a pediatric indication. Instead, pediatric trials have been largely focused on investigating safety, pharmacokinetics and appropriate dosing in children. Discuss the shortfalls, if any, to this approach in the ways it has been used to guide and inform the clinical use of opioid analgesics in pediatric patients.


  1. Discuss approaches to dose finding and the evaluation of pain in the very young.
  1. As new products become available for home use in younger patients, there may be a risk to family members of accidental ingestion, overdose, or deliberate abuse and diversion of these medications. Discuss the strategies for risk communication and risk management that should be considered at the time of pediatric opioid drug approval.



Anesthetic and Life Support Drugs Advisory Committee

January 31, 2002

Questions to the Committee

Prescription Drug Abuse

January 31, 2002

Dr. Katz welcomed everyone to the meeting and asked the committee and guests to introduce themselves.

The Conflict of interest statement was read into the record.

Dr. Bob Rappaport thanked the participants for their work yesterday and introduced the topic for todayís discussions on risk management and addiction.

The Open Public Hearing was started with the following making presentations: Catherine Underwood, American Pain Society, Randall C. Cork, M.D., Ph.D., LSU Health Sciences Center, Mary Baluss, Palliative Care Law Project, Ellen Battista, DNS, ANP, PNP, Pain Treatment Consultants of Western New York, Rollin M. Gallagher, M.D., MPH, American Academy of Pain Medicine, Rick Lieb, The National Pain Foundation, Michael Cinque, American Pharmaceutical Association, Rebecca Burkeholder, National Consumers League, Dennis Buede, Ph.D., Kerry W. Cranmer, MD, CMD, Jim Monahan, Houston Hospice, Michael Gloth, M.D., Johns Hopkins University School of Medicine, John Coleman, MA, MS,Dennis Fisher,MD, Durect Corporation of California, Dorothy Steffler, Parent of Pain Patient, Randolph V. Merrick, M.D., UVA Health Services Foundation, Paul Desjardins, MD, Scirex Corporation. Dr. Katz thanked everyone for their presentations and then provided a brief overview of the previous dayís discussions.

Dr. J. David Haddox, representing Purdue Pharma, presented an industry view of risk management development, the disease burden of pain, treatment of chronic pain and addiction management. When researching the disease burden of pain they found that there were not many studies to provide data so they did a brief study of their own and discovered that 10% of those surveyed contemplated suicide as a means to end their pain, 77% had been in pain for more than 1 year and 13% had been denied pain medication. He explained that Purdueís risk management plans include the education of health care professionals, education of care givers, surveillance activities and stepped interventions.

Dr. Bob Rappaport introduced the topic of prescription drug abuse and reminded the committee that what we put in the label may be used for marketing claims which may have a profound impact on drug prescribing and use.. Dr. Kweder clarified that once the drug is on the market it is used however the prescribing physician desires and not always within the labeling guidelines.

Dr. Judy Ball, Substance Abuse and Mental Health Services, discussed the findings from the drug abuse warning network. She explained the DAWN system, the systems strengths and weaknesses, how the data is gathered and provided examples of the data available from this system.

Dr. Deborah Leiderman, Director Controlled Substance Staff, FDA provided the regulatory background in which they work. She explained that potential abuse assessment is mandated by two distinct acts. She explained each act and what the FDA does to fulfill the requirements of the acts.

Mr. Howard Davis, Chief, Domestic Drug Unit, Office of Diversion and Control, Drug Enforcement Agency, provided n overview of the role of the DEA in the Diversion of prescription Drugs. He explained there were six categories of opiate analgesic abuse. These included: "Doc" shopping, prescription drug rings with prescription forgery; employee thefts, infividual theft (realestate agent stealing from homes they show), robbery, and intratransit thefts.

Dr. Howard Chilcoat from Johns Hopkins University provided an epidemiologic overview of prescription drug misuse. His findings showed there is a prevalence of abuse of Rx drugs that is comparable to that of cocaine with analgesics being most commonly misused, ages 18 - 25 have the highest risk, girls 12 - 17 ar particularly vulnerable. They also showed there is a hight level of comorbidity with other psychiatric disorders, a strong relationship with antisocial personality disorders and cocaine abuse and the lifetime prevalence of Rx drug dependence is similar to that of cocaine.

Dr. Steven Passik, Director, Oncology Symptom Control and Research Community Cancer Care discussed substance abuse issues in chronic pain management. He explained substance abuse issues are complex during pain management and they defy simple solutions and these issues require tactical and humane approaches that combine thoughtful diagnosis, structure and a team approach.

Dr. Sharon Hertz, FDA discussed the regulatory approaches to Risk Management of prescription opioid drug abuse. She explained there are many approaches to managing abuse potential and amoung these are scheduling under the Controlled Substances Act, labeling, risk management plans, formulation changes, and restricted distribution. Risk management plans provide key messages, identify risk potential, utilize prograns to identify abuse, misuse, and diversion, develop prevention and intervention prograns and develop monitoring efforts. She then presented five vignettes for the committee to use in the discussion of the questions.

The Agency is aware of the growing problems of abuse, misuse and diversion prescription drugs, including the opioid analgesics, among patients and non-patients.

1. Discuss the adequacy of the available data to determine the prevalence of addiction among patients treated with opioids for chronic pain. What can we currently say about the prevalence?

2. Discuss how addiction in a chronic pain patient on opioid therapy can be accurately assessed in the office setting.

  1. Discuss the pros and cons of excluding patients with a prior history of substance abuse from clinical trials.
  1. Discuss the methods of monitoring for addiction in the clinical setting that may be extended to the Clinical Trials setting.


  1. In the context of increasing awareness of the problems of diversion and addiction to prescription opioids among patients and non-patients, comment on what measures might be appropriate to consider in the development of an overall risk management strategy that could reduce abuse and diversion without restricting access to drugs by patients in need of treatment. Comment on what components should be incorporated into such programs.

The chair thanked everyone for the intensely constructive discussion on such important issues and the meeting closed at 4:42PM.