Circulation 60,475 • Volume 14, No. 2 • Summer 1999

Pharmacist Defends FDA, Believes Propofol Issues Mainly Financial

Harold J. DeMonaco, M.S.

To the Editor

I enjoyed reading the letter to the editor from Dr. Tinker raising questions on the recent approval of generic propofol. Dr. Tinker has written a thoughtful and articulate letter of concern. His concerns are likely to be shared by many anesthesiologists and CRNA’s when faced with a new “replacement” for a product in such widespread use as propofol. The issues he brings to bear are multiple and relate to pharmaceutical issues, clinical issues, and issues of fairness. Let me speak to each of these:

Unless you are a pharmacist or you lead an amazingly boring existence, most clinicians have never heard of the FDA’s so-called Orange Book. The Orange Book details the compendial requirements for different levels of FDA approval and lists all of the drugs granted official status. The FDA granted approval to Gensia Sicor for a “generic” version of propofol based on its demonstrated therapeutic equivalence. Therapeutic equivalent is defined as follows:

“Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.”

“FDA classifies as therapeutically equivalent those products that meet the following general criteria: (1) they are approved as safe and effective; (2) they are pharmaceutical equivalents in that they (a) contain identical amounts of the same active drug ingredient in the same dosage form and route of administration, and (b) meet compendial or other applicable standards of strength, quality, purity, and identity; (3) they are bioequivalent in that (a) they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or (b) if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard; (4) they are adequately labeled; and (5) they are manufactured in compliance with Current Good Manufacturing Practice regulations.”

Quoting further from the FDA Orange Book, “FDA considers drug products to be therapeutically equivalent if they meet the criteria outlined above, even though they may differ in certain other characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration date/time and minor aspects of labeling (e.g., the presence of specific pharmacokinetic information). When such differences are important in the care of a particular patient, it may be appropriate for the prescribing physician to require that a particular brand be dispensed as a medical necessity. With this limitation, however, FDA believes that products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product.”

Sulfite Amount is Key

This brings us to the sulfite issue. Dr. Tinker raises a legitimate concern about the presence of a compound he himself may react to. However, to be complete, Dr. Tinker should be raising the same concerns with lidocaine 2% with epinephrine, dobutamine, levarterenol, phenylephrine and many other drugs commonly used by anesthesiologists in the operating room and in the care of critically ill patients in the intensive care unit [although the total amount of sulfite in a routine dose would be much, much less than in a routine induction dose of propofol –Ed.]. My review of medical literature published from 1966 to 1999 only identified one English-language citation the topic of sulfites and anesthesia, the results of a conference on the topic. I was unable to identify a single case report of an adverse event related to the administration of a sulfite containing medication during the course of anesthesia. While I appreciate Dr. Tinker’s concerns, the literature does not support his contention that there is, in fact, a safety issue.

Dr. Tinker’s last comments relate to fairness and the impact of the economic health of AstraZeneca and the need for new drugs in anesthesia. Sales of propofol exceeded $257 million in 1997. During the past 52 weeks, the price of the company stock has risen from approximately 30 to a high of 48. Sales in the United States of AstraZeneca products have increased by 27%. Although I do not have specific data for AstraZeneca given their recent merger, the U.S. pharmaceutical industry routinely spends 2-3 times its research budget on advertising and marketing. This is hardly the profile of a struggling company needing to reduce its expenditures to salvage research.

For all of the above reasons, I respectfully suggest that Dr. Tinker’s safety concerns are misplaced. The issues swirling around propofol are not clinical, they are financial. The FDA’s decision to grant therapeutic equivalence status to generic propofol was based on data. Since it inception in 1984, this data-driven process of drug review has led to dramatically lower drug prices without any demonstrated negative clinical impact. Every published clinical trial comparing a generic equivalent drug to its brand name competitor has failed to demonstrate a clinically significant difference in efficacy or effectiveness.

I would be remiss if I did not conclude by acknowledging that the Massachusetts General Hospital has contracted with Baxter for generic propofol. My comments should be viewed with that consideration in mind. The decision to switch to generic propofol was made with the full acknowledgement and agreement of the Department of Anesthesia and was based on a thorough examination of the relevant issues of cost and quality.

Harold J. DeMonaco, M.S. Director of Drug Therapy Management Massachusetts General Hospital Massachusetts General Physicians Organization