AMERICAN JOURNAL OF OPHTHALMOLOGY FRANK
W.
NEWEIX,
Editor-in-Chief
Tribune Tower, Suite 1415, 435 North Michigan Ave., Chicago, Illinois 60611 EDITORIAL BOARD Mathea R. Allansmith, Boston Douglas R. Anderson, Miami Crowell Beard, San Jose Bernard Becker, St. Louis Benjamin F . Boyd, Panama Charles J. Campbell, New York Ronald E. Carr, New York Thomas Chalkley, Chicago Claes H. Dohlman, Boston Fred Ederer, Bethesda
Published
DuPont Guerry III, Richmond Paul Henkind, Bronx Robert W. Hollenhorst, Rochester Herbert E. Kaufman, New Orleans Arthur H. Keeney, Louisville Carl Kupfer, Bethesda Irving H. Leopold, Irvine A. Edward Maumenee, Baltimore Irene H. Maumenee, Baltimore Edward W. D. Norton, Miami G. Richard O'Connor, San Francisco
monthly by the Ophthalmic
Arnall Patz, Baltimore Steven M. Podos, New York Albert M. Potts, Louisville Algernon B. Reese, New York Robert D. Reinecke, Albany Marvin L. Sears, New Haven David Shoch, Chicago Bruce E . Spivey, San Francisco Bradley R. Straatsma, Los Angeles Gunter K. von Noorden, Houston
Publishing
Company
Tribune Tower, Suite 1415, 435 North Michigan Avenue, Chicago, Illinois
60611
Directors: A. E D W A R D M A U M E N E E , President; D A V I D S H O C H , Vice President; F R A N K W. N E W E L L , Secretary and Treasurer; E D W A R D W. D. N O R T O N , B R U C E E. SPIVEY, B R A D L E Y R. STRAATSMA
NON-APPROVED USE O F F O O D AND DRUG ADMINISTRATION APPROVED DRUGS
looked in the PDR under methotrexate (Lederle). There it states that as an anti dote foroverdosage, Leucovorin, " m a y b e Considerable confusion and fear exist administered by intravenous infusion in concerning the legal status of the Food doses up to 75 mg within 12 hours." and Drug Administration (FDA) ap Because the dose ordered was in excess of proved package insert that accompanies 75 mg, the nurse refused to give it. She each medication (and which is printed in cited the PDR statement and her fear of the Physician's Desk Reference). This being sued for nursing malpractice. The confusion affects not only physicians but chief of the service gave the Leucovorin the nursing profession and the drug in himself. dustry as well. T w o examples demon 2. In Wilmington, Delaware, on Sept. strate the situation: 29, 1977, oral argument was heard in a 1. At a teaching hospital a resident preliminary injunction by the Pharma Manufacturers Association physician mistakenly ordered a lethal ceutical dose of methotrexate, a folic acid antago (PMA) against the FDA and the Depart nist, for a patient in the oncology ser ment of Health, Education and Welfare. vice. Immediately after its administra It concerned patient package inserts for tion, the resident realized his error and estrogen drug products. The FDA had rushed to the chief of his service, w h o proposed a regulation that would require personally ordered the antidote, Leucov- package inserts for these drugs in order orin (folinic acid). In the Physician's that patients could determine the risks Desk Reference (PDR) under Leucovorin and benefits of treatment. Judge Stapleton (Lederle) the correct dose is "to be given heard the PMA's case against the FDA. in amounts equal to the weight of the On the point that the regulation would antagonist given." However, the nurse interfere with the practice of medicine, he 626
VOL. 88, NO. 3, PART II concluded that it did not prohibit the physician from exercising his own profes sional judgement nor would it constitute third party control. If, because of the package insert, the patient altered his decision with regard to taking the drug, this was not construed by the judge as interference with the practice of medi cine. Judge Stapleton denied the prelimi nary injunction. The purpose of the preceding was not to promote fear and confusion but to show that they exist and that they extend to other groups besides physicians. In deed, the head of the FDA, Donald Ken nedy, Ph.D., has made written statements that should clear the air and provide con siderable relief to our profession. The following, excerpted from an article in The Western Journal of Medicine (127: 429-534, 1977), makes clear that the FDA is attempting to control the claims of the drug manufacturers and not the practice of medicine. Real communication between the medical pro fession and FDA depends upon exorcising sev eral myths about the regulatory process. These myths are pernicious as well as persistent, for they divert the free flow of understanding be tween those who deliver health care and those who seek to support their efforts. Myth Number One: Drug labeling is FDA's way of telling physicians exactly what they can and cannot do with prescription medicines, and physicians who prescribe for unlisted indica tions are violating the law. Myth Number Two: In those instances where there is widespread prescribing for an indica tion not specified in the labeling, FDA seems unwilling or at least insensitive to the need to eliminate the unjustified threat of malpractice litigation by expanding the list of approved indications. With regard to the first of these, the plain fact is that FDA approves the accuracy of what is on the official labeling; the physician takes it from there. He or she is responsible for making the final judgment about which, if any, of the available drugs the patient will receive in light of the information contained in the drug label ing and other available data. The law requires that when a new drug is approved for marketing, the conditions of use that the manufacturer or other drug sponsor has claimed and proved must be set forth in detail in the official labeling. . . All of this informa
EDITORIAL
627
tion is derived from the data submitted with the new drug application. Once the new drug is marketed, the physician may, as part of the practice of medicine, lawful ly prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert—without informing or obtaining approval of the Food and Drug Administration. Although the law does not require a physician to file a notice of claimed exemption for an investigational new drug (IND) before prescribing an approved drug for an indication not specified in the labeling, or to submit to FDA data concerning the therapeutic results and any adverse reac tions observed, it is sometimes in the best interests of both physician and public that these things be done. I know that there are legitimate concerns on the part of physicians that failure to follow the labeling of a drug may be used as evidence of malpractice. Although failure to follow labeling has sometimes been cited as showing a lack of adherence to the usual practice of medicine, it is only one element among many considered by the courts—some of the others being scientific articles, texts, and expert opinion. The impor tant consideration is whether departure from approved indications is documented by a legit imate scientific rationale for such use. . . . What about the other problem: FDA's failure to expand the list of indications even when, it seems, prescribing for an indication is wide spread? One example often cited in this regard is the labeling of propranolol, which was criticized for being confined to use in arrhythmias, hypertrophic subaortic stenosis, and pheochromocytoma, at a time when a number of physicians had reported using propranolol with good re sults in other disorders, notably angina pectoris and later hypertension. When FDA approves a new indication, the law requires that we ap prove it on the basis of adequate and wellcontrolled trials providing scientific evidence that the drug is useful for the specific indica tion. If the drug sponsor—or anyone else for that matter—does not submit evidence of this kind, there is simply no way we can approve such indications, and no way to flex regulatory muscle to force the sponsor to do the often expensive research necessary.
Although the FDA does not intend or believe it is controlling the practice of medicine, as a practical matter, doctors, nurses, and drug manufacturers are wor ried about the legal implications of the package insert. However, courts have also recognized that in appropriate cases drugs may be used for indications other than those set
628
AMERICAN JOURNAL OF OPHTHALMOLOGY
forth in the package insert. As stated by Judge Varner in United States v. Evers, 453 F. Supp. 1141 (M.D. Ala. 1978), a recent case in a federal court in Alabama: It is well recognized that a package insert may not contain the most up-to-date information about a drug and the physician must be free to use the drug for an indication not in the package insert when such usage is part of the practice of medicine and for the benefit of the patient. Hopefully, the physician would welcome a well-documented package insert because he finds it useful because the information in it is supported by substantial documented evidence. However, the physician can ascertain from the medical literature and from medical meetings new and interesting proposed uses for drugs marketed under package inserts not including the new proposed usages. The package insert's most important educational value derives from the fact that it is a well-reviewed, authoritative document. New uses for drugs are often discov ered, reported in medical journals and at medi cal meetings, and subsequently may be widely used by the medical profession. But the Food and Drug Administration does not permit the package insert to be amended to include such uses unless the manufacturer submits convinc ing evidence supporting the change. The manu facturer may not have sufficient commercial interests or financial wherewithal to warrant following the necessary procedures to obtain FDA approval for the additional use of the drug. When physicians go beyond the directions given in the package insert it does not mean they are acting illegally or unethically and Congress did not intend to empower the FDA to interfere with medical practice by limiting the ability of physicians to prescribe according to their best judgment.
Moreover, the Supreme Court has long recognized that direct control of medical practice in the United States is beyond the power of the federal government. Therefore, what constitutes bona fide medical practice must be determined upon consideration of evidence and at tending circumstances. In making such a determination in malpractice litigation, the package insert is admissible into evi dence, but it does not establish conclu sive evidence of the standard or accepted practice in the use of the drug by physi cians and surgeons, or that a departure from such directions is negligence. Therefore, physicians should continue to prescribe medications as the interest of
SEPTEMBER, 1979
the patient and good medical practice dictate. This is the best protection against unfavorable malpractice verdicts. J O E L S. M I N D E L ,
M.D.,
New York, New York AND J O S E P H I. G O L D S T E I N ,
Philadelphia,
J.D.
Pennsylvania
OBITUARY Maynard C. Wheeler, M.D. 1903-1979 On April 24, 1979, American ophthal mology lost one of its most loyal and devoted members, Maynard C. Wheeler. The son of an eye, ear, nose, and throat physician, he was born March 21, 1903, in Fargo, North Dakota. He grew up in Tacoma, Washington. He received his preliminary education at the Phillips Exeter Academy, Dartmouth College, and Stanford University before receiving his M.D. from Columbia University. After an internship in New York, he joined the resident staff at the newly opened Insti tute of Ophthalmology of Presbyterian Hospital at New York's Columbia Presby terian Medical Center where he remained until his retirement in 1973, as clinical professor. In keeping with his primary clinical interest in ocular motility, he es tablished an orthoptic department and muscle clinic, both of which continue to function strongly. As chief of the Eye Clinic, member of the board of surgeons, and director of undergraduate teaching, he was an individual upon whom the directors of the Eye Institute depended heavily. Always eager and ready to help the younger residents, his contributions in the teaching of the young cannot be overestimated. Thoroughly knowledgable in the history of American ophthalmolo gy, he wrote a most entertaining book, "The American Ophthalmological Socie-
W.
NEWEIX,
Editor-in-Chief
Tribune Tower, Suite 1415, 435 North Michigan Ave., Chicago, Illinois 60611 EDITORIAL BOARD Mathea R. Allansmith, Boston Douglas R. Anderson, Miami Crowell Beard, San Jose Bernard Becker, St. Louis Benjamin F . Boyd, Panama Charles J. Campbell, New York Ronald E. Carr, New York Thomas Chalkley, Chicago Claes H. Dohlman, Boston Fred Ederer, Bethesda
Published
DuPont Guerry III, Richmond Paul Henkind, Bronx Robert W. Hollenhorst, Rochester Herbert E. Kaufman, New Orleans Arthur H. Keeney, Louisville Carl Kupfer, Bethesda Irving H. Leopold, Irvine A. Edward Maumenee, Baltimore Irene H. Maumenee, Baltimore Edward W. D. Norton, Miami G. Richard O'Connor, San Francisco
monthly by the Ophthalmic
Arnall Patz, Baltimore Steven M. Podos, New York Albert M. Potts, Louisville Algernon B. Reese, New York Robert D. Reinecke, Albany Marvin L. Sears, New Haven David Shoch, Chicago Bruce E . Spivey, San Francisco Bradley R. Straatsma, Los Angeles Gunter K. von Noorden, Houston
Publishing
Company
Tribune Tower, Suite 1415, 435 North Michigan Avenue, Chicago, Illinois
60611
Directors: A. E D W A R D M A U M E N E E , President; D A V I D S H O C H , Vice President; F R A N K W. N E W E L L , Secretary and Treasurer; E D W A R D W. D. N O R T O N , B R U C E E. SPIVEY, B R A D L E Y R. STRAATSMA
NON-APPROVED USE O F F O O D AND DRUG ADMINISTRATION APPROVED DRUGS
looked in the PDR under methotrexate (Lederle). There it states that as an anti dote foroverdosage, Leucovorin, " m a y b e Considerable confusion and fear exist administered by intravenous infusion in concerning the legal status of the Food doses up to 75 mg within 12 hours." and Drug Administration (FDA) ap Because the dose ordered was in excess of proved package insert that accompanies 75 mg, the nurse refused to give it. She each medication (and which is printed in cited the PDR statement and her fear of the Physician's Desk Reference). This being sued for nursing malpractice. The confusion affects not only physicians but chief of the service gave the Leucovorin the nursing profession and the drug in himself. dustry as well. T w o examples demon 2. In Wilmington, Delaware, on Sept. strate the situation: 29, 1977, oral argument was heard in a 1. At a teaching hospital a resident preliminary injunction by the Pharma Manufacturers Association physician mistakenly ordered a lethal ceutical dose of methotrexate, a folic acid antago (PMA) against the FDA and the Depart nist, for a patient in the oncology ser ment of Health, Education and Welfare. vice. Immediately after its administra It concerned patient package inserts for tion, the resident realized his error and estrogen drug products. The FDA had rushed to the chief of his service, w h o proposed a regulation that would require personally ordered the antidote, Leucov- package inserts for these drugs in order orin (folinic acid). In the Physician's that patients could determine the risks Desk Reference (PDR) under Leucovorin and benefits of treatment. Judge Stapleton (Lederle) the correct dose is "to be given heard the PMA's case against the FDA. in amounts equal to the weight of the On the point that the regulation would antagonist given." However, the nurse interfere with the practice of medicine, he 626
VOL. 88, NO. 3, PART II concluded that it did not prohibit the physician from exercising his own profes sional judgement nor would it constitute third party control. If, because of the package insert, the patient altered his decision with regard to taking the drug, this was not construed by the judge as interference with the practice of medi cine. Judge Stapleton denied the prelimi nary injunction. The purpose of the preceding was not to promote fear and confusion but to show that they exist and that they extend to other groups besides physicians. In deed, the head of the FDA, Donald Ken nedy, Ph.D., has made written statements that should clear the air and provide con siderable relief to our profession. The following, excerpted from an article in The Western Journal of Medicine (127: 429-534, 1977), makes clear that the FDA is attempting to control the claims of the drug manufacturers and not the practice of medicine. Real communication between the medical pro fession and FDA depends upon exorcising sev eral myths about the regulatory process. These myths are pernicious as well as persistent, for they divert the free flow of understanding be tween those who deliver health care and those who seek to support their efforts. Myth Number One: Drug labeling is FDA's way of telling physicians exactly what they can and cannot do with prescription medicines, and physicians who prescribe for unlisted indica tions are violating the law. Myth Number Two: In those instances where there is widespread prescribing for an indica tion not specified in the labeling, FDA seems unwilling or at least insensitive to the need to eliminate the unjustified threat of malpractice litigation by expanding the list of approved indications. With regard to the first of these, the plain fact is that FDA approves the accuracy of what is on the official labeling; the physician takes it from there. He or she is responsible for making the final judgment about which, if any, of the available drugs the patient will receive in light of the information contained in the drug label ing and other available data. The law requires that when a new drug is approved for marketing, the conditions of use that the manufacturer or other drug sponsor has claimed and proved must be set forth in detail in the official labeling. . . All of this informa
EDITORIAL
627
tion is derived from the data submitted with the new drug application. Once the new drug is marketed, the physician may, as part of the practice of medicine, lawful ly prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert—without informing or obtaining approval of the Food and Drug Administration. Although the law does not require a physician to file a notice of claimed exemption for an investigational new drug (IND) before prescribing an approved drug for an indication not specified in the labeling, or to submit to FDA data concerning the therapeutic results and any adverse reac tions observed, it is sometimes in the best interests of both physician and public that these things be done. I know that there are legitimate concerns on the part of physicians that failure to follow the labeling of a drug may be used as evidence of malpractice. Although failure to follow labeling has sometimes been cited as showing a lack of adherence to the usual practice of medicine, it is only one element among many considered by the courts—some of the others being scientific articles, texts, and expert opinion. The impor tant consideration is whether departure from approved indications is documented by a legit imate scientific rationale for such use. . . . What about the other problem: FDA's failure to expand the list of indications even when, it seems, prescribing for an indication is wide spread? One example often cited in this regard is the labeling of propranolol, which was criticized for being confined to use in arrhythmias, hypertrophic subaortic stenosis, and pheochromocytoma, at a time when a number of physicians had reported using propranolol with good re sults in other disorders, notably angina pectoris and later hypertension. When FDA approves a new indication, the law requires that we ap prove it on the basis of adequate and wellcontrolled trials providing scientific evidence that the drug is useful for the specific indica tion. If the drug sponsor—or anyone else for that matter—does not submit evidence of this kind, there is simply no way we can approve such indications, and no way to flex regulatory muscle to force the sponsor to do the often expensive research necessary.
Although the FDA does not intend or believe it is controlling the practice of medicine, as a practical matter, doctors, nurses, and drug manufacturers are wor ried about the legal implications of the package insert. However, courts have also recognized that in appropriate cases drugs may be used for indications other than those set
628
AMERICAN JOURNAL OF OPHTHALMOLOGY
forth in the package insert. As stated by Judge Varner in United States v. Evers, 453 F. Supp. 1141 (M.D. Ala. 1978), a recent case in a federal court in Alabama: It is well recognized that a package insert may not contain the most up-to-date information about a drug and the physician must be free to use the drug for an indication not in the package insert when such usage is part of the practice of medicine and for the benefit of the patient. Hopefully, the physician would welcome a well-documented package insert because he finds it useful because the information in it is supported by substantial documented evidence. However, the physician can ascertain from the medical literature and from medical meetings new and interesting proposed uses for drugs marketed under package inserts not including the new proposed usages. The package insert's most important educational value derives from the fact that it is a well-reviewed, authoritative document. New uses for drugs are often discov ered, reported in medical journals and at medi cal meetings, and subsequently may be widely used by the medical profession. But the Food and Drug Administration does not permit the package insert to be amended to include such uses unless the manufacturer submits convinc ing evidence supporting the change. The manu facturer may not have sufficient commercial interests or financial wherewithal to warrant following the necessary procedures to obtain FDA approval for the additional use of the drug. When physicians go beyond the directions given in the package insert it does not mean they are acting illegally or unethically and Congress did not intend to empower the FDA to interfere with medical practice by limiting the ability of physicians to prescribe according to their best judgment.
Moreover, the Supreme Court has long recognized that direct control of medical practice in the United States is beyond the power of the federal government. Therefore, what constitutes bona fide medical practice must be determined upon consideration of evidence and at tending circumstances. In making such a determination in malpractice litigation, the package insert is admissible into evi dence, but it does not establish conclu sive evidence of the standard or accepted practice in the use of the drug by physi cians and surgeons, or that a departure from such directions is negligence. Therefore, physicians should continue to prescribe medications as the interest of
SEPTEMBER, 1979
the patient and good medical practice dictate. This is the best protection against unfavorable malpractice verdicts. J O E L S. M I N D E L ,
M.D.,
New York, New York AND J O S E P H I. G O L D S T E I N ,
Philadelphia,
J.D.
Pennsylvania
OBITUARY Maynard C. Wheeler, M.D. 1903-1979 On April 24, 1979, American ophthal mology lost one of its most loyal and devoted members, Maynard C. Wheeler. The son of an eye, ear, nose, and throat physician, he was born March 21, 1903, in Fargo, North Dakota. He grew up in Tacoma, Washington. He received his preliminary education at the Phillips Exeter Academy, Dartmouth College, and Stanford University before receiving his M.D. from Columbia University. After an internship in New York, he joined the resident staff at the newly opened Insti tute of Ophthalmology of Presbyterian Hospital at New York's Columbia Presby terian Medical Center where he remained until his retirement in 1973, as clinical professor. In keeping with his primary clinical interest in ocular motility, he es tablished an orthoptic department and muscle clinic, both of which continue to function strongly. As chief of the Eye Clinic, member of the board of surgeons, and director of undergraduate teaching, he was an individual upon whom the directors of the Eye Institute depended heavily. Always eager and ready to help the younger residents, his contributions in the teaching of the young cannot be overestimated. Thoroughly knowledgable in the history of American ophthalmolo gy, he wrote a most entertaining book, "The American Ophthalmological Socie-
