COMMENTARY
ETHICS OF ORGAN TRANSPLANTATION KARL HOLUBAR, M,D,
Two recent articles in the Sounding Board of the New England Journal of Medicine raise additional questions of ethical importance.'-^ Spital and Veatch elaborately discuss the problems of incentives and deterrents for (post mortem) organ donation and the associated legal problems. Both authors agree on one point, namely, the suggestion to put the question of consent or dissent before the potential donor, that is, before all of us (e.g., when applying for a driver's licence or on the income-tax return). Both ways look practical and promising, possibly providing the public (and the medical community) with an identifiable means of securing a person's own will in this special regard. In Austria, in contrast to the United States, "presumed consent" is already practiced today when the possibility of organ donation arises (e.g., in victims of accidents of which no relatives can be contacted in time). Suggestions (or motions, eventually) like the above by a leading nation may well change the situation and would have to be considered. Let us assume that, a decade hence, the majority of the populace in the United States, Japan, or Europe
will carry their positive or negative statements on their drivers' licences, have it stored in a central computer, or have it included in any routine medical history, as suggested above.^ As an inevitable consequence, doctors may then be facing (also) a reverse situation as compared to now, i.e., a given patient with a documented negative will (to donate his organs), who has become the potential recipient and not the possible donor of an organ. Once the necessity has arisen to perform a transplantation, will a patient with a declared unwillingness to donate his own organs have the same moral right to receive organ(s) from others? Will he be placed far down the waiting list with such a negative decision on record? Or will he perhaps be able to improve bis position by changing his earlier decision and adopting a positive stance? Or will the price tag just be higher? An irritating and disquieting array of questions, indeed, even if sensu strictiori such considerations are out of question and only medical parameters must count. REFERENCES
1,
From the Institute for the History of Medicine, University of Vienna, Vienna, Austria.
2,
Address for correspondence: Karl Holubar, M,D., Wahringer Strasse 25, A1090 Vienna, Austria.
Spital A, The shortage of organs for transplantation. Where do we go from here? New Engl J Med 1991325:1243-1246. Veatch RM, Routine inquiry about organ donation—an alternative to presumed consent. New Engl J Med 1991; 325:1246-1249.
DRUG DELAY AND THE EDA VINCENT P. BARRANCO, M.D,
In the area of infectious disease, it is well known that microorganisms may become resistant to certain commonly used antimicrobial agents. Some antimicrobial agents have more favorable pharmacologic properties in certain individuals and certain organ systems. Some antimicrobial agents have a broad spectrum of activity.
and of course, some patients are allergic to certain agents. It seems evident that the pharmaceutical industry must actively pursue new and better agents. Then, why am I sometimes frustrated by the lack of adequate antimicrobial therapy for my patients with infection? Colleagues in other areas of medicine have expressed similar concerns and frustrations regarding not only new and better antimicrobial agents, but also new and better cardiovascular, renal, oncologic, and neuropharmaceutical agents. Certainly, the pharmaceutical industry might share some of the blame, but there are some facts regarding the Food and Drug Administration (FDA) that I would
From the Department of Dermatology, University of Oklahoma Gollege of Medicine, Tulsa, Oklahoma, Address for correspondence: Vincent P, Barranco, M,D., 2121 East 21st Street, Tulsa, OK 74152, 691
International Journal of Dermatology Vol, 31, No, 10, Oetober 1992
The World Health Organization (WHO) is a third world health advocacy organization. In 1987, the WHO Essential Drug Use was reviewed. Nearly 25% of the indications that were listed were for new indications other than those originally approved.'' It was concluded that discovering new therapeutic uses is of medical importance to both developed and undeveloped nations. Clearly, the patient benefits from the pharmaceutical industry's research in new indications. Examples include dapsone for dermatitis herpetiform is, the protozoal agent pentamidine for Pneumocystis carinii pneumonia, beta blockers and aspirin for protection against myocardial infarction and coronary death, to only mention a few. Factors that cause a long review phase for new indications reduce the pharmaceutical company's ability to recoup its financial investment. This discourages pharmaceutical companies from pursuing new indications and in other instances increases drug costs. It should be easier and cheaper to get new indications approved by tbe FDA, because most toxicity and safety concerns should not be required for new indications; however, in two studies covering the time from 1963 to 1988, there were very little differences between the average length of time required to obtain approval for original and new indication drugs.^-*^ It seems to me tbis is unfair and unnecessary, and the patient suffers the ill consequences. In addition, the physician suffers the fear of criticism and litigation when using drugs for new indications not approved by tbe FDA. All physicians, and especially dermatologists, know all too well the need for new indications and should be applauded for tbeir courage and innovation. There are times when patients simply cannot and should not wait on FDA approval, when new indications are clearly rational and beneficial.
like to discuss, specifically this has to do with the delay in (1) the introduction of new drugs and (2) the approval of new indications for already approved drugs. NEW DRUG INTRODUCTION
The FDA classifies new drugs into three categories: IA (important therapeutic gain), IB (modest gain), lC (little or no gain). Most studies regarding new drugs' introductions usually compare the United States (us) with certain other countries, especially the United Kingdom (UK) because of their similar regulatory systems, scientific standards, and medical practices. One sucb study analyzed 46 new drugs, which were approved in 1985 and 1986.' Of the 46 new drugs, 33 (71.7%) were available in foreign markets prior to the US approval with a mean lead time of 5.5 years. This trend continued between 1987 and 1989, when 44 of 55 new drugs (80%) were available in foreign markets before US approval by a mean lead time of 6.5 years.^ This trend is evident in a comparison of 150 new drugs introduced mutually in the US and UK from 1977 through 1987.' Seventy-six percent were introduced in the UK first with a mean lead time of 37.1 months. This means the US had a greater than 3 year lag time. The lag times in the US of a few drugs of interest were terfenadine (Seldane) 39 months, clobetasol propionate (Temovate) 152 months, mupirocin (Bactroban) 32 months, econazole nitrate (Spectazole) 54 months, etretinate (Tegison) 59 months, and whatever happened to terbinafine. Terbinafine has been available in the UK and other foreign countries for almost 2 years while some of my patients with intractable onychomycosis linger in despair and others might be subjected to more potentially toxic or extremely expensive agents. Is this lag time important? The US consistently lags behind the UK in the introduction of drugs classified as IA, as well as the less significant, but nevertbeless important, categories of IB and lC. If patient access to important new drugs (IA) is a valid indicator, then the lag time in the US is deleterious.' As noted in the beginning of this paper, if access to a wide range of therapeutic options to meet the needs of patient variability is important, then the lag time in IB and IC drugs is also undesirable. It might be argued that increased drug safety justifies this lag time. If this was true, that might be, but this is not the case. One important measure of drug safety is how many highly toxic drugs appear on the market and require discontinuation. Of the drugs approved after 1974, the numbers withdrawn in each country were very similar (4 in the US versus 3 in the UK).' This does not support the argument that delay protects the public from unforseen adverse effects.
REFERENCES
1,
Kaitin Kl, Richard BW, Lasagna L. Trends in drug development: the 1985-86 new drug approvals, J Glin Pharmacol 1987; 27:542-548,
2,
Kaitin Kl, DiGerbo PA, Lasagna L, The new drug approvals of 1987, 1988, and 1989: trends in drug development, J Glin Pharmacol 1991; 31:116-122,
3,
Kaitin Kl, Mattison N, Northington FK, et al. The drug lag: an update of new drug introductions in the United States and in the United Kingdom, 1977 through 1987, Glin Pharmacol Ther 1989; 46:121-138,
4,
Wastila LJ, Ulcickas ME, Lasagna L. The World Health Organization's essential drug list, J Glin Res Drug Dev 1989; 3:105-115,
5,
Spivey RN, Lasagna L, Trimble AG, New indications for already-approved drugs: time trends for the new drug application review phase, Glin Pharmacol Ther 1987; 41:368-370, DeMasi JA, Kaitin Kl, Garol GF, et al. New indications for already-approved drugs: an analysis of regulatory review times, J Glin Pharmacol 1991; 31:205-215,
NEW INDICATIONS FOR ALREADY-APPROVED DRUGS
6,
Are new indications for drugs an important development by the pharmaceutical industry in their concern for patient care, or just their desire to increase profits? 692
ETHICS OF ORGAN TRANSPLANTATION KARL HOLUBAR, M,D,
Two recent articles in the Sounding Board of the New England Journal of Medicine raise additional questions of ethical importance.'-^ Spital and Veatch elaborately discuss the problems of incentives and deterrents for (post mortem) organ donation and the associated legal problems. Both authors agree on one point, namely, the suggestion to put the question of consent or dissent before the potential donor, that is, before all of us (e.g., when applying for a driver's licence or on the income-tax return). Both ways look practical and promising, possibly providing the public (and the medical community) with an identifiable means of securing a person's own will in this special regard. In Austria, in contrast to the United States, "presumed consent" is already practiced today when the possibility of organ donation arises (e.g., in victims of accidents of which no relatives can be contacted in time). Suggestions (or motions, eventually) like the above by a leading nation may well change the situation and would have to be considered. Let us assume that, a decade hence, the majority of the populace in the United States, Japan, or Europe
will carry their positive or negative statements on their drivers' licences, have it stored in a central computer, or have it included in any routine medical history, as suggested above.^ As an inevitable consequence, doctors may then be facing (also) a reverse situation as compared to now, i.e., a given patient with a documented negative will (to donate his organs), who has become the potential recipient and not the possible donor of an organ. Once the necessity has arisen to perform a transplantation, will a patient with a declared unwillingness to donate his own organs have the same moral right to receive organ(s) from others? Will he be placed far down the waiting list with such a negative decision on record? Or will he perhaps be able to improve bis position by changing his earlier decision and adopting a positive stance? Or will the price tag just be higher? An irritating and disquieting array of questions, indeed, even if sensu strictiori such considerations are out of question and only medical parameters must count. REFERENCES
1,
From the Institute for the History of Medicine, University of Vienna, Vienna, Austria.
2,
Address for correspondence: Karl Holubar, M,D., Wahringer Strasse 25, A1090 Vienna, Austria.
Spital A, The shortage of organs for transplantation. Where do we go from here? New Engl J Med 1991325:1243-1246. Veatch RM, Routine inquiry about organ donation—an alternative to presumed consent. New Engl J Med 1991; 325:1246-1249.
DRUG DELAY AND THE EDA VINCENT P. BARRANCO, M.D,
In the area of infectious disease, it is well known that microorganisms may become resistant to certain commonly used antimicrobial agents. Some antimicrobial agents have more favorable pharmacologic properties in certain individuals and certain organ systems. Some antimicrobial agents have a broad spectrum of activity.
and of course, some patients are allergic to certain agents. It seems evident that the pharmaceutical industry must actively pursue new and better agents. Then, why am I sometimes frustrated by the lack of adequate antimicrobial therapy for my patients with infection? Colleagues in other areas of medicine have expressed similar concerns and frustrations regarding not only new and better antimicrobial agents, but also new and better cardiovascular, renal, oncologic, and neuropharmaceutical agents. Certainly, the pharmaceutical industry might share some of the blame, but there are some facts regarding the Food and Drug Administration (FDA) that I would
From the Department of Dermatology, University of Oklahoma Gollege of Medicine, Tulsa, Oklahoma, Address for correspondence: Vincent P, Barranco, M,D., 2121 East 21st Street, Tulsa, OK 74152, 691
International Journal of Dermatology Vol, 31, No, 10, Oetober 1992
The World Health Organization (WHO) is a third world health advocacy organization. In 1987, the WHO Essential Drug Use was reviewed. Nearly 25% of the indications that were listed were for new indications other than those originally approved.'' It was concluded that discovering new therapeutic uses is of medical importance to both developed and undeveloped nations. Clearly, the patient benefits from the pharmaceutical industry's research in new indications. Examples include dapsone for dermatitis herpetiform is, the protozoal agent pentamidine for Pneumocystis carinii pneumonia, beta blockers and aspirin for protection against myocardial infarction and coronary death, to only mention a few. Factors that cause a long review phase for new indications reduce the pharmaceutical company's ability to recoup its financial investment. This discourages pharmaceutical companies from pursuing new indications and in other instances increases drug costs. It should be easier and cheaper to get new indications approved by tbe FDA, because most toxicity and safety concerns should not be required for new indications; however, in two studies covering the time from 1963 to 1988, there were very little differences between the average length of time required to obtain approval for original and new indication drugs.^-*^ It seems to me tbis is unfair and unnecessary, and the patient suffers the ill consequences. In addition, the physician suffers the fear of criticism and litigation when using drugs for new indications not approved by tbe FDA. All physicians, and especially dermatologists, know all too well the need for new indications and should be applauded for tbeir courage and innovation. There are times when patients simply cannot and should not wait on FDA approval, when new indications are clearly rational and beneficial.
like to discuss, specifically this has to do with the delay in (1) the introduction of new drugs and (2) the approval of new indications for already approved drugs. NEW DRUG INTRODUCTION
The FDA classifies new drugs into three categories: IA (important therapeutic gain), IB (modest gain), lC (little or no gain). Most studies regarding new drugs' introductions usually compare the United States (us) with certain other countries, especially the United Kingdom (UK) because of their similar regulatory systems, scientific standards, and medical practices. One sucb study analyzed 46 new drugs, which were approved in 1985 and 1986.' Of the 46 new drugs, 33 (71.7%) were available in foreign markets prior to the US approval with a mean lead time of 5.5 years. This trend continued between 1987 and 1989, when 44 of 55 new drugs (80%) were available in foreign markets before US approval by a mean lead time of 6.5 years.^ This trend is evident in a comparison of 150 new drugs introduced mutually in the US and UK from 1977 through 1987.' Seventy-six percent were introduced in the UK first with a mean lead time of 37.1 months. This means the US had a greater than 3 year lag time. The lag times in the US of a few drugs of interest were terfenadine (Seldane) 39 months, clobetasol propionate (Temovate) 152 months, mupirocin (Bactroban) 32 months, econazole nitrate (Spectazole) 54 months, etretinate (Tegison) 59 months, and whatever happened to terbinafine. Terbinafine has been available in the UK and other foreign countries for almost 2 years while some of my patients with intractable onychomycosis linger in despair and others might be subjected to more potentially toxic or extremely expensive agents. Is this lag time important? The US consistently lags behind the UK in the introduction of drugs classified as IA, as well as the less significant, but nevertbeless important, categories of IB and lC. If patient access to important new drugs (IA) is a valid indicator, then the lag time in the US is deleterious.' As noted in the beginning of this paper, if access to a wide range of therapeutic options to meet the needs of patient variability is important, then the lag time in IB and IC drugs is also undesirable. It might be argued that increased drug safety justifies this lag time. If this was true, that might be, but this is not the case. One important measure of drug safety is how many highly toxic drugs appear on the market and require discontinuation. Of the drugs approved after 1974, the numbers withdrawn in each country were very similar (4 in the US versus 3 in the UK).' This does not support the argument that delay protects the public from unforseen adverse effects.
REFERENCES
1,
Kaitin Kl, Richard BW, Lasagna L. Trends in drug development: the 1985-86 new drug approvals, J Glin Pharmacol 1987; 27:542-548,
2,
Kaitin Kl, DiGerbo PA, Lasagna L, The new drug approvals of 1987, 1988, and 1989: trends in drug development, J Glin Pharmacol 1991; 31:116-122,
3,
Kaitin Kl, Mattison N, Northington FK, et al. The drug lag: an update of new drug introductions in the United States and in the United Kingdom, 1977 through 1987, Glin Pharmacol Ther 1989; 46:121-138,
4,
Wastila LJ, Ulcickas ME, Lasagna L. The World Health Organization's essential drug list, J Glin Res Drug Dev 1989; 3:105-115,
5,
Spivey RN, Lasagna L, Trimble AG, New indications for already-approved drugs: time trends for the new drug application review phase, Glin Pharmacol Ther 1987; 41:368-370, DeMasi JA, Kaitin Kl, Garol GF, et al. New indications for already-approved drugs: an analysis of regulatory review times, J Glin Pharmacol 1991; 31:205-215,
NEW INDICATIONS FOR ALREADY-APPROVED DRUGS
6,
Are new indications for drugs an important development by the pharmaceutical industry in their concern for patient care, or just their desire to increase profits? 692
