EurJ Clin Pharmacol (1991) 41:325 328
© Springer-Verlag 1991
Impact of clinical trials on the adoption of new drugs within a university hospital p. Denigl, F.M.Haaijer.Ruskampl, 2, H. Wesseling 2, and A. Versluis 3 Departments of ~ Health Sciences and 2 Pharmacology and Clinical Pharmacology, University of Groningen, and 3 Department of Pharmacy, University Hospital Groningen, Groningen, The Netherlands Received: September 24, 1990/Accepted in revised form: December 8, 1990
Summary. To assess the influence that clinical trials m a y have on the introduction of new drugs into prescribing routines, the adoption of drugs has been studied in a university hospital in the Netherlands. A significant relation was found between the testing of semi-innovative drugs in clinical trials in the hospital and the introduction of these drugs into general use in the same hospital. No such relationship was found for innovative drugs. E m p l o y m e n t in clinical trials only affected the frequency of adoption of semi-innovative drugs. It did not influence the quantity of their use once they had been adopted. The idea that the stimulating effect of clinical trials on the adoption of semi-innovative drugs is only due to acceleration of the adoption process was not confirmed. These findings support the idea that clinical trials can lower the barriers for adoption of semi-innovative drugs. Key words: New drugs; prescribing pattern, clinical trials, semi-innovative drugs, adoption
It has been suggested that clinical trials can stimulate the early adoption of new drugs by prescribing physicians [1, 2]. W h e t h e r this is true and to what extent prescribing quality is affected by this mechanism is not known. It appears that no experimental data have been made available to support these statements. In theory, there could be several reasons why e m p l o y m e n t in a clinical trial would lower some of the barriers to the adoption of new drugs [3, 4]. In the first place, physicians are m a d e aware of the existence of the new drug and its possible uses. Even a drug that would not normally have attracted much attention could reach the awareness and interest of physicians asked to test it in a clinical trial. Second, the decision to use a new drug for the first time is easier in a trial setting, because additional beneficial outcomes are possible. Not only the patient, but also science might benefit from the new therapy. Third, once a drug has b e e n tried in a n u m b e r of patients within a trial, the physician becomes m o r e familiar with it. This personal experience will override the
hesitation of most doctors to use drugs they do not known much about. Finally, if the trial does not result in rejection of the drug, i. e. the drug does not fall short of its expectations, it is difficult to discontinue its use after the clinical trial has been finished. Being an active participant in the trial, it is not easy to admit that a drug has nothing to offer above (more extensively documented) alternatives. Because of these considerations, it is expected that clinical trials will stimulate the adoption of new drugs. This is a positive effect if it involves truly innovative drugs, but could be negative in the case of drugs whose innovative quality is limited or questionable (the "semi-innovative" drugs). It is hypothesized, however, that clinical trials only affect the adoption of semi-innovative drugs, while innovative drugs will be introduced anyhow. Additional stimuli caused by trials are not expected to have much influence on the introduction of real innovations, because the barriers to their adoption are low [1]. This hypothesis has been tested in a retrospective study in the 1000-bed University Hospital in Groningen, The Netherlands.
Material and methods From the lists of new drug registrations in the Netherlands all new drugs registered between January 1985 and October 1988 were selected. A drug was considered new if its compound(s) were not already on the market in a comparable form (see Table 1). The new drugs were then classified independently by two of the authors (HW and AV) as either innovative or semi-innovative using the classification of Dukes and Lunde (Table 1) [5]. There was good agreement on the classification (93 % agreement, kappa = 0.84), and the disagreements were settled by achieving consensus. A comparison was also made with the FDA classifications of FDA approved drugs [6]L
The FDA classification system uses three categories for the therapeutic potential: Type A for important therapeutic gain, which is comparable to Class 1 of Dukes and Lunde; Type B for modest therapeutic gain, comparable to Class 2b/c of Dukes and Lunde; and Type C for little or no therapeutic gain, comparable to Class 2a of Dukes and Lunde.
E Denig et al.: Adoption of new drugs
326 Table 1. Classification of new and innovative drugs (Dukes et al. 1979)
1. New Innovative drugs a. New Chemical Entities (NCEs) with new claims b. New preparations of existing compounds designed for novel fields of application c. Novel types of combinations, claiming to serve new purposes
2. New Semi-innovative drugs a. NCEs belonging to existing therapeutic groups without clearly novel elements in their claims ("Me-too") b. Pharmaceutical innovationsclaiming to represent minor advantages (e. g. duration of action, convenience of use) c. Other new products claiming to represent minor advantages
3. Notnew drugs a. New brands of existing compounds b. New forms of dosage strengths of known compounds that do not belong to 2b. c. Fixed combinations, herbal remedies or infusion fluids of an entirely traditional type d. Other non-innovativesubmissions (e. g. parallel imported products)
500 DDD was considered as large scale use, providing that the use was 10 DDD per 100 beds per day on at least one ward, or 5 DDD per 100 beds per day on at least 2 wards. In fact, of all the semiinnovative drugs registered between 1985 and 1988, only 7 had been studied in a clinical trial our hospital. Therefore, the analysis of drug use quantity was extended to all semi-innovative drugs that had been or were still under study, irrespective of their registration date. This meant that all drugs studied in a trial had to be classified either as innovative or semi-innovative (by HW and AV). Again, agreement on classification proved to be good (98% agreement, kappa = 0.96), but 11 drugs could not (yet) be classified by either of the authors. Those drugs were excluded from the analysis. This resulted in the recognition of 31 semi-innovative drugs that had been tested in the hospital since 1982. The effect of employment in clinical trials on the adoption of drugs might be limited to a time-related effect, i. e. only accelerating the adoption process. Therefore, a test was done to show whether clinical trials influenced the adoption rate of new drugs. In order to do so, the time of adoption was ranked in four categories: before registration, during the registration year, 1 year after the registration year, and 2-3 years after the registration year. Differences both in quantities of use and adoption rate between drugs that either had or had not been studied in a hospital trial were tested using the Mann-Whitney U-test. A difference was considered significant at P < 0.05.
Table 2. Adoption of recently registered semi-innovative drugs in relation to their employment in clinical trials Results
Not Adopted
Adopted
Total
n
n
n
In trial Not in trial
0 32
7 14
7 46
Semi-innovative drugs
Total
32
21
53
O f the 76 n e w drugs registered in the N e t h e r l a n d s bet w e e n J a n u a r y 1985 a n d O c t o b e r 1988, 23 were classified by us as i n n o v a t i v e a n d 53 as s e m i - i n n o v a t i v e . T h e F D A classification was available for 23 of those drugs. T h e r e was good a g r e e m e n t b e t w e e n the two classifications (91% a g r e e m e n t ; k a p p a = 0.84). Of the 53 s e m i - i n n o v a t i v e drugs registered in the N e t h e r l a n d s b e t w e e n 1985 and 1988, only 7 h a d b e e n studied in a clinical trial in our hospital. A l l 7 were i n t r o d u c e d into prescribing routines, w h e r e a s only 14 of the r e m a i n ing 46 s e m i - i n n o v a t i v e drugs were a d o p t e d (Table 2; chi 2 = 10.2, P < 0.05). This indicates that the a d o p t i o n of s e m i - i n n o v a t i v e drugs was positively r e l a t e d to local clinical trials, T h e q u e s t i o n r e m a i n s w h e t h e r e m p l o y m e n t in clinical trials also led to m o r e extensive use of the drugs involved. To answer that q u e s t i o n the q u a n t i t i e s used of all s e m i - i n n o vative drugs that h a d b e e n or still were u n d e r study in the hospital was analysed, irrespective of their registration date (n = 31 i n s t e a d of 7). T h e q u a n t i t i e s used (insignificant, small, or large scale) were c o m p a r e d to the g r o u p of 46 s e m i - i n n o v a t i v e drugs n o t i n v e s t i g a t e d in the hospital u n d e r study (i. e., the 53 - 7 -- 46 recently registered semii n n o v a t i v e drugs). O f the 31 drugs in the f o r m e r group, 20 were in use at the time of the investigation; there was insignificant use of 5, small scale use of 9, a n d large scale use of 6 of the drugs. Of the 46 s e m i - i n n o v a t i v e drugs that h a d n o t b e e n studied the hospital, 14 were in use; insignificant use was o b s e r v e d of 5, small scale use of 7, a n d large scale use of 2 drugs. T h e r e was n o significant difference in q u a n t i t y b e t w e e n the two groups of drugs that were b e i n g used (Table 3, P > 0.05). If " n o t used at all" were i n c l u d e d as a fourth ca-
To establish which drugs had been or were still under study in the hospital, the records of the Institutional Review Board were used. From 1981 onwards, clinical drug trials required approval by this board before they could be carried out. All applicants for approved clinical trials were approached to establish whether the trial had actually been (or still was being) conducted. The method provides a reliable description of the trials that have taken place since 1982. Trials unknown to the board are assumed to be rare, since in such cases the investigator is personally held liable for its consequences in case of problems. Drug utilization data were obtained from the hospital pharmacy. At the time of the study, data were available from 1984 to October 1988. The hypothesis tested was that employment in clinical trials would affect the adoption of semi-innovativedrugs, but not of innovative drugs. Therefore, the relation between clinical trials and the number of new drugs adopted was examined. We tested whether recently registered drugs that had been studied in a trial were more often adopted than those that had not been investigated in the hospital. This was clone separately for innovative and semi-innovative drugs, using chi2-tests with Yates correction if one or more cell frequencies < 5. If drugs under study were more frequently adopted, an additional test was done to show whether having been in a trial also affected the quantity of the drug used. To do so, drug use in 1987 and 1988 was expressed as the total number of Defined D ally Doses (DDD) in one year and as the number of DDD per 100 beds per day [7]. Insignificant drug use was defined as a total use of less than 50DDD in that year. This corresponds to a maximum use of 1 DDD per 100 beds per day on any one ward. Small scale use was defined as a total use of 50-500 DDD, or a total use of more than 500 DDD, in addition to which use on not more than one ward exceeded 5 DDD per 100beds per day, and on no ward did it exceed 10 DDD per 100 beds per day. A total use of more than
327
E D e n i g et al.: A d o p t i o n of n e w drugs
Discussion
Table 3. Quantity of semi-innovative drug use
In trial Not in trial
Not (yet) Insignificant Small Scale in Use Use Use
Large Scale Total Use
g/
n
n
n
n
11 32
5 5
9 7
6 2
31 46
Table 4. A d o p t i o n of innovative drugs in relation to their employ-
m e n t in clinical trials Not A d o p t e d
Adopted
Total
/1
/1/
n
In trial Not in trial
1 5
9 8
10 13
Total
6
17
23
Table 5. Time of a d o p t i o n of recently registered drugs in t h e hospital before re- in registra- 1 year after 2-3 years after gistration tion year registration registration n n n n Total semiinnovative
In trial Not in trial
2 2
3 4
6 4
3 4
1
1
7
6
2
14
innovative
In trial Not in trial
tegory, there was a significant difference in quantity of use between the groups, confirming the relation between trials and the adoption of semi-innovative drugs (Table 3, P : 0.002).
Innovative drugs Of the 23 recently registered innovative drugs, 10 had been or were still being investigated in a clinical trial within the hospital. All but one had been adopted in the prescribing practices of the physicians. This number was not significantly different from the number of adopted innovative drugs not included in local drug trials (Table 4; chi 2 = 1.3, P > 0.05).
Adoption rate No significant relationship was found between the time of adoption of a drug and of its study in a local trial (Table 5, P = 0.3 for semi-innovative drugs, and P = 0.5 for innovative drugs). This implies that the relationship found between trials and the adoption of semi-innovative drugs was not due to acceleration of the adoption rate. Apart from that, the adoption rate of semi-innovative drugs was significantly slower than that of innovative drugs (Table 5, P = 0.001).
The hypothesis that drug trials have a selective influence on the adoption of semi-innovative drugs has been confirmed in a university hospital setting. As expected, a positive relationship was found between the adoption of semiinnovative drugs and the fact that they had been studied in a clinical trial. No such relationship was found for the adoption of innovative drugs. The effect is not due to an acceleration of the adoption process for semi-innovative drugs. Semi-innovative drugs of both groups, i.e. those which had been or had not been investigated, were mostly introduced within one year after registration, and significantly different adoption rates were not found. Also, no difference was found in the quantities of semi-innovative drugs used. Therefore, it seems that trials only stimulate the likelihood that a particular drug will be used at all, without affecting the scale of its use. This is consistent with the idea that clinical trials lower the barriers to the adoption of the drugs in trial. Once a drug has been adopted, no further effect is anticipated from employment in a clinical trial. Classification as a 'semi-innovative' drug does not necessarily mean that the use of such a drug is irrational or undesirable. Within this group there are drugs that offer some advantages over the alternatives already in use, such as convenience of use or small kinetic benefits. It is possible that especially semi-innovative drugs with such advantages have been studied in our hospital, and this could explain why these drugs were more frequently adopted. It is not believed, however, that this explanation is valid; several semi-innovative drugs that do not seem to offer any substantial advantage over the alternatives were adopted after having been studied in a clinical trial (e. g. bisoprolol, felodipine, isradipine, budesonide and pefloxacin). Further prospective research on the adoption of semi-innovative drugs should afford a more definite conclusion about the influence of employment in clinical trials. Of course, employment in clinical trials is not the only factor that influences the adoption of a new drug. Promotion campaigns and outpatient prescribing, for instance, can also stimulate adoption. The influence of these factors, however, is expected to be equal for all semi-innovative drugs, irrespective of whether they have been studied in a local trial. What are the implications of the findings? There are positive and negative aspects associated with trials of semi-innovative drugs. Improvements in drug therapy can be developed by experimenting with small variations, i. e. semi-innovative drugs. On the other hand, there appears to be a limit to the number of semi-innovative drugs that are needed to realise such improvements. Whereas the second, third or even sixth drug within one drug class may be useful in clinical practice, the fifteenth is usually unnecessary. A trial of such a drug might be financially attractive for a hospital in terms of free drug supply during the investigational period, or employment of physicianresearchers, but it burdens patients, and indirectly it increases costs for the health insurance companies. After all, most trials require extra tests for which patients have to stay longer or come more often to the hospital, and
328 which are not always paid for. Moreover, if clinical trials stimulate the a d o p t i o n of semi-innovative drugs, as shown here, the quality of prescribing m a y be negatively affected. This is not the case w h e n the semi-innovative drugs offer useful advantages over the alternatives, as stated above. However, it is often a point of discussion w h e t h e r the possible advantages are clinically relevant. In s o m e cases, it could be argued that the expense is not in p r o p o r t i o n to the m i n o r advantages. In others, the advantages m a y not even be substantiated. A d o p t i o n of such drugs in prescribing routines offers no benefits and can only increase the use of drugs with less extensively d o c u m e n t e d risks. F r o m the present findings, it is r e c o m m e n d e d that after a trial with a semi-innovative drug has b e e n concluded, hospitals should encourage a restrictive policy concerning the use of that drug for new patients. If a clinical trial does not show clear advantages of the new drug, further use should be discouraged.
Acknowledgements. We thank I.Lunde and R.Vos for their review comments. The study was supported by the University Hospital Groningen Stimulation Program.
P. Denig et al.: Adoption of new drugs
References 1. Roscam Abbing HDC (1989) Geneesmiddelen: voorschrijfbeleid in ziekenhuizen. Pharm Weekblad 124:343-347 2. Plumridge RJ (1983) A review of factors influencing drug prescribing (part 1 + 2). Am JHosp Pharm 13: 16-19, 44-48 3. Miller RR (1973-1974) Prescribing habits of physicians pts I-VIII. Drug Intell Clin Pharm 7: 557-564, 8:81-91 4. Plumridge RJ (1984) Intervention strategies aimed at modifying prescribing behaviour. Austr J Hosp Pharm 14:93-100 5. Dukes MNG, Lunde I (1979) Measuring the effects of drug control - an emerging challenge. Pharm J 223:511-513 6. Drugdex 1990, Micromedex Inc., vol 63, Denver, Co, USA. Topic: FDA approved drugs 1985,1987, 1988. 7. Hekster YA, Vree TB, Goris RJA, Boerema JBJ (1982) The DDD per 100 bed-days as a unit of comparison and a parameter for studying antimicrobial drug use in a university hospital. A retrospective study of the effects of guidelines and audit on antimicrobial drug use. J Clin Hosp Pharm 7:251-260 Dr. R Denig Department of Health Sciences Ant. Deusinghlaan 1 NL-9713 AV Groningen The Netherlands
© Springer-Verlag 1991
Impact of clinical trials on the adoption of new drugs within a university hospital p. Denigl, F.M.Haaijer.Ruskampl, 2, H. Wesseling 2, and A. Versluis 3 Departments of ~ Health Sciences and 2 Pharmacology and Clinical Pharmacology, University of Groningen, and 3 Department of Pharmacy, University Hospital Groningen, Groningen, The Netherlands Received: September 24, 1990/Accepted in revised form: December 8, 1990
Summary. To assess the influence that clinical trials m a y have on the introduction of new drugs into prescribing routines, the adoption of drugs has been studied in a university hospital in the Netherlands. A significant relation was found between the testing of semi-innovative drugs in clinical trials in the hospital and the introduction of these drugs into general use in the same hospital. No such relationship was found for innovative drugs. E m p l o y m e n t in clinical trials only affected the frequency of adoption of semi-innovative drugs. It did not influence the quantity of their use once they had been adopted. The idea that the stimulating effect of clinical trials on the adoption of semi-innovative drugs is only due to acceleration of the adoption process was not confirmed. These findings support the idea that clinical trials can lower the barriers for adoption of semi-innovative drugs. Key words: New drugs; prescribing pattern, clinical trials, semi-innovative drugs, adoption
It has been suggested that clinical trials can stimulate the early adoption of new drugs by prescribing physicians [1, 2]. W h e t h e r this is true and to what extent prescribing quality is affected by this mechanism is not known. It appears that no experimental data have been made available to support these statements. In theory, there could be several reasons why e m p l o y m e n t in a clinical trial would lower some of the barriers to the adoption of new drugs [3, 4]. In the first place, physicians are m a d e aware of the existence of the new drug and its possible uses. Even a drug that would not normally have attracted much attention could reach the awareness and interest of physicians asked to test it in a clinical trial. Second, the decision to use a new drug for the first time is easier in a trial setting, because additional beneficial outcomes are possible. Not only the patient, but also science might benefit from the new therapy. Third, once a drug has b e e n tried in a n u m b e r of patients within a trial, the physician becomes m o r e familiar with it. This personal experience will override the
hesitation of most doctors to use drugs they do not known much about. Finally, if the trial does not result in rejection of the drug, i. e. the drug does not fall short of its expectations, it is difficult to discontinue its use after the clinical trial has been finished. Being an active participant in the trial, it is not easy to admit that a drug has nothing to offer above (more extensively documented) alternatives. Because of these considerations, it is expected that clinical trials will stimulate the adoption of new drugs. This is a positive effect if it involves truly innovative drugs, but could be negative in the case of drugs whose innovative quality is limited or questionable (the "semi-innovative" drugs). It is hypothesized, however, that clinical trials only affect the adoption of semi-innovative drugs, while innovative drugs will be introduced anyhow. Additional stimuli caused by trials are not expected to have much influence on the introduction of real innovations, because the barriers to their adoption are low [1]. This hypothesis has been tested in a retrospective study in the 1000-bed University Hospital in Groningen, The Netherlands.
Material and methods From the lists of new drug registrations in the Netherlands all new drugs registered between January 1985 and October 1988 were selected. A drug was considered new if its compound(s) were not already on the market in a comparable form (see Table 1). The new drugs were then classified independently by two of the authors (HW and AV) as either innovative or semi-innovative using the classification of Dukes and Lunde (Table 1) [5]. There was good agreement on the classification (93 % agreement, kappa = 0.84), and the disagreements were settled by achieving consensus. A comparison was also made with the FDA classifications of FDA approved drugs [6]L
The FDA classification system uses three categories for the therapeutic potential: Type A for important therapeutic gain, which is comparable to Class 1 of Dukes and Lunde; Type B for modest therapeutic gain, comparable to Class 2b/c of Dukes and Lunde; and Type C for little or no therapeutic gain, comparable to Class 2a of Dukes and Lunde.
E Denig et al.: Adoption of new drugs
326 Table 1. Classification of new and innovative drugs (Dukes et al. 1979)
1. New Innovative drugs a. New Chemical Entities (NCEs) with new claims b. New preparations of existing compounds designed for novel fields of application c. Novel types of combinations, claiming to serve new purposes
2. New Semi-innovative drugs a. NCEs belonging to existing therapeutic groups without clearly novel elements in their claims ("Me-too") b. Pharmaceutical innovationsclaiming to represent minor advantages (e. g. duration of action, convenience of use) c. Other new products claiming to represent minor advantages
3. Notnew drugs a. New brands of existing compounds b. New forms of dosage strengths of known compounds that do not belong to 2b. c. Fixed combinations, herbal remedies or infusion fluids of an entirely traditional type d. Other non-innovativesubmissions (e. g. parallel imported products)
500 DDD was considered as large scale use, providing that the use was 10 DDD per 100 beds per day on at least one ward, or 5 DDD per 100 beds per day on at least 2 wards. In fact, of all the semiinnovative drugs registered between 1985 and 1988, only 7 had been studied in a clinical trial our hospital. Therefore, the analysis of drug use quantity was extended to all semi-innovative drugs that had been or were still under study, irrespective of their registration date. This meant that all drugs studied in a trial had to be classified either as innovative or semi-innovative (by HW and AV). Again, agreement on classification proved to be good (98% agreement, kappa = 0.96), but 11 drugs could not (yet) be classified by either of the authors. Those drugs were excluded from the analysis. This resulted in the recognition of 31 semi-innovative drugs that had been tested in the hospital since 1982. The effect of employment in clinical trials on the adoption of drugs might be limited to a time-related effect, i. e. only accelerating the adoption process. Therefore, a test was done to show whether clinical trials influenced the adoption rate of new drugs. In order to do so, the time of adoption was ranked in four categories: before registration, during the registration year, 1 year after the registration year, and 2-3 years after the registration year. Differences both in quantities of use and adoption rate between drugs that either had or had not been studied in a hospital trial were tested using the Mann-Whitney U-test. A difference was considered significant at P < 0.05.
Table 2. Adoption of recently registered semi-innovative drugs in relation to their employment in clinical trials Results
Not Adopted
Adopted
Total
n
n
n
In trial Not in trial
0 32
7 14
7 46
Semi-innovative drugs
Total
32
21
53
O f the 76 n e w drugs registered in the N e t h e r l a n d s bet w e e n J a n u a r y 1985 a n d O c t o b e r 1988, 23 were classified by us as i n n o v a t i v e a n d 53 as s e m i - i n n o v a t i v e . T h e F D A classification was available for 23 of those drugs. T h e r e was good a g r e e m e n t b e t w e e n the two classifications (91% a g r e e m e n t ; k a p p a = 0.84). Of the 53 s e m i - i n n o v a t i v e drugs registered in the N e t h e r l a n d s b e t w e e n 1985 and 1988, only 7 h a d b e e n studied in a clinical trial in our hospital. A l l 7 were i n t r o d u c e d into prescribing routines, w h e r e a s only 14 of the r e m a i n ing 46 s e m i - i n n o v a t i v e drugs were a d o p t e d (Table 2; chi 2 = 10.2, P < 0.05). This indicates that the a d o p t i o n of s e m i - i n n o v a t i v e drugs was positively r e l a t e d to local clinical trials, T h e q u e s t i o n r e m a i n s w h e t h e r e m p l o y m e n t in clinical trials also led to m o r e extensive use of the drugs involved. To answer that q u e s t i o n the q u a n t i t i e s used of all s e m i - i n n o vative drugs that h a d b e e n or still were u n d e r study in the hospital was analysed, irrespective of their registration date (n = 31 i n s t e a d of 7). T h e q u a n t i t i e s used (insignificant, small, or large scale) were c o m p a r e d to the g r o u p of 46 s e m i - i n n o v a t i v e drugs n o t i n v e s t i g a t e d in the hospital u n d e r study (i. e., the 53 - 7 -- 46 recently registered semii n n o v a t i v e drugs). O f the 31 drugs in the f o r m e r group, 20 were in use at the time of the investigation; there was insignificant use of 5, small scale use of 9, a n d large scale use of 6 of the drugs. Of the 46 s e m i - i n n o v a t i v e drugs that h a d n o t b e e n studied the hospital, 14 were in use; insignificant use was o b s e r v e d of 5, small scale use of 7, a n d large scale use of 2 drugs. T h e r e was n o significant difference in q u a n t i t y b e t w e e n the two groups of drugs that were b e i n g used (Table 3, P > 0.05). If " n o t used at all" were i n c l u d e d as a fourth ca-
To establish which drugs had been or were still under study in the hospital, the records of the Institutional Review Board were used. From 1981 onwards, clinical drug trials required approval by this board before they could be carried out. All applicants for approved clinical trials were approached to establish whether the trial had actually been (or still was being) conducted. The method provides a reliable description of the trials that have taken place since 1982. Trials unknown to the board are assumed to be rare, since in such cases the investigator is personally held liable for its consequences in case of problems. Drug utilization data were obtained from the hospital pharmacy. At the time of the study, data were available from 1984 to October 1988. The hypothesis tested was that employment in clinical trials would affect the adoption of semi-innovativedrugs, but not of innovative drugs. Therefore, the relation between clinical trials and the number of new drugs adopted was examined. We tested whether recently registered drugs that had been studied in a trial were more often adopted than those that had not been investigated in the hospital. This was clone separately for innovative and semi-innovative drugs, using chi2-tests with Yates correction if one or more cell frequencies < 5. If drugs under study were more frequently adopted, an additional test was done to show whether having been in a trial also affected the quantity of the drug used. To do so, drug use in 1987 and 1988 was expressed as the total number of Defined D ally Doses (DDD) in one year and as the number of DDD per 100 beds per day [7]. Insignificant drug use was defined as a total use of less than 50DDD in that year. This corresponds to a maximum use of 1 DDD per 100 beds per day on any one ward. Small scale use was defined as a total use of 50-500 DDD, or a total use of more than 500 DDD, in addition to which use on not more than one ward exceeded 5 DDD per 100beds per day, and on no ward did it exceed 10 DDD per 100 beds per day. A total use of more than
327
E D e n i g et al.: A d o p t i o n of n e w drugs
Discussion
Table 3. Quantity of semi-innovative drug use
In trial Not in trial
Not (yet) Insignificant Small Scale in Use Use Use
Large Scale Total Use
g/
n
n
n
n
11 32
5 5
9 7
6 2
31 46
Table 4. A d o p t i o n of innovative drugs in relation to their employ-
m e n t in clinical trials Not A d o p t e d
Adopted
Total
/1
/1/
n
In trial Not in trial
1 5
9 8
10 13
Total
6
17
23
Table 5. Time of a d o p t i o n of recently registered drugs in t h e hospital before re- in registra- 1 year after 2-3 years after gistration tion year registration registration n n n n Total semiinnovative
In trial Not in trial
2 2
3 4
6 4
3 4
1
1
7
6
2
14
innovative
In trial Not in trial
tegory, there was a significant difference in quantity of use between the groups, confirming the relation between trials and the adoption of semi-innovative drugs (Table 3, P : 0.002).
Innovative drugs Of the 23 recently registered innovative drugs, 10 had been or were still being investigated in a clinical trial within the hospital. All but one had been adopted in the prescribing practices of the physicians. This number was not significantly different from the number of adopted innovative drugs not included in local drug trials (Table 4; chi 2 = 1.3, P > 0.05).
Adoption rate No significant relationship was found between the time of adoption of a drug and of its study in a local trial (Table 5, P = 0.3 for semi-innovative drugs, and P = 0.5 for innovative drugs). This implies that the relationship found between trials and the adoption of semi-innovative drugs was not due to acceleration of the adoption rate. Apart from that, the adoption rate of semi-innovative drugs was significantly slower than that of innovative drugs (Table 5, P = 0.001).
The hypothesis that drug trials have a selective influence on the adoption of semi-innovative drugs has been confirmed in a university hospital setting. As expected, a positive relationship was found between the adoption of semiinnovative drugs and the fact that they had been studied in a clinical trial. No such relationship was found for the adoption of innovative drugs. The effect is not due to an acceleration of the adoption process for semi-innovative drugs. Semi-innovative drugs of both groups, i.e. those which had been or had not been investigated, were mostly introduced within one year after registration, and significantly different adoption rates were not found. Also, no difference was found in the quantities of semi-innovative drugs used. Therefore, it seems that trials only stimulate the likelihood that a particular drug will be used at all, without affecting the scale of its use. This is consistent with the idea that clinical trials lower the barriers to the adoption of the drugs in trial. Once a drug has been adopted, no further effect is anticipated from employment in a clinical trial. Classification as a 'semi-innovative' drug does not necessarily mean that the use of such a drug is irrational or undesirable. Within this group there are drugs that offer some advantages over the alternatives already in use, such as convenience of use or small kinetic benefits. It is possible that especially semi-innovative drugs with such advantages have been studied in our hospital, and this could explain why these drugs were more frequently adopted. It is not believed, however, that this explanation is valid; several semi-innovative drugs that do not seem to offer any substantial advantage over the alternatives were adopted after having been studied in a clinical trial (e. g. bisoprolol, felodipine, isradipine, budesonide and pefloxacin). Further prospective research on the adoption of semi-innovative drugs should afford a more definite conclusion about the influence of employment in clinical trials. Of course, employment in clinical trials is not the only factor that influences the adoption of a new drug. Promotion campaigns and outpatient prescribing, for instance, can also stimulate adoption. The influence of these factors, however, is expected to be equal for all semi-innovative drugs, irrespective of whether they have been studied in a local trial. What are the implications of the findings? There are positive and negative aspects associated with trials of semi-innovative drugs. Improvements in drug therapy can be developed by experimenting with small variations, i. e. semi-innovative drugs. On the other hand, there appears to be a limit to the number of semi-innovative drugs that are needed to realise such improvements. Whereas the second, third or even sixth drug within one drug class may be useful in clinical practice, the fifteenth is usually unnecessary. A trial of such a drug might be financially attractive for a hospital in terms of free drug supply during the investigational period, or employment of physicianresearchers, but it burdens patients, and indirectly it increases costs for the health insurance companies. After all, most trials require extra tests for which patients have to stay longer or come more often to the hospital, and
328 which are not always paid for. Moreover, if clinical trials stimulate the a d o p t i o n of semi-innovative drugs, as shown here, the quality of prescribing m a y be negatively affected. This is not the case w h e n the semi-innovative drugs offer useful advantages over the alternatives, as stated above. However, it is often a point of discussion w h e t h e r the possible advantages are clinically relevant. In s o m e cases, it could be argued that the expense is not in p r o p o r t i o n to the m i n o r advantages. In others, the advantages m a y not even be substantiated. A d o p t i o n of such drugs in prescribing routines offers no benefits and can only increase the use of drugs with less extensively d o c u m e n t e d risks. F r o m the present findings, it is r e c o m m e n d e d that after a trial with a semi-innovative drug has b e e n concluded, hospitals should encourage a restrictive policy concerning the use of that drug for new patients. If a clinical trial does not show clear advantages of the new drug, further use should be discouraged.
Acknowledgements. We thank I.Lunde and R.Vos for their review comments. The study was supported by the University Hospital Groningen Stimulation Program.
P. Denig et al.: Adoption of new drugs
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