A Physician Survey on Generic Drugs andSubstitution of Critical Dose MedicationsBenjamin F. Banahan III, PhD; E. M. Kolassa, PhD

Background: Generic substitution has become a com-

mon practice since the late 1970s. Because of the in-creased use of generic alternatives and concerns aboutthe Food and Drug Administration standards for bio-equivalency, especially with respect to narrow therapeu-tic index drugs, the awareness and attitudes of prescrib-ing physicians to generic drugs and generic substitutionare important.Methods: A questionnaire designed to assess attitudes,beliefs, knowledge, and experiences with generic drugsand generic substitution was sent to 3639 physicians na-

tionwide. Cluster analysis was used to identify attitudi-nal groups that were then analyzed with respect to dif-ferences in beliefs, knowledge, and experience withgeneric drugs. Perceptions of the therapeutic index for15 branded drugs and comfort in substituting those prod-ucts with generic alternatives were assessed.

Results: Physicians were classified into prosubstitu-tion and antisubstitution groups, with a further divisionof antisubstitution physicians according to whether they

felt influenced by outside pressures to substitute. Sig-nificant differences were found between the prosubsti-tution and antisubstitution groups with respect to be-liefs about and experiences with generics and knowledgeof the Food and Drug Administration bioequivalency stan-dards. Of particular significance was the low percentage(17%) of physicians who correctly identified the Foodand Drug Administration standards for bioequivalency.Prosubstitution physicians generally rated therapeutic in-dexes as wider than antisubstitution physicians. Physi-cians in all groups identified similar products they be-lieved were not appropriate for substitution.

Conclusions: Attitudes toward generic substitution arerelated to prescribing behaviors, beliefs about and expe-rience with generic substitution, and perceptions of thera-peutic index and comfort with substitution. Physiciansneed to understand the issues surrounding generic sub-stitution and remain empowered to influence decisionsto substitute.

Arch Intern Med. 1997;157:2080-2088

The substitution ofbrandedmedications that have lostpatent protection with lessexpensive generic versionshas become a common

practice in pharmacies today. In the early1970s, state antisubstitution laws pre¬vented generic substitution and the prac¬tice was resisted by physicians and manypharmacists.1 The environment changedquickly after the US Department of Healthand Human Services established maxi¬mum allowable costs for many genericproducts during the middle of the 1970s,and by 1978 almost every state and the Dis¬trict of Columbia had enacted laws thatmade generic substitution permissible andin some cases mandatory.2 By the middleof the 1980s, federal legislation had beenpassed making it easier to obtain ap¬proval of generic products3 and physi¬cians had become more accepting of ge¬neric substitution.4 Generic substitutions

now account for more than half the pre¬scriptions filled in the United States eachyear.5

The appeal of generic drugs is theirlower cost, which can result in substan¬tial savings compared with some prescrip¬tion products. Although some tbink thatgeneric substitution comes at the cost ofreduced funding for research of new phar¬maceutical agents,67 the potential for mon¬

etary savings appears to overshadow thisconcern for most health care profession¬als and patients. The clinical acceptanceof generic drugs also has been ques¬tioned on several occasions, especially af¬ter the so-called generic drug scandal of1989 and 1990, when investigations re¬

vealed corruption within the generic drugindustry.810 However, consumers andpharmacists quickly overcame the doubtscaused by the generic drug scandal andtheir confidence and interest in genericsrebounded shortly after the scandal.11

From the Research Institute ofPharmaceutical Sciences andSchool of Pharmacy, Universityof Mississippi, University(Dr Banahan), and StrategicPricing Group Inc,Framingham, Mass(Dr Kolassa).

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METHODS

SAMPLE AND DATA COLLECTION

Surveyed physicians were selected from an American Medi¬cal Association, Chicago, 111, file of active, licensed physi¬cians. A random and geographically stratified sample of thefile was systematically obrained by taking an nth sample fromall physicians in each specialty (family practitioners, gen¬eral practitioners, internists, neurologists, cardiologists, andcardiovascular surgeons). A questionnaire and cover letterwere mailed to the 3639 physicians in the sample. As an in¬centive to respond, physicians were offered a summary re¬

port and an opportunity to participate in a drawing for 1 of4 $250 honoraria to be awarded to 4 physicians from the first100 responses from within each specialty. Approximately 1month later another questionnaire and cover letter weremailed to the physicians who had not responded.

SURVEY INSTRUMENT

The questionnaire consisted of 5 major sections: (1) basicphysician demographics and practice characteristics,(2) knowledge and beliefs about the bioavailability rangeallowed for generic drugs by the FDA, (3) attitudes and be¬liefs about generic drugs and generic substitution, (4) per¬ceived therapeutic index (subtherapeutic blood level to toxicblood level range) and comfort with generic substitutionfor 15 selected products, and (5) past experiences with ge¬neric substitution. Immediately following the demo¬graphic and practice characteristics section, respondentswere provided the following definition:The term critical dose drugs will be used to refer to any prescrip¬tion drug product for which slight changes in dosage could re¬

sult in blood level fluctuations moving the patient from an ef¬fective level to either ineffectiveness or toxicity.

Bioavailability refers to the rate (how fast) and the extent(how much) ro which an active ingredient is absorbed and be¬comes available at the site of drug action. The Food and Drug Ad¬ministration considers a generic product to be bioequivalent if itsbioavailability is within an allowable range compared with the cur¬

rently marketed brand product.Respondents were informed that the FDA considers

a generic drug as bioequivalent if its bioavailability is withinan allowable range compared with the currently marketedbrand product.DATA ANALYSIS AND STATISTICAL METHODS

Cluster analysis of the 14 attitudinal statements was usedto identify groups of physicians who differed in terms oftheir attitudes toward generic drugs and generic substitu¬tion. Clusters were identified using the Ward hierarchicalclustering method with squared euclidian distance mea¬sures. A 3-cluster solution provided the most meaningfulgroupings. The overall multivariate analysis of variance testindicated that the 3 groups differed significantly (P<.05)across the 14 attitudinal items. One-way analyses of vari¬ance with Duncan post hoc comparisons were used to iden¬tify the individual differences among the groups.

The 3 attitudinal groups were analyzed with respect todifferences in practice setting, beliefs and experiences withgeneric drugs and generic substitution, and knowledge andbeliefs about the bioavailability range allowed by the FDA forparticular drugs. The groups were also compared with respectto perceptions of the therapeutic index and their personal com¬fort in having a generic drug substituted for 15 branded drugs.Statistical tests for differences among the groups were madeusing 1-way analyses ofvariance with Duncan post hoc com¬

parisons or ti coefficients from cross-tabulation tables depend¬ing on level of measurement of the dependent variable beingexamined. Differences are noted in tables for both the P<.05and P<.01 levels. All analyses were performed using SPSS-PC for Windows (SPSS Inc, Chicago, 111).

Although pharmacists and physicians consider mostgeneric drugs to be acceptable clinical alternatives for theoriginal branded pharmaceutical agents, concern has beenexpressed about the use of generic drugs for selected drugproducts. Clinical and therapeutic problems have beenreported for some generic alternatives, including warfa¬rin sodium,12 pancrelipase,13 carbamazepine,14 theoph-ylline,15 and primidone.16 Pharmacy professional and con¬

tinuing education often emphasizes the additionalconsiderations in drug product selection arising from bio-equivalence issues for several drug categories, includ¬ing digitalis glycosides, warfarin anticoagulants, theoph-ylline products, thyroid preparations, conjugated andesterified estrogens, antiarrhythmic agents, and antiepi-leptic agents.17 Specific issues related to the substitutionof these products are narrow therapeutic indexes, uniquepharmacological activities, and interactions with otherdrugs. Some products are also influenced by individualpatient characteristics and may have markedly variableinterpatient and intrapatient activity.

Most physicians and pharmacists have come to relyon the Food and Drug Administration's (FDA's) ratingsof bioequivalence to determine which products are ac-

ceptable substitutes. Although the federal ratings havebecome the standard used by most practitioners, somestates have performed their own reviews of bioequiva-lence for selected products.18 Some practitioners havecalled for more rigid FDA guidelines for drugs with a nar¬row therapeutic index, but others have suggested that thisapproach would only raise the cost of generic approvaland not appropriately address pharmacokinetic-pharmacodynamic relationships and the intrasubject vari¬ability inherent to each drug product.19 Since May 1992,the FDA has been studying a new standard for determin¬ing bioequivalence using an individual bioequivalencestandard for each drug rather than the measure of aver¬

age bioequivalence used today.20 The concept of indi¬vidual bioequivalence would compare a test drug with a

reference drug while controlling for variability among andwithin individual patients.

With the increased attention given to generic bio-equivalency standards, questions arise as to the aware¬ness and attitudes of prescribing physicians over poten¬tial differences between brand name and generic drugs,especially narrow therapeutic index drugs. To answerthese questions, a national survey to assess the opinions

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Table 1. Demographic and PracticeCharacteristics of Survey Respondents

Characteristic Percent

GenderM 84F 16

Age, y=s39 2540-49 3150-59 24>60 20

SpecialtyGeneral or family 34Internal medicine 21Cardiology 9Cardiovascular surgery 11Neurology 25

Practice settingSolo 34Group 47Medical school 8Health maintenance organization 2Other 9

Population of practice community<30000 2330000-999999 19==100000 58

Prescriptions written per day<10 3011-20 2221-39 17>40 31

Percent of patients covered by medical insuranceMedicaid 12Medicare 36Preferred provider organization 16Health maintenance organization 16Uninsured 9

of prescribing physicians on generic substitution and thesubstitution of critical dose drugs was conducted by theResearch Institute of Pharmaceutical Sciences, The Uni¬versity of Mississippi, University, in 1995. The results ofthat survey are presented in this article.

RESULTS

DEMOGRAPHICS AND PRACTICECHARACTERISTICS

After 2 mailings, 396 usable responses were received foran effective response rate of 12%. Although this responserate is lower than desired, it is not atypical for a nationalsurvey of physicians. As with all survey research, how¬ever, potential bias from nonresponse needs to be as¬

sessed. Nonresponse becomes a problem only if those whorespond are different in attitudes or opinions than thosewho do not respond. One method for assessing potentialnonresponse bias is the time trends extrapolation method.The basis for this test is that persons responding later to a

questionnaire are assumed to be more similar to nonre-

spondents than are early responders.21The 2 sections in the questionnaire that were most

subject to nonresponse bias were the items addressing

attitudes about generic substitution and the ratings of theperceived therapeutic indexes of the 15 products. Therespondents were divided into 2 groups based on whetherthey responded to the first (early responders) or second(late responders) mailing of the questionnaire. Differ¬ences between the groups on the 2 sets of items were testedusing multivariate analysis of variance for each overallset of items and univariate F tests for the individual items.No significant differences (P<.05) were found betweenthe early and late responders for the overall multivariateanalysis ofvariance tests or for any of the individual items.These results and the wide range in scores on the ge¬neric substitution attitudinal items indicate that nonre¬

sponse bias is probably not a problem in this study.Approximately 84% of the respondents were men

and most (31%) were between 40 to 49 years old(Table I ). Most respondents were family or general prac¬tice physicians (34%) who practiced in a group or solosetting. More than half (58.3%) practiced in communi¬ties larger than 100 000 population. The mean numberof patients seen daily was 18.9 in the office and 5.7 inthe hospital; a mean of 12.7 patients were cared for byrespondents in long-term care facilities. Physicians in thesurvey prescribed generic and brand name products inapproximately equal percentages and most patients ac¬

cepted substitutions when recommended by the physi¬cian. The prescriptions written by generic name were

50.3% and brand name, 49.5%. The mean percentage ofpatients who asked for substitution was 19.3%; ac¬

cepted substitutions when recommended by physician,75.8%; and refused substitutions, 10.5%. Almost twothirds (61.7%) of respondents reported that insuranceplans encouraged or required them to write for genericalternatives.

PROSUBSTITUTION AND ANTISUBSTITUTIONGROUPS DEFINED BY CLUSTER ANALYSIS

A major objective of this project was to examine the re¬

lationships among physicians' attitudes toward genericsubstitution and the other issues being studied. It wasassumed that differences exist in physicians' attitudes to¬ward generic drugs; therefore, cluster analysis was usedto classify the responding physician into attitudinalgroups. Cluster analysis is a statistical technique fre¬quently used in marketing research for grouping respon¬dents into clusters such that individuals in the same clus¬ter are more like each other than they are like individualsin other clusters. Identifying clusters in this manner makesit possible to examine how physicians' opinions on theother survey items vary with respect to general attitudestoward generic drugs.

The cluster analysis identified 3 groups that dif¬fered significantly with respect to attitudes about ge¬neric drugs and generic substitution. Based on the meansfor the 3 groups on the 14 attitudinal statements(Table 2), the groups were labeled antisubstitution, lowinfluence (114 [29.8%]); antisubstitution, high influence(103 [27.0%]); and prosubstitution (165 [43.2%]). Influ¬ence refers to the degree to which respondents felt in¬fluenced by others to prescribe or allow the substitutionof generic alternatives. In general, the prosubstitution

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Table 2. Physician Agreement Ratings to Attitudinal Statements by Cluster*

Statement

Antisubstitution,Low Influence

(1141301)

Antisubstitution,High Influence

(103 [27])Prosubstitution

(165 [43]) TotalDuncan Post Hoc

DifferencesA. All products that are rated by the Food and Drug 2.54

Administration as generic equivalents can beconsidered therapeutically equivalent with the brandproduct and with each other

B. Patients want me to prescribe products with generic 3.70equivalents

C. Wider use of generic pharmaceuticals will mean that 4.72less money will be used for research anddevelopment on new pharmaceuticals

D. Therapeutic failures are a serious problem with some 5.44generic products

E. Managed care increasingly is forcing pharmacists to 5.42dispense generics

F. I willingly support generic substitution for brand 3.45name prescription products

G. Dosing on some prescription drugs is too critical to 6.01accept the wide range of bioavailability that the Foodand Drug Administration allows among genericdrugs

H. In order to keep patients, I have to support generic 2.41substitution

I, Being required to write for generics for "critical dose 4.49drugs" will increase my exposure to lawsuits

J. The price difference between generic and brand 4.56products is often so great I feel I must offer patientsproducts with generic substitutes

K. Few physicians are opposed to the use of generics 3.61today

L. There is no real difference between most brand 2.80products and their generic equivalents

M. There are some "critical dose drugs" that I do not 6.54think should be substituted even when required bythird parties

N. Managed care increasingly is forcing me to prescribe 3.98products with generic alternatives

2.32

4.01

5.34

5.82

6.56

2.83

6.36

4.69

5.51

5.42

3.70

2.74

6.42

6.14

4.48

5.01

3.77

3.78

5.39

5.41

4.60

3.17

3.48

5.51

5.07

4.88

5.35

4.53

3.32

4.35

4.48

4.82

5.72

4.13

5.49

3.35

4.33

5.20

4.26

3.68

5.99

4.80

* Levels of agreement with statements rated on a 7-point scale with 1 indicating strongly disagree and 7, strongly agree.IProsubstitution group significantly (P<.05) differs from antisubstitution groups.XAH groups differed significantly from one another (P<.05).§Antisubstitution, high-influence group differed significantly (P<.05).WAntisubstitution, low-influence group differed significantly (P<.05) from other 2 groups.

group was most likely to view all generic drugs as beingequivalent (statements A and L) and to be the least con¬

cerned about the use of generic drugs for critical dosedrugs (statements D, G, I, and M). Although 2 of thegroups were labeled as antisubstitution, they differed sig¬nificantly in their attitudes about external influences en¬

couraging or forcing generic substitution. The antisub¬stitution, high-influence group expressed significantlystronger agreement with almost all the influence state¬ments pertaining to external forces encouraging the useof generic drugs (statements C, E, H, J, and N).

When compared by physician specialty, significantdifferences (P<.01) were found between the attitudinalgroups (Table 3). General or family practitioners and neu¬

rologists were more likely to be antisubstitution, low in¬fluence, than were the internists or cardiologist or cardio¬vascular surgeons, who were more likely to be in theprosubstitution cluster. Overall, 163 (43%) of the physi¬cians were classified as being prosubstitution, with 113(30%) being classified as antisubstitution, low influence,and 100 (27%) as antisubstitution, high influence.

BELIEFS AND EXPERIENCES WITH GENERICDRUGS AND SUBSTITUTION

The groups had significantly different opinions about pa¬tient attitudes toward generic drugs and their prescribingbehaviors. As shown in Table 4, the prosubstitution groupreported that 60% of their prescriptions were written bygeneric name compared with only 46% and 40% for the 2antisubstitution groups. Physicians in the antisubstitu¬tion, high-influence cluster reported that a significantlyhigher percentage of patients asked them to use genericdrugs than did the physicians in the other 2 groups. Theprosubstitution group reported that a higher percentage ofpatients accepted generic drugs when they recommendedthem, while this group also reported the lowest percent¬age of patients refusing generic drugs. The antisubstitu¬tion, high-influence group also reported the highest per¬centage of patients having insurance plans that require thephysician to write for products with generic alternatives.All the differences reported in Table 4 are consistent withthe attitudinal labels assigned to the 3 clusters.

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Table 3. Physician Specialty by Attitudinal Group*

SpecialtyAntisubstitution,

Low Influence

Group, No. (%)Antisubstitution,High Influence Prosubstitution

General or family practiceInternal medicineCardiology or cardiovascular surgeryNeurologyTotal

43 (32.3)14(17.9)17(22.7)39 (43.3)

113(30.1)

43 (32.3)19(24.4)18(24.0)20 (22.2)

100 (26.6)

47 (35.3)45 (57.7)40 (53.3)31 (34.4)

163 (43.3)

x222.3, ?<.01.

Table 4. Prescribing Behavior and Patient Attitudes by Attitudinal Group

Specialty

Group, Mean, %

Antisubstitution,Low Influence

Antisubstitution,High Influence Prosubstitution Total

DuncanPost Hoc

Differences

Percentage of prescriptions written by generic name 40Percentage of patients who

Ask you to use generic drugs 16Accept generic drugs when you recommend them 70Refuse generic drugs 13

Percentage of patients having insurance plans thatEncourage you to write for products with generic alternatives 40Require you to write for products with generic alternatives 14

46

247212

4624

1983

4419

50

197610

4419

Not applicablet*

* Prosubstitution group significantly (P<.05) differs from other groups.IAntisubstitution, high-Influence group significantly (P<.05) differs from other groups.XAntisubstitution, low-influence group significantly (?<.05) differs from other groups.

Table 5. Perceived Pressure From Managed Care Plans by Attitudinal Group

Group*

Perceived PressureAntisubstitution,

Low InfluenceAntisubstitution,

High Influence Prosubstitution TotalDo you believe that managed care plans have forced you to prescribe

medications other than your first choice when, in your professionaljudgment, these products were not in the best interest of your patients?

n

YesfNo

If yesDo you think this will occur more frequently in the future?

nYesNo

Do you think this increases your exposure to lawsuits?n

YesfNo

11148.651.4

5498.1

1.9

5388.711.3

10081,019.0

81100.0

0.0

7790.9

9.1

16338.062.0

6098.3

1.7

6066.733.3

37452.747.3

19599.0

1.0

19082.617.4

*AII data are expressed in percentages, except for n, which is the sample size.^Significant relationship (P<.05).

To directly measure the perception of managed care

influence on their prescribing, respondents were asked,"Do you believe that managed care plans have forced youto prescribe medications other than your first choice when,in your professional judgment, these products were notin the best interest of your patients?" Overall, more thanhalf the respondents indicated they felt pressured by man-

aged care to alter their prescribing choices (Table 5).However, most of the physicians responding affirma¬tively to this question were in the antisubstitution, high-influence cluster. Only 38% of the prosubstitution clus¬ter and 49% of the antisubstitution, low-influence clusterresponded affirmatively compared with 81% of the an¬

tisubstitution, high-influence cluster. Regardless of clus-

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Table 6. Beliefs About Food and Drug Administration (FDA) Bioequivalency Ranges by Attitudinal Group

Group, No. (%)IAntisubstitution, Antisubstitution,

Belief Low Influence High Influence Prosubstitution TotalHow much variation in bioavailability does the FDA allow

for generically equivalent products?Respondents indicating "Don't know"Mean percent variation reportedRespondents indicating range of 20%-25%

In your professional judgment, what is a maximumacceptable variation for

Most medications}Critical dose drugs}

'Significant relationship (P<.05).X Prosubstitution group significantly (P<.05) differs from other groups.XMean values.

68 (60)2024 (22)

56 (55)2118(19)

105

104

116(71)*16f19(12)

240 (64)1961 (17)

125

115

ter, almost all the physicians who felt pressured by man¬

aged care to alter their prescribing behaviors believe thepressure will increase in the future and that making suchcompromises increases their exposure to lawsuits.

KNOWLEDGE AND BELIEFS ABOUTTHE BIOAVAILABILITY RANGE

ALLOWED BY THE FDA

Since most states allow or require generic substitutionof products rated by the FDA as being equivalent, andin most states it is difficult for physicians to prevent ge¬neric substitution,22 it is important to determine whetberphysicians know what the current standards are andwhether these standards are consistent with their clini¬cal expectations. Immediately following the definitionsfor critical dose drugs and bioavailability, the physi¬cians were asked, "How much variation in bioavailabil¬ity does the FDA allow for generically equivalent prod¬ucts?" Respondents were given an option to check "don'tknow" instead of providing a percentage. As shown inTable 6, 243 (64%) of the respondents checked the don'tknow box. The antisubstitution, high-influence group hadthe fewest percentage of respondents checking don't know(56 [55%]), while the prosubstitution group had the great¬est percentage of don't know responses (116 [71%]). Theoverall mean value for respondents belief in the amountof variation allowed by the FDA was 19%. The prosub¬stitution group had a significantly lower mean (16%) thandid the 2 antisubstitution groups (20% and 21%).

According to the current FDA regulation, 2 formu¬lations whose rate and extent of absorption differ by lessthan -20% or 4- 25% are generally considered bioequiva¬lent.23 Physicians were considered to know the correct rangeallowed by the FDA if their responses were 20% to 25%.Only 62 physicians (17%) identified the correct range al¬lowed by the FDA. Only 19 (12%) of the prosubstitutionphysicians were able to specify this range. As a follow-upquestion, all respondents were asked what in their pro¬fessional judgment was an acceptable variation in bio¬availability for most medications and for critical dose drugs.With little variation, the physicians indicated that 11% was

acceptable for most medications and that 5% was accept-

able for critical dose drugs. Of particular interest is the find¬ing that the prosubstitution group did not differ from ei¬ther of the antisubstitution groups with respect to whatthey considered to be acceptable variation for most medi¬cations or for critical dose medications. It appears that phy¬sicians' opinions about what is an acceptable level ofvaria¬tion in medication are fairly universal and are not relatedto their overall attitude toward generic drugs. These re¬

sults also indicate that the majority of the physicians sur¬

veyed do not know what the FDA standards are and mayactually be practicing with the belief that the standard ismore rigid than it actually is.

RATINGS OF THERAPEUTIC INDEXAND COMFORT LEVEL

Another important issue in the current debate about ge¬neric equivalence standards is whether narrow therapeu¬tic index drugs should be evaluated using the same bio¬equivalence standards as all other products. One of theobjectives of our study was to determine whether physi¬cians differentiate products based on perceived therapeu¬tic index and how perceptions of therapeutic indexes re¬late to physicians' comfort with substitution of products.To determine whether prescribing physicians differenti¬ate pharmaceutical products with respect to therapeuticindex, the respondents were asked to rate the therapeuticindexes of 15 products. Each product's therapeutic indexwas rated using a 10-point scale where 1 represented a verynarrow index and 10 represented a very wide index. Theproducts included in the questionnaire were selected torepresent a wide range of therapeutic indexes and wereidentified by brand name. The products were listed in al¬phabetical order to eliminate any perceived order bias. Themean product ratings, in ascending order, are shown inTable 7 by attitudinal cluster.

Although the 3 attitudinal groups had approxi¬mately the same range of scores from the lowest to high¬est rating (4.3, 4.4, and 4.2), the prosubstitution clusterrated the therapeutic indexes of 13 of the 15 products as

being significantly higher than did the 2 antisubstitu¬tion clusters. It would appear that part of the prosubsti¬tution mind-set of this group is that all products have

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Table 7. Rating of Therapeutic Indexes* by Attitudinal Group

Group

ProductAntisubstitution,

Low InfluenceAntisubstitution,High Influence Prosubstitution Total

DuncanPost Hoc

DifferencesCoumadinLanoxinTegretolDilantinProcan SRTheo DurClozarilProzacOrtho NovumPremarinLasixCapotenTagametCeclorNaprosyn

2.62.93.13.33.93.64.75.24.95.55.95.96.46.96.9

2.32.62.93.23.13.34.04.55.15.85.25.66.26.66.7

3.23.93.84.24.34.54.66.16.37.07.16.77.37.47.3

2.83.23.33.73.83.94.45.45.56.26.26.26.77.07.0

XXXXXtt

*XX§

XXXXX

* Therapeutic index rated using a 10-point scale where 1 indicates very narrow therapeutic index and 10, very wide therapeutic index.XAntisubstitution, high-influence group significantly (P<.05) differs from other groups.XProsubstitution group significantly (P<.05) differs from other groups.§/!// groups significantly (P<.05) different from each other.

Table 8. Percentage of Physicians Selecting Products as Being Most Reluctant to Have Substituted* by Cluster Membership

Group,%

ProductCoumadinLanoxinDilantinTegretolProcan SRTheo DurLasix

Antisubstitution,Low Influence

55423521

752

Antisubstitution,High Influence

56323629

5

Prosubstitution53503427

666

Total54413525

665

* Respondents were asked to select the 2 products from among the products listed in Table 7 that they would be most reluctant to have substituted. Onlyproducts selected by 5% or more of the respondents are listed.

wider therapeutic indexes than what other physicians per¬ceive. Only a few statistical differences were found be¬tween the product ratings from the 2 antisubstitutiongroups. When differences were found (Coumadin, Pro-can SR, Lasix, Ceclor, and Naprosyn) the mean for theantisubstitution, high-influence group was lower than themean for the antisubstitution, low-influence group.

Respondents were also asked to rate their comfortwith substituting each of the 15 products using a 10-point scale. As expected, there was a nearly perfect lin¬ear relationship between the physicians' ratings of thera¬peutic index and comfort with substitution. As anadditional measure of their comfort with generic substi¬tution of these products, physicians were asked to indi¬cate the 2 products from the list presented that they wouldbe most reluctant to have substituted (even if the prod¬uct was not available generically at that time). The prod¬ucts selected by 5% or more of the respondents are listedin Table 8. Although the order of the products variesslightly from the overall ratings of therapeutic indexes,the 6 most frequently mentioned products are the 6 prod-

ucts rated as having the narrowest therapeutic indexes.Coumadin was the most frequently selected product inall 3 attitudinal groups with more than half the physi¬cians identifying it as 1 of the 2 products they were mostreluctant to have substituted. The order of the productsvaries somewhat among the 3 attitudinal groups, but no

meaningful patterns appear to exist among the productsthat were selected by the different attitudinal groups. Lasixrepresents the only unusual finding in Table 8, in that itwas the seventh most frequently identified product thatphysicians were reluctant to have substituted even thoughit was not rated as having a narrow therapeutic index.

For each of the products the physicians indicated theywere reluctant to have substituted, the respondents were

asked to mark the reasons for their selection. Table 9 sum¬marizes the reasons physicians were reluctant to have sub¬stitution performed for each of the products identifiedabove. The percentage of physicians indicating narrow

therapeutic index as a reason for their reluctance to havethe products substituted was directly related to the per¬ceived therapeutic index ratings shown in Table 7. Other

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Table 9. Percentage of Physicians Indicating Reason for Selecting Products as Being Reluctant to Have Substituted*

Percent

Reason Coumadin Lanoxin Dilantin Tegretol Procan SR Theo Dur Lasix

Use in elderlyPotential drug interactionsSide effectsMonitoring or testing neededProfessional liabilityNarrow therapeutic indexDosing adjustment requiredDietary, lifestyle issuesRelatively low priced alreadyOther

546656843573843835

2

73506165258158

759

5

25465563256367

737

9

27456366185867

69

13

30357461267078

499

43717676387667

543

0

63222833171744172828

* Respondents were asked to select the 2 products from among the products listed in Table 7 that they would be most reluctant to have substituted. Selectionreasons are given for the only products selected by 5% or more of the respondents.

issues related to titration difficulties (monitoring and/ortesting required and dosing adjustments required) were

also selected by a large percentage of the physicians forall the products except Lasix. Another factor contribut¬ing to the physicians reluctance to substitute these prod¬ucts (Coumadin, Lanoxin, Dilantin, Theo Dur, and Lasix)was the relatively low price of the brand product. Appar¬ently the limited potential for cost savings with generic al¬ternatives to these products was a serious considerationfor physicians. It would appear that the reasons listed didnot adequately explain the reluctance to have Lasix sub¬stituted. Other than use in elderly and dosing adjust¬ments required, relatively small percentages of physi¬cians indicated that these were the reasons for theirreluctance. Lasix also had the highest percentage (28%)of physicians indicating "other" as a reason for their re¬

luctance to substitute this product.

The overall mean scores on the attitudinal items wouldindicate that physicians have rather neutral attitudes withrespect to generic substitution and moderately high con¬cerns about substitution of critical dose drugs. How¬ever, cluster analysis of the attitudinal items revealed that3 different groups of physicians exist with respect to theirattitudes toward generic substitution. Approximately 163physicians (43%) were classified as prosubstitution, ex¬

pressing somewhat fairly strong acceptance of generic sub¬stitution in general and the least amount of concern forsubstitution of critical dose drugs. It would appear fromthe information reported by the physicians in this groupthat their attitudes are closely related to their prescrib¬ing behaviors and their perceptions of the therapeutic in¬dexes associated with various products.

Even though the majority (213 [57%]) of the phy¬sicians were classified as antisubstitution, approxi¬mately one fourth of the physicians were classified as be¬longing to the antisubstitution, high-influence group. Thisgroup appears to be aware of the growing managed care

and cost-control environment and perceives outsidesources (patients, managed care organizations, prescrip¬tion prices) as exerting a high level of pressure on themto allow and facilitate generic substitution. Members of

the antisubstitution, low-influence group have fairly strongantisubstitution attitudes that appear to be largely basedon concerns about clinical issues. These physicians be¬lieve that substitution of critical dose drugs can be a prob¬lem, yet they do not believe that a great deal of pressureis being placed on them by outside forces to allow ge¬neric substitution.

Despite the differences that exist among physi¬cians with respect to their attitudes toward generic sub¬stitution and their concerns about substitution of criti¬cal dose drugs, physicians in the 3 groups consistentlyrecognized the relative range of therapeutic indexes thatexist for products and indicated that their levels of com¬

fort in substitution were closely related to their percep¬tion of products' therapeutic indexes. The 3 groups alsowere fairly consistent in their identification of productsthat they were reluctant to have substituted, with the larg¬est percentages selecting products rated as having the nar¬

rowest therapeutic indexes.Perhaps the finding of greatest concern was the low

percentage of physicians who were knowledgeable of theFDA standards used to determine whether products are

bioequivalent and can thus be substituted. The FDA con¬

siders 2 formulations as bioequivalent when the rate of ab¬sorption varies no more than -20% or 4-25% comparedwith the currently marketed brand product. The fact thatonly 62 (17%) of the physicians responding to the surveycould correctly identify the variation in bioavailability al¬lowed by the FDA indicates that for the vast majority ofphysicians their opinions about generic substitution maybe based on incorrect assumption about how products are

determined to be acceptable substitutes. Such a conclu¬sion is somewhat supported by the fact that regardless oftheir attitudes toward generic drugs and generic substi¬tution, the physicians considered 11% variation in bio¬availability to be the maximum acceptable for most medi¬cations and only 5% variation to be acceptable for criticaldose drugs. Based on this latter finding, it is likely that manyof the 243 physicians (64%) who indicated they did notknow the FDA standards may believe the standards aremore rigid than what is actually allowed. The current gapsbetween the ranges deemed appropriate by prescribers, theranges prescribers believe are in effect, and those that are

currently used by the FDA imply that many physicians may

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be allowing generic substitution under a set of beliefs thatare inaccurate.

That physicians identified a consistent list of prod¬ucts for which they believe generic substitution would notbe appropriate, regardless of their attitudes toward ge¬neric products in general, is significant. In a similar studyperformed by the Research Institute ofPharmaceutical Sci¬ences,24 pharmacists in several practice settings identi¬fied the same agents as products for which they would bereluctant to perform generic substitution. The facts thatboth groups of medical professionals share similar beliefsabout these agents and that both groups believe that ex¬

ternal forces are increasingly requiring greater levels of sub¬stitution should raise concerns about whether ever-

increasing cost-containment efforts are not potentiallyendangering patients. It appears that both physicians andpharmacists recognize the existence of drug classes forwhich generic substitution may be problematic and wherespecial considerations must be given in product selec¬tion. In the medical literature, a good guideline for howsubstitution of these drug products should be ap¬proached was presented in a review by Nuwer and col¬leagues25 of generic substitution for antiepileptic drugs:Uncontrolled generic substitution should not be allowed forantiepileptic medications, especially phenytoin and carbamaz-epine. Once a patient is carefully titrated and optimally con¬trolled on one specific formulation of those drugs, that formu¬lation should not be changed. Each generic formulation of thosedrugs should be clearly labeled and identified as to the manu¬facturer. Switching between different formulations should bedisallowed, except with the informed consent of the physicianand patient.

A similar recommendation was made in a recent phar¬macy continuing education article on generic substitu¬tion and cost containment26:In general, when a medication demonstrates a narrow thera¬peutic index or a drug category indicates a serious or life threat¬ening condition, it may be best to ensure that a constant sup¬ply of medication is available from the same manufacturer.

Of particular importance in these recommenda¬tions is that the switching of formulations (ie, manufac¬turers) of narrow therapeutic index drugs after the pa¬tient has been titrated and adequately controlled is more

often the problem than the use of the generic agent it¬self. For narrow therapeutic agents in particular, it is im¬portant that physicians, pharmacists, and patients un¬derstand the issues surrounding generic substitution andwork closely together to prevent uncontrolled switch¬ing of formulations. Physicians and pharmacists shouldalso remain empowered to make decisions about substi¬tution when prescriptions for narrow therapeutic indexdrugs are being dispensed.Accepted for publication May 30, 1997.

This study was supported by a research grantfrom Du¬pont Pharma, Wilmington, Del.

Pharmaceutical products were identified by brand name

in the survey instrument. Brand names are used in the manu¬

script to accurately reflect the stimuli used in the study.Reprints: Benjamin F. Bañaban 111, PhD, Research In¬

stitute of Pharmaceutical Sciences, University of Missis¬sippi, 107 Waller Laboratory Complex, University, MS 38677(e-mail: ribfb@olemiss.edu).

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