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If you have any questions on BMJ Open’s open peer review process please email editorial.bmjopen@bmj.com BMJ Open Interactions between Physicians and Pharmaceutical Industry-Systematic Review Journal: BMJ Open Fo Manuscript ID bmjopen-2017-016408 Article Type: Research rp Date Submitted by the Author: 18-Feb-2017 Complete List of Authors: Urbach, Ewout; Crowd for Cure Fickweiler, Freek; Crowd for Cure Fickweiler, Ward; Crowd for Cure, ee <b>Primary Subject Health policy Heading</b>: rr Secondary Subject Heading: Patient-centred medicine Change management < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Health policy < HEALTH SERVICES ADMINISTRATION & Keywords: ev MANAGEMENT, Protocols & guidelines < HEALTH SERVICES ADMINISTRATION & MANAGEMENT ie w on ly For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 27 BMJ Open 1 2 3 Interactions between Physicians and Pharmaceutical Industry- 4 5 Systematic Review 6 7 8 9 10 Urbach E1, Fickweiler F1, Fickweiler W1 11 12 13 14 15 1: Crowd for Cure, Jacob van Ruysdaelstraat 34, 9718 SG Groningen, the Netherlands Fo 16 17 18 19 rp 20 All authors have completed the ICMJE uniform disclosure form at 21 22 http://www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation 23 for the submitted work; no financial relationships with any organisations that might ee 24 25 have an interest in the submitted work in the previous three years, no other 26 27 relationships or activities that could appear to have influenced the submitted work rr 28 29 Contributor Statement: All authors have contributed equally and have substantial 30 ev 31 contributions to the conception or design of the work; Author Ewout Urbach for the 32 33 acquisition, analysis, and interpretation of data for the work; Author Ewout Urbach for 34 ie drafting the work and Authors Freek Fickweiler and Ward Fickweiler for revising it 35 36 critically for important intellectual content; and all authors (Ewout Urbach, Freek w 37 38 Fickweiler and Ward Fickweiler) contributed to final approval of the version to be 39 published and agreed to be accountable for all aspects of the work in ensuring that 40 on 41 questions related to the accuracy or integrity of any part of the work are appropriately 42 43 investigated and resolved. 44 ly 45 Competing interest: no financial relationships with any organisations that might have 46 47 an interest in the submitted work in the previous three years, no other relationships or 48 49 activities that could appear to have influenced the submitted work 50 51 Funding: all authors declare no support from any organisation for the submitted work. 52 53 54 Data sharing statement: any data relevant to a published article will be made available 55 56 alongside the article when published. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 27 1 2 3 4 5 6 7 8 Abstract 9 10 11 12 Objectives 13 The objective of this review is to explore the frequency of physician and pharmaceutical 14 15 industry interactions, their impact on physicians’ attitude, knowledge and behavior Fo 16 17 Data Sources 18 Pubmed, Embase, Cochrane library and Google scholar electronic databases were searched 19 rp 20 from 1992 to August 2016 using free text words and medical subject headings relevant to the 21 22 topic. 23 Study Selection ee 24 25 Studies included were cross sectional studies, cohort studies, randomized trials and survey 26 27 designs. Studies with narrative reviews, case reports, opinion polls, letters to the editor, rr 28 systematic reviews and non-English studies were excluded from data synthesis. 29 30 Data Extraction ev 31 32 Two reviewers independently extracted the data. Data on study design, study year, country, 33 participant characteristics, setting, and number of participants were collected. 34 ie 35 Data Synthesis 36 PSR interactions influences the physicians’ attitudes towards the representatives, their w 37 38 prescribing behavior and increases the number of formulary addition requests for the 39 40 company’s drug. Other interactions such as CME and attending pharmaceutical industry on 41 42 sponsored seminars lead to higher prescribing of the company drug and increasing irrational 43 prescribing behavior. 44 ly 45 Conclusion 46 47 Physician-PSR interactions and acceptance of gifts and favors from the company’s PSRs 48 have been found to affect the physicians’ prescribing behavior and contribute to irrational 49 50 prescription of the company’s drug. Therefore, intervention in the form of policy 51 52 implementation and education about the implications of these interactions are needed. 53 54 55 Strengths and limitations of the Study 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 27 BMJ Open 1 2 3 - Large up-to-date systematic review of studies exploring the effects of physician and 4 pharmaceutical industry representative interactions and their impact on physician 5 6 attitudes, knowledge and behavior. 7 8 - Pubmed, Embase, Cochrane library and Google scholar electronic databases were not 9 searched before 1992 and other databases were not searched. 10 11 Introduction 12 13 The relationship between physicians and the pharmaceutical industry has evoked heated 14 15 debate since decades1. In 2012, pharmaceutical industry spent $89.5 billion on physician- Fo 16 pharmaceutical sales representative (PSR) interactions, accounting for 60% of the global 17 18 sales and marketing spending3-6. Previous reports have demonstrated that PSRs may influence 19 prescribing behavior,11, 14, 36, 38, 39. However, the attitudes about PSR interactions are divided rp 20 21 and contradictory. Studies have indicated that physicians may be unable to distinguish 22 23 between promotional information and scientific evidence, while their colleagues more than ee 24 25 themselves are susceptible to PSR marketing strategies22, 27, 32, 34 Most medical and 26 governmental institutions have installed guidelines and self-regulatory and legislative checks 27 rr 28 to address this controversy-5,8,9 However, while administration’s proposals for deregulatory 29 30 reforms of Big Pharma are increasing, scientific evidence rigoursly examining this ev 31 controversy are needed. This review address this question by critically and systemically 32 33 evaluating the evidence on the impact of PSR interactions on the attitudes of physicians. 34 ie 35 36 w 37 Methodology 38 39 Inclusion and exclusion criteria: 40 on 41 The following inclusion and exclusion criteria were used to perform this systematic review. 42 43 (a) Types of studies: Included for data synthesis in this review were cross sectional studies, 44 ly cohort studies, randomized trials and survey designs that have used analytical methodologies 45 46 and have focused on at least one facet of extent, impact on behavior and attitude. Excluded 47 48 were narrative reviews, case reports, opinion polls, letters to the editor, systematic reviews 49 50 and non-English studies. 51 (b) Types of participants: Physicians and pharmaceutical representatives. 52 53 (c) Types of exposure: Any type of interaction between physicians and the pharmaceutical 54 55 industry such as meeting with drug representatives, participating in pharmaceutical-sponsored 56 continuing medical education program, and receiving travel funding, free drug samples, 57 58 industry-provided meals and gifts. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 27 1 2 3 (d) Types of outcome: Knowledge, beliefs, and/or attitudes of physicians regarding 4 5 physician-industry interactions. 6 7 8 9 10 Search strategy: 11 Pubmed, Embase, Cochrane library and Google scholar electronic databases were searched 12 13 from 1992 to August 2016 using free text words and medical subject heading relevant to the 14 15 topic. Databases were not searched before 1992, introducing reporting bias. However, while Fo 16 the relationship between physicians and pharmaceutical representatives is likely to change in 17 18 time, we did not found studies before 1992 to be reflective of this relationship. Search terms 19 rp 20 were physician, doctor, healthcare professional, attitude, knowledge, behavior, hospital 21 formulary, professional behavior, prescribing behavior, pharmaceutical 22 23 representative, interests, marketing strategy, research grant, gifts and meals. Two independent ee 24 25 reviewers assessed selected articles as per inclusion/exclusion criteria and shortlisted them 26 for writing the review. Full review protocol is available upon request to the corresponding 27 rr 28 author. 29 30 ev 31 32 33 34 ie 35 36 w 37 38 39 40 on 41 42 43 44 ly 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 27 BMJ Open 1 2 3 4 5 6 7 8 9 10 Results 11 12 We independently screened the titles and abstracts of the 2170 identified records for potential 13 14 eligibility. Out of 2170, full text of 49 eligible citations, which matched the inclusion criteria, 15 were retrieved and used for qualitative assessment during the writing of the review (Figure 1, Fo 16 17 Table 1). 18 19 Characteristics of included studies rp 20 21 22 The identified studies were published between 1992 and August 2016. Most of the studies 23 included were cross-sectional studies1, 11-15, 19-23, 26-43, 55, 57, 62, 63, 72, 76. Only two studies were ee 24 25 cohort studies16, 18, three were randomized trials17, 25, 74 and one study was a case-control 26 24 27 study . rr 28 29 Extent of interactions between physicians and the pharmaceutical industry 30 ev 31 32 We found that PSR interactions are a regular feature in the daily lives of physicians across the 33 34 world 11, 14, 31, 36, 39, 55. Most of the attending physicians and residents have at least one ie 35 interaction with the industry representatives per month 14,21, 31, 32, 33. The frequency of 36 w 37 interactions or gifts offered and accepted varies with private versus public hospital setting 38 39 and the position of the physicians in the medical hierarchy 12, 14, 17, 26, 31, 34, 39, 55, 56. Medical 40 students are exposed to PSRs from the beginning of their career 34,56. Junior residents on 41 42 received twice as much free drug samples from PSR interactions than senior residents 14. PSR 43 44 interactions were significantly higher at the beginning of residency39. The majority of ly 45 program directors of internal medicine residencies in USA allowed PSRs to meet with 46 47 residents during working hours and permitted PSR sponsorship of conferences29. Attending 48 49 physicians and physician specialists have greater encounters with PSRs and received more 50 number of medical samples and promotional material than residents11,31. Participants working 51 52 in private practice alone or in both sectors were more likely to receive gifts than doctors 53 54 working in the public sector 31, 55. Physicians in academic or hospital-based practice settings 55 had less PSR interactions and significantly lower prescribing costs than physicians in 56 57 nonacademic and nonhospital practices 26. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 27 1 2 3 Most common gifts received were medical samples11, 12, 21, 22, 31, 32, 33, promotional material11, 4 19, 31 5 invitations for dinners11, invitations for CMEs19, 33 , scientific journals19 and free 6 lunches22, 32. 7 8 9 10 Attitude of physicians towards the interactions 11 12 We found that physicians have a positive attitude towards PSRs.1, 12, 13, 17, 23, 27, 29, 33, 39, 43 13 14 Physicians perceived PSRs as important sources of education and funding 13, 14, 33, 34, 37, 40; 15 Fo 16 while some studies reporting skeptical attitudes about contribution of PSRs towards teaching 17 and education 21, 28, 29, 32, 43. Conference registration fees, informational luncheons, 18 19 sponsorship of departmental journal clubs, anatomical models, and free drug samples were rp 20 21 considered as appropriate gifts 17, 23, 28, 57. Most of the physicians considered pharmaceutical 22 information provided by PSRs, industry sponsored conferences and CME events as important 23 ee 24 instruments for enhancing their scientific knowledge 13, 33, 37, 40. Compared to senior residents, 25 26 significantly more junior residents felt that pharmaceutical representatives have a valuable 27 teaching role 14. rr 28 29 30 Most of the physicians considered themselves immune to the influence of gifts1, 13, 14, 15, 20 22, ev 31 25, 34 32 . We found that better scores on knowledge and attitudes were significantly associated 33 34 with lesser number of interactions with representatives and their gifts23. Most studies found ie 35 that physicians do not believe that PSR interactions impact their prescribing behavoir 1,11, 14, 36 36, 38, 39, 66, 67 , while other studies report found that there was some extent of influence 19, 21, 22, w 37 38 28, 32, 33, 34 39 . In addition, physicians considered their colleagues more susceptible than 40 themselves to PSR marketing strategies 1, 22, 27, 32, 34 . There was a strong correlation between on 41 42 the amount of gifts and the belief that PSR interactions did not influence their prescribing 43 44 behavior 14. ly 45 46 47 Gifts 48 49 Most common gifts received were medical samples11, 12, 21, 22, 31, 32, 33, 34, 35, 41 , promotional 50 material11, 19, 31, 58 invitations for dinners11 and scientific journals19. 51 52 53 54 Drug samples 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 27 BMJ Open 1 2 3 Most of the physicians who accepted drug samples had a positive attitude towards the 4 5 pharmaceutical representatives11, 12, 21, 22, 31, 32, 33, 34. Accepting samples lead to higher branded 6 drug prescription rather than generic prescribing 33, 41. 7 8 9 10 11 Pharmaceutical representative speakers 12 Sponsored lectures/symposia of pharmaceutical companies influenced behavior of the 13 14 attendees, as they prescribed more drugs of the industry without sufficient evidence 15 supporting the drug’s superiority 16, 18. The majority of attending physicians failed to identify Fo 16 17 inaccurate information about the company drug59. 18 19 rp 20 21 Honoraria and Research Funding 22 23 Physicians who received money to attend pharmaceutical symposia or conduct research for ee 24 the company’s drug requested formulary addition of that company’s drug more often than 25 26 other physicians24 (Table 2). Brief encounters with PSRs and receipt of honoraria or research 27 rr 28 support were predictors of faculty requested change in hospital formulary60. Physicians 29 considered company funded clinical trials with skepticism albeit their prescribing behavior 30 ev 31 was affected favoring the company’s drug61. 32 33 34 Conference travel ie 35 36 Pharmaceutical company sponsored conference travels to touristic locations have w 37 quantifiable impact on the prescribing rational of attendees. A significant increase (three 38 39 times) in the prescribing rate of two company drugs was observed after the physicians 40 on 41 attended a company sponsored symposium with all their expenses covered. Despite this 42 significant difference in the prescribing patterns, physicians insisted there was no impact on 43 44 their prescribing behaviour.18 ly 45 46 47 Industry paid lunches 48 49 Most physicians received invitations for dinners11 and free lunches 14, 20, 32, 34. Clerks, interns 50 14 51 and junior residents attended more company sponsored lunches than senior residents . 52 28 Pharmaceuticals also sponsored departmental lunches during journal clubs . There was no 53 54 significant association between attending industry paid lunches22 and dinners11 and formulary 55 56 request for that company’s drug (Table 2). However, there was a significant association 57 between attending industry paid lunches and increased prescription of branded drugs 62, 63, 64. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 27 1 2 3 4 5 CME sponsorship 6 Physicians who attended company sponsored CME events had more positive attitudes 7 8 towards and inclination to prescribe the branded drugs 19, 34, 58, 61, 65. We found that physicians 9 10 who refused CME sponsorship were seen to prescribe higher proportion of generics and 11 lower expenditure medicines when compared to physicians who attended CMEs34. 12 13 14 15 Discussion Fo 16 We report that there is widespread interaction between the pharmaceutical industry and 17 18 physicians11, 14, 31, 36, 39, 55. Interactions are in the form of personal communications, free gifts 19 rp 20 such as drug samples, sponsored meals, sponsored conference travel, funding for research 21 and CMEs and honoraria11, 12, 21, 22, 31, 32, 33. The frequency of these interactions is comparable 22 23 between residents and physicians14, 21, 31, 32, 33. However, the amount and type of gifts vary ee 24 25 with the position of the physician in medical hierarchy, specialization and location of 26 practice12, 14, 17, 26, 31, 34, 39, 55, 56. In general, trainees (residents, interns) are treated with more 27 rr 28 drug samples, stationery items and free meals than senior physicians14, 39. Senior physicians 29 30 usually avail of sponsored conferences/ trips, research funding, honoraria and CME events. ev 31 The extent of these interactions varies with academic versus non-academic institutions: non- 32 33 academic hospitals record more interactions than others12, 26, 31, 55, 76 . The majority of the 34 ie 1, 13, 14, 15, 20 22, 25, 34 35 physicians do not believe that they are affected by PSR interactions . 36 However, a sizeable percentage in various surveys responded in the affirmative when asked w 37 38 whether they thought that their peers are vulnerable1, 22, 27, 32, 34. 39 40 on 41 We observe that there is a positive correlation between acceptance of gifts and physicians’ 42 43 urge to reciprocate favorably towards the benefactor33, 38, 41. More the amount and monetary 44 ly 45 value of the interactions, Considering that physicians have a social contract with society at 46 large to provide unbiased and altruistic service, this is an alarming observation. Countries 47 48 have put into effect legislation and policies to curb activities that abuse the role of physicians 49 50 as gatekeepers of society’s health, which are discussed below. 51 52 53 Policies and educational intervention 54 55 The relationship of physicians with patients is of fiduciary nature. Hence activities that might 56 affect that relationship by altering physicians’ clinical behavior are not acceptable. Physician- 57 58 PSR interactions may put the trust of patients in physicians at risk. Interaction with PSRs 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 27 BMJ Open 1 2 3 begins at medical school. Trainees are exposed to PSR marketing and promotional techniques 4 5 from the initial years of their medical education, which impact their prescribing behavior in 6 future. Overall, trainees, i.e., residents and interns, are more vulnerable to PSR interactions 7 8 than senior physicians30,36,56. Physicians are susceptible to PSR interactions, which influences 9 10 their clinical decision-making leading to greater prescriptions of branded drugs over low cost 11 generic medicines and increasing healthcare cost 33, 41, 62, 63, 64 . In addition, this is 12 13 accompanied by requests to add the benefactor company’s drug to existing hospital 14 15 formulary24.. Therefore, there is need to institute and implement stringent policies curtailing Fo 16 physician-PSR relationships, as well as educational programs to increase awareness among 17 18 medical students in their formative years. Previous reports have indicated that implementing 19 rp 20 policies and conducting educational programs are effective in increasing awareness of 21 physician’s attitudes towards PSR interactions25,51,71, 72, 73, 74. . 22 23 ee 24 25 Limitiations of the study 26 Pubmed, Embase, Cochrane library and Google scholar electronic databases were not 27 rr 28 searched before 1992 and other databases were not searched. 29 30 Future implications ev 31 32 33 PSR interactions compromise the objectivity of the physicians and results in irrational 34 ie 35 prescribing behavior and increasing healthcare cost Educating physicians and increasing 36 regulation of PSR interactions may lower the likelihood of prescribing new non-superior w 37 38 industry drugs and irrational prescription behavior. 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Japanese practicing physicians' relationships with w 37 pharmaceutical representatives: a national survey. PLoS One. 2010 Aug 13; 5(8): 38 39 e12193. 40 59. Ziegler MG, Lew P, Singer BC. The accuracy of drug information from on 41 pharmaceutical sales representatives. JAMA. 1995; 273(16): 1296-8. 42 43 60. Lurie N, Rich EC, Simpson DE, Meyer J, Schiedermayer DL, Goodman JL, 44 McKinney WP. Pharmaceutical representatives in academic medical centers: ly 45 interaction with faculty and housestaff. J Gen Intern Med. 1990; 5(3): 240-3. 46 47 61. Lexchin J. Interactions between physicians and the pharmaceutical industry: What 48 49 does the literature say? CMAJ. 1993 Nov 15; 149(10): 1401–1407. 50 51 62. DeJong C, Aguilar T, Tseng CW, Lin GA, Boscardin WJ, Dudley RA. 52 Pharmaceutical Industry-Sponsored Meals and Physician Prescribing Patterns for 53 Medicare Beneficiaries. JAMA Intern Med. 2016; 176(8): 1114-10. 54 55 63. Yeh JS, Franklin JM, Avorn J, Landon J, Kesselheim AS. Association of Industry 56 Payments to Physicians With the Prescribing of Brand-name Statins in Massachusetts. 57 JAMA Intern Med. 2016;176(6):763-8. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 27 BMJ Open 1 2 3 4 64. Steinbrook R. Industry Payments to Physicians and Prescribing of Brand-name Drugs. 5 JAMA Intern Med. 2016 Aug 1;176(8):1123. 6 7 65. Bowman MA, Pearle DL. Changes in drug prescribing patterns related to commercial 8 9 company funding of continuing medical education. J. Contin. Educ. Health Prof. 10 1988;8(1): 13-20. 11 12 66. Fischer MA, Keough ME, Baril JL, et al. Prescribers and pharmaceutical 13 representatives: why are we still meeting? J Gen Intern Med. 2009; (7): 795-801. 14 15 67. Chimonas S, Brennan TA, Rothman DJ. Physicians and drug representatives: Fo 16 exploring the dynamics of the relationship. J Gen Intern Med. 2007; 22(2): 184-190. 17 18 68. Grande D. Limiting the influence of pharmaceutical industry gifts on physicians: self- 19 regulation or government intervention? J Gen Intern Med. 2010; 25(1): 79-83. rp 20 21 69. Brennan TA, Rothman DJ, Blank L, Blumenthal D, Chimonas SC, Cohen JJ, 22 Goldman J, Kassirer JP, Kimball H, Naughton J, Smelser N. Health industry practices 23 that create conflicts of interest: a policy proposal for academic medical centers. ee 24 25 JAMA. 2006; 295(4): 429-433. 26 70. Greenland P. Time for the medical profession to act: new policies needed now on 27 interactions between pharmaceutical companies and physicians. Arch Intern Med. rr 28 2009; 169(9): 829-831. 29 30 71. Montague BT, Fortin AH 6th, Rosenbaum J. A systematic review of curricula on ev 31 relationships between residents and the pharmaceutical industry. Med Educ. 2008; 32 42(3): 301-8. 33 34 ie 72. Yeh JS, Austad KE, Franklin JM, Chimonas S, Campbell EG, Avorn J, Kesselheim 35 AS. Association of medical students' reports of interactions with the pharmaceutical 36 and medical device industries and medical school policies and characteristics: a cross- w 37 38 sectional study. PLoS Med. 2014; 11(10): e1001743. 39 40 73. Larkin I, Ang D, Avorn J, Kesselheim AS. Restrictions on pharmaceutical detailing on 41 reduced off-label prescribing of antidepressants and antipsychotics in children. Health 42 Aff (Millwood). 2014; 33(6): 1014-23. 43 44 74. Esmaily HM, Silver I, Shiva S, Gargani A, Maleki-Dizaji N, Al-Maniri A, Wahlstrom ly 45 R. Can rational prescribing be improved by an outcome-based educational approach? 46 A randomized trial completed in Iran. J. Contin. Educ. Health Prof. 2010 Winter; 30 47 (1): 11-8. 48 49 50 75. Shalowitz DI, Spillman MA, Morgan MA. Interactions with industry under the 51 Sunshine Act: an example from gynecologic oncology. Am. J. Obstet. Gynecol. 2016; 52 214(6): 703-7 53 54 76. Parikh K, Fleischman W, Agrawal S. Industry Relationships With Pediatricians: 55 Findings From the Open Payments Sunshine Act. Pediatrics. 2016; 137(6). 56 57 77. Birkhahn RH, Jauch E, Kramer DA, Nowak RM, Raja AS, Summers RL, Weber JE, 58 Diercks DB. A review of the federal guidelines that inform and influence 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 27 1 2 3 relationships between physicians and industry. Acad. Emerg. Med. 2009; 16(8): 776- 4 81. 5 6 78. Chressanthis GA, Khedkar P, Jain N, Poddar P, Seiders MG. Can access limits on 7 sales representatives to physicians affect clinical prescription decisions? A study of 8 recent events with diabetes and lipid drugs. J Clin Hypertens (Greenwich). 2012; 9 10 14(7): 435-46. 11 12 79. Grundy Q, Bero L, Malone R. Interactions between non-physician clinicians and 13 industry: a systematic review. PLoS Med. 2013;10(11): e1001561. 14 15 Fo 16 17 18 19 Legends rp 20 21 22 Figure 1: PRISMA flow diagram showing search strategy and included studies 23 ee 24 25 Table 1: Characteristics of included studies 26 27 rr 28 29 Table 2: Impact of physician-pharmaceutical industry interaction on physician 30 ev 31 32 33 34 The Corresponding Author has the right to grant on behalf of all authors and does ie 35 36 grant on behalf of all authors, a worldwide licence w 37 (http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%2020 38 39 13.doc) to the Publishers and its licensees in perpetuity, in all forms, formats and media 40 on 41 (whether known now or created in the future), to i) publish, reproduce, distribute, 42 display and store the Contribution, ii) translate the Contribution into other languages, 43 44 create adaptations, reprints, include within collections and create summaries, extracts ly 45 46 and/or, abstracts of the Contribution and convert or allow conversion into any format 47 including without limitation audio, iii) create any other derivative work(s) based in 48 49 whole or part on the on the Contribution, iv) to exploit all subsidiary rights to exploit all 50 51 subsidiary rights that currently exist or as may exist in the future in the Contribution, 52 v) the inclusion of electronic links from the Contribution to third party material where- 53 54 ever it may be located; and, vi) licence any third party to do any or all of the above. All 55 56 research articles will be made available on an Open Access basis (with authors being 57 asked to pay an open access fee—see http://www.bmj.com/about-bmj/resources- 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 27 BMJ Open 1 2 3 authors/forms-policies-and-checklists/copyright-open-access-and-permission-reuse). 4 5 The terms of such Open Access shall be governed by a Creative Commons licence— 6 details as to which Creative Commons licence will apply to the research article are set 7 8 out in our worldwide licence referred to above. 9 10 11 12 13 14 15 Fo 16 17 18 19 rp 20 21 22 23 ee 24 25 26 27 rr 28 29 30 ev 31 32 33 34 ie 35 36 w 37 38 39 40 on 41 42 43 44 ly 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Fo 16 17 18 19 rp 20 21 22 23 ee 24 25 26 27 rr 28 29 30 ev 31 32 33 34 ie 35 36 w 37 38 39 PRISMA flow diagram showing search strategy and included studies 40 on 180x171mm (72 x 72 DPI) 41 42 43 44 ly 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 27 BMJ Open 1 2 3 Study Authors Study sample Study Interaction Summary 4 design 5 1 Steinman et Residents Cross- Interaction Impact on 6 al., 2001 sectional with prescribing 7 representative, 8 drug samples 9 11 De Ferrari et Physicians Cross- Interaction, Positive 10 al., 2014 sectional medical attitude 11 samples, towards 12 promotional representatives 13 material, 14 dinners 15 12 Thomson et Physicians Cross- Interaction Positive Fo 16 al., 1994 sectional with attitude 17 representative, towards 18 drug samples industry 19 13 Kamal et al., Physicians Cross- Interaction Positive rp 20 2015 sectional with attitude 21 representative towards 22 industry 23 14 Hodges, Residents of Cross- Interaction Positive ee 24 25 1995 psychiatry sectional with attitude 26 representative towards gifts 27 15 Gibbons et Physicians and Cross- Gifts, Positive rr 28 al., 1998 residents sectional samples, attitude 29 travel, lunches towards gifts 30 16 Spingarn et Internal Cohort Teaching Negative effect ev 31 al., 1996 medicine on prescribing 32 residents 33 17 Zaki, 2014 Physicians Randomized, Conferences, Favorable 34 cross- drug samples towards ie 35 sectional promotion 36 survey w 37 18 Orlowski et Physicians Cohort Conference Negative effect 38 al., 1994 travel on prescribing 39 19 Scheffer et Physicians Cross- Interaction Frequency of 40 al., 2014 prescribing sectional with interaction on 41 antiretroviral representative, 42 drugs drug samples, 43 journals 44 20 Brett et al., Physicians Cross- Interaction ly Impact on 45 2003 sectional with attitudes 46 representative 47 21 Gupta et al., Doctors Cross- Interaction Impact on 48 2016 sectional with prescribing 49 representative, 50 drug samples, 51 journals 52 22 Morgan et Obstetrician- Cross- Drug samples, Impact on 53 al., 2006 gynaecologists sectional lunch prescribing, 54 positive 55 attitudes 56 57 23 Alosaimi et Physicians Cross- Interaction Positive 58 al., 2014 sectional with attitude 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 27 1 2 3 representative towards 4 industry 5 24 Chren et al., Faculty Case control Honoraria, Requested 6 1994 physicians research formulary 7 additions of 8 drug 9 25 Randall et Residents Controlled Interaction Impact on 10 al., 2005 trial with prescribing and 11 representative attitudes 12 26 Caudil et al., Physicians Cross- Interaction Negative 13 1996 sectional with impact on 14 representative prescribing 15 patterns Fo 16 27 Andaleeb et Physicians Cross- Interaction Positive 17 al., 1995 sectional with attitude 18 representative towards 19 industry rp 20 28 Reeder et Residents of Cross- Interaction Believed that 21 al., 1993 emergency sectional with no impact on 22 23 medicine representative their prescribing ee 24 25 29 Lichstein et Directors, Cross- Interaction Positive 26 al., 1992 internal sectional with attitude 27 medicine representative towards rr 28 industry 29 30 Brotzman et Directors, Cross- Interaction No guidelines 30 al., 1992 residency sectional with for interaction ev 31 programs representative with 32 representatives 33 31 Alssageer et Doctors Cross- Interaction Positive 34 al., 2012 sectional with attitude ie 35 representative, towards 36 drug samples, industry w 37 printed 38 materials 39 32 Lieb & Physicians Cross- Interaction Frequency and 40 Brandtonies, sectional with impact on on 41 2010 representative, attitudes 42 drug samples, 43 printed 44 materials, ly 45 lunches 46 33 Lieb & Physicians Cross- Interaction High 47 Scheurich, sectional with expenditure 48 2014 representative, prescribing 49 drug samples, 50 printed 51 materials, 52 CME 53 34 Lieb & Medical Cross- Interaction Positive 54 Koch, 2013 students sectional with attitude 55 representative, towards 56 drug samples, industry, 57 printed impact on their 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 27 BMJ Open 1 2 3 materials, prescribing 4 lunches 5 35 Brown et Directors, Cross- Interaction Negative 6 al., 2015 residency sectional with attitude 7 programs representative, towards 8 gifts, lunches industry 9 37 Rahmana et Doctors Cross- Interaction Impact on their 10 al., 2015 sectional with prescribing 11 representative 12 38 Lee & Physicians Cross- Gifts Negative 13 Begley, sectional impact on their 14 2016 prescribing 15 39 Montastruc Medical Cross- Interaction Negative Fo 16 et al., 2014 residents sectional with attitude 17 representative towards 18 industry 19 Believed that rp 20 no impact on 21 their 22 prescribing 23 40 Ketis & Family Cross- Interaction Positive effect ee 24 25 Kersnik, physicians sectional with on knowledge 26 2013 representative 27 41 Hurley et Dermatologists Cross- Free drug Impact on their rr 28 al., 2014 sectional samples prescribing 29 (less generic 30 prescribing) ev 31 42 Makowska, Doctors Cross- Gifts Positive 32 2014 sectional attitude 33 towards 34 industry ie 35 43 Siddiqui et Medical Cross- Interaction Positive 36 al., 2014 students sectional with attitude w 37 representative towards 38 industry 39 55 Workneh Physicians Cross- Interaction Positive 40 BD et al., sectional with attitude on 41 2016 representative, towards 42 gifts industry, 43 impact on 44 prescribing ly 45 behavior 46 57 Khan N et Doctors Cross- Interaction Positive 47 al., 2016 sectional with attitude 48 representative, towards 49 gifts industry 50 58 Saito S et al. Physicians National Interaction Positive 51 2010 Survey with industry, attitude 52 receipt of towards 53 gifts, funds, representatives 54 CME, and gifts, value 55 samples information 56 from 57 representatives, 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 27 1 2 3 interactions 4 higher with 5 physicians who 6 prefer to 7 prescribe brand 8 names. 9 59 Ziegler MG Pharmaceutical Survey Accuracy of Incorrect 10 et al. 1995 representative information information 11 speakers provided by often provided 12 PSRs about by speakers 13 drugs goes unnoticed 14 by physicians 15 60 Lurie N et Internal Survey Effect of Impact on Fo 16 al., 1990 medicine conversation prescribing 17 house staff and with PSRs, behavior and 18 faculty free meals, formuary 19 honoraria and change rp 20 research requests. 21 support 22 62 DeJong C et Physicians Cross- Industry Receipt of 23 al., 2016 sectional sponsored industry- ee 24 meals sponsored 25 meals was 26 27 associated with rr 28 an increased 29 rate of brand 30 name ev 31 prescription. 32 63 Yeh JS et Physicians Cross- Effect of Payment for 33 al., 2016 sectional industry meals and 34 payment on educational ie 35 prescription programs 36 of branded increased drugs for prescription of w 37 38 cholesterol brand names. 39 control 40 65 Bowman Physician Self report Effect of Sponsoring on 41 MA et al., attendees survey CME on company’s 42 1988 prescribing drugs were 43 behavior favored during 44 prescription ly 45 66 Fischer MA Physicians, Survey of Effect of Believed that 46 et al., 2009 trainees focused industry no impact on 47 groups marketing their 48 strategies on prescribing, 49 prescription have ability to 50 and cognitive evaluate 51 dissonance of information of 52 physicians PSRs 53 67 Chimonas S Physicians Survey of Determine Physicians 54 et al., 2007 focused how understood the 55 groups physicians conflict of 56 handle their interests but 57 cognitive developed 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 27 BMJ Open 1 2 3 dissonance denials and 4 rationalizations 5 to deal with 6 cognitive 7 dissonance. 8 72 Yeh JS et Medical Cross- Interaction Policies 9 al., 2014 students sectional with separating 10 representative, students from 11 gifts, lunches representatives 12 reduced 13 number of 14 interactions 15 73 Larkin I et Pediatricians, Survey Interaction Anti detailing Fo 16 al., 2014 child & with policies 17 adolescent representative reduced the 18 psychitrist prescription of 19 off-label rp 20 antidepressants 21 and anti 22 psychotics for 23 children ee 24 74 Esmaily General Randomized Effect of Outcome based 25 HM et al., physicians trial outcome CME reduced 26 27 2010 based CME total number of rr 28 prescriptions, 29 prescriptions of 30 antibiotics, ev 31 anti- 32 inflammatories 33 and injections 34 compared to ie 35 traditional 36 CME. It also improved w 37 38 compliance to 39 regulations. 40 76 Parikh K et Pediatricians Cross- Comparison Pediatricians on 41 al., 2016 sectional of industry get fewer gifts 42 interactions from industry 43 between than internists. 44 pediatricians There is ly 45 and other variation 46 specialists; among sub 47 among specialities for 48 subspecialities extent of 49 of pediatrics. interaction. 50 78 Chressanthis Physicians Survey Effect of Restricting 51 GA et al. restricting PSRs affected 52 2012 PSRs on information 53 clinical flow about 54 practice and drugs, both 55 knowledge negative and 56 positive. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 27 1 2 3 # Attitudes Prescribing Knowledge Formulary 4 behavior requests 5 Gifts Receiving higher - - - 6 number of gifts was 7 associated with belief 8 that PRs have no 9 impact on their 10 prescribing behaviour 11 (p<0.05)14 12 Drug samples Positive attitude Higher - - 13 towards the drug prescription of 14 industry and the the company 15 representatives11, 12, 21, drug21, 33, 41 Fo 16 22, 31, 32, 33, 34 17 18 Pharmaceutical - Rational Inability to identify Request for 19 representative treatment (OR, the false claims16, 59 sponsor’s drug rp 20 speakers 8.4; 95% CI, vs physicians 21 2.1-38.9) who did not 22 Irrational benefit (OR, 3.9; 23 treatment 95% CI, 1.2- (p= 0.03 16) 16, 12.7)24 ee 24 18, 34 25 26 Honoraria and Positive attitude - - Request for 27 Research Funding towards sponsor’s drug sponsor’s drug rr 28 (p<0.05 19)19, 60, 61 vs physicians 29 who did not 30 benefit (OR, 3.9; ev 31 95% CI, 1.2- 32 12.7)24 33 Conference travel - Significant - Request for 34 increase in sponsor’s drug ie 35 prescribing of vs physicians 36 sponsor drug who did not w 37 (about 3 times benefit (OR, 3.9; 38 higher than 95% CI, 1.2- 39 before 12.7)24 40 attending) on 41 (p<0.001)18 42 Industry paid Positive attitude Significant - There was no 43 lunches towards sponsor’s drug increase in significant 44 (p<0.05)19, 14, 20, 32, 34 prescribing of association ly 45 sponsor drug between 46 62, 63, 64 attending the 47 industry paid 48 lunches21 and 49 dinners11 and 50 formulary 51 request for that 52 company drug 53 CME sponsorship Positive attitude High 54 towards sponsor’s drug expenditure 55 (p<0.05 19) 19, 34, 58, 61, prescribing34 56 65 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 27 BMJ Open 1 2 3 Interaction with Interaction with PR Higher A significant Interaction with 4 PR was associated with prescription of positive correlation PR resulted in 5 positive attitude the company was found between increased 6 towards PR (p= 0.02) drug21 the physicians’ request for PR’s 7 Positive attitude prescribing cost drug vs 8 towards the gifts, and the information physicians who 9 travel, samples, etc provided by the had no 10 (r = 0.706; p = 0.02)30 drug representative interactions with 11 during the PR (OR, 12 interaction (P < 3.4; 95% CI, 13 0.01)26 1.8-6.6)24 14 15 Fo 16 OR-Odds ratio, PR-Pharmaceutical representative, CI-Confidence interval 17 18 19 rp 20 21 22 23 ee 24 25 26 27 rr 28 29 30 ev 31 32 33 34 ie 35 36 w 37 38 39 40 on 41 42 43 44 ly 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 27 1 PRISMA 2009 Checklist 2 3 4 Reported 5 Section/topic # Checklist item 6 on page # 7 TITLE 8 9 Title Fo 1 Identify the report as a systematic review, meta-analysis, or both. 1 10 ABSTRACT 11 12 Structured summary 13 14 2 rp Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. 2 15 16 INTRODUCTION 17 Rationale 3 ee Describe the rationale for the review in the context of what is already known. 3 18 19 Objectives 4 rr Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 3 ev 20 21 METHODS 22 23 Protocol and registration iew 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide 4 24 registration information including registration number. 25 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, 3 26 language, publication status) used as criteria for eligibility, giving rationale. 27 28 Information sources 29 30 Search 7 additional studies) in the search and date last searched. on Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify 4 ly 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be 4 31 repeated. 32 33 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, 3/4 34 included in the meta-analysis). 35 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes 4 36 for obtaining and confirming data from investigators. 37 38 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and 4 39 simplifications made. 40 Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was 41 studies 3 done at the study or outcome level), and how this information is to be used in any data synthesis. 42 43 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 3 44 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency 3 45 2 (e.g., I ) for each meta-analysis. 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 Page 27 of 27 BMJ Open 1 PRISMA 2009 Checklist 2 3 4 Page 1 of 2 5 Reported 6 Section/topic # Checklist item on page # 7 8 Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective 3 9 10 11 Additional analyses 16 Fo reporting within studies). Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating 3 rp which were pre-specified. 12 13 RESULTS 14 15 Study selection ee 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at 5 16 each stage, ideally with a flow diagram. 17 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and 5-8 18 19 20 Risk of bias within studies 19 provide the citations. rr Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 5-8 21 Results of individual studies 22 20 ev For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 5-8 23 24 Synthesis of results 25 Risk of bias across studies 26 21 22 iew Present results of each meta-analysis done, including confidence intervals and measures of consistency. Present results of any assessment of risk of bias across studies (see Item 15). NA 5-8 27 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). NA 28 29 DISCUSSION 30 Summary of evidence on ly 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to 8-9 31 key groups (e.g., healthcare providers, users, and policy makers). 32 33 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of 9 34 identified research, reporting bias). 35 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 36 9 37 FUNDING 38 39 Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the 1 40 systematic review. 41 42 From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. 43 doi:10.1371/journal.pmed1000097 44 For more information, visit: www.prisma-statement.org. 45 Page 2 of 2 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 BMJ Open Association between pharmaceutical sales representatives’ interaction on physicians’ attitudes and prescribing habits: A systematic review Fo Journal: BMJ Open Manuscript ID bmjopen-2017-016408.R1 Article Type: Research rp Date Submitted by the Author: 03-May-2017 Complete List of Authors: Fickweiler, Freek; Crowd for Cure Fickweiler, Ward; Crowd for Cure, ee Urbach, Ewout; Crowd for Cure <b>Primary Subject Health policy Heading</b>: rr Secondary Subject Heading: Patient-centred medicine Change management < HEALTH SERVICES ADMINISTRATION & ev MANAGEMENT, Health policy < HEALTH SERVICES ADMINISTRATION & Keywords: MANAGEMENT, Protocols & guidelines < HEALTH SERVICES ADMINISTRATION & MANAGEMENT ie w on ly For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 32 BMJ Open 1 1 2 3 4 1 Association between pharmaceutical sales representatives’ 5 6 7 2 interaction on physicians’ attitudes and prescribing habits: A 8 9 3 systematic review 10 11 12 4 Fickweiler F1, Fickweiler W1, Urbach E1, 13 14 5 15 Fo 16 17 6 1: Crowd for Cure, Jacob van Ruysdaelstraat 34, 9718 SG Groningen, the Netherlands, 18 19 7 Correspondence to: F. Fickweiler, MD; freek@crowdforcure.com rp 20 21 8 22 23 ee 24 9 All authors have completed the ICMJE uniform disclosure form at 25 26 10 http://www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation 27 11 for the submitted work; no financial relationships with any organisations that might rr 28 29 12 have an interest in the submitted work in the previous three years, no other 30 13 relationships or activities that could appear to have influenced the submitted work ev 31 32 33 14 Contributor Statement: All authors have contributed equally and have substantial 34 ie 35 15 contributions to the conception or design of the work; Author Freek Fickweiler for the 36 16 acquisition, analysis, and interpretation of data for the work; Author Freek Fickweiler w 37 38 17 for drafting the work and Authors Ewout Urbach and Ward Fickweiler for revising it 39 40 18 critically for important intellectual content; and all authors (Freek Fickweiler, Ward on 41 19 Fickweiler and Ewout Urbach) contributed to final approval of the version to be 42 43 20 published and agreed to be accountable for all aspects of the work in ensuring that 44 ly 45 21 questions related to the accuracy or integrity of any part of the work are appropriately 46 47 22 investigated and resolved. 48 49 23 Competing interest: no financial relationships with any organisations that might have 50 51 24 an interest in the submitted work in the previous three years, no other relationships or 52 25 activities that could appear to have influenced the submitted work 53 54 55 26 Funding: all authors declare no support from any organisation for the submitted work. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 32 2 1 2 3 27 Data sharing statement: any data relevant to a published article will be made available 4 5 28 alongside the article when published. 6 7 29 Abstract 8 9 30 Objectives 10 11 31 The objective of this review is to explore the frequency of physician and pharmaceutical 12 32 industry interactions, their impact on physicians’ attitude, knowledge and behavior. 13 14 33 Data Sources 15 Pubmed, Embase, Cochrane library and Google scholar electronic databases were searched Fo 16 34 17 35 from 1992 to August 2016 using free text words and medical subject headings relevant to the 18 19 36 topic. rp 20 21 37 Study Selection 22 38 Studies included were cross sectional studies, cohort studies, randomized trials and survey 23 ee 24 39 designs. Studies with narrative reviews, case reports, opinion polls, letters to the editor, 25 26 40 systematic reviews and non-English studies were excluded from data synthesis. 27 rr 41 Data Extraction 28 29 42 Two reviewers independently extracted the data. Data on study design, study year, country, 30 participant characteristics, setting, and number of participants were collected. ev 31 43 32 44 Data Synthesis 33 34 45 Pharmaceutical sales representative (PSR) interactions influences the physicians’ attitudes ie 35 36 46 towards the representatives, their prescribing behavior and increases the number of formulary w 37 47 addition requests for the company’s drug. Other interactions such as continuing medical 38 39 48 education (CME) and attending pharmaceutical industry sponsored seminars lead to higher 40 on 41 49 prescribing of the company drug and increasing irrational prescribing behavior. 42 50 Conclusion 43 44 51 Physician-pharmaceutical sales representatives interactions and acceptance of gifts and favors ly 45 46 52 from the company’s pharmaceutical sales representatives have been found to affect the 47 53 physicians’ prescribing behavior and are likely to contribute to irrational prescription of the 48 49 54 company’s drug. Therefore, intervention in the form of policy implementation and education 50 51 55 about the implications of these interactions are needed. 52 56 53 54 55 57 Strengths and limitations of the study 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 32 BMJ Open 3 1 2 3 58 - Large up-to-date systematic review of studies exploring the effects of physician and 4 5 59 pharmaceutical industry representative interactions and their impact on physician 6 60 attitudes, knowledge and behavior. 7 8 9 61 - This systematic review used the recommendations outlined in the Cochrane 10 62 Handbook for conducting systematic reviews and the GRADE methodology to assess 11 12 63 the quality of the evidence by outcome. 13 14 15 64 - Pubmed, Embase, Cochrane library and Google scholar electronic databases were Fo 16 65 searched from 1992, as well as grey literature. 17 18 19 66 - Most studies identified were observational and of varying methodological design rp 20 21 67 - Some studies did not provide evidence for the significance of their findings 22 23 ee 24 68 Keywords: pharmaceutical sales representative; physicians, drug industry; brand 25 69 prescriptions; conflict of interest ;physicians-industry interactions; pharmaceutical industry; 26 27 70 attitude of health personnel; gifts to physicians; medical education; irrational prescriptions rr 28 29 30 ev 31 32 33 34 ie 35 36 w 37 38 39 40 on 41 42 43 44 ly 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 32 4 1 2 3 71 Introduction 4 5 72 The relationship between physicians and the pharmaceutical industry has evoked heated 6 7 73 debate for many decades 1. In 2012, the pharmaceutical industry spent $89.5 billion on 8 9 74 physician-pharmaceutical sales representative (PSR) interactions, accounting for 60% of the 10 75 global sales and marketing spending 2-8. Previous reports have demonstrated that PSRs may 11 12 76 influence prescribing behavior 9-16. However, the attitudes about PSR interactions are divided 13 14 77 and contradictory. Studies have indicated that physicians may be unable to distinguish 15 78 between promotional information and scientific evidence 17, 18. Physicians on the other hand Fo 16 17 79 believe their colleagues are more susceptible to PSR marketing strategies than themselves 19- 18 22 19 80 . Most medical and governmental institutions have installed guidelines and self-regulatory rp 20 81 and legislative checks to address this controversy 5, 15, 16, 23-26. However, while administrative 21 22 82 proposals for deregulatory reforms of the pharmaceutical industry are increasing, scientific 23 ee 24 83 evidence rigorously examining this controversy are needed. This review addresses this 25 84 question by critically and systemically evaluating the evidence on the impact of PSR 26 27 85 interactions on the attitudes of physicians. rr 28 29 30 86 Methodology ev 31 32 87 Protocol 33 34 88 We followed a detailed methodology that we described in our review protocol, which is ie 35 36 89 available upon request to the corresponding author. Two independent reviewers assessed w 37 90 selected articles as per inclusion/exclusion criteria as per standardization in the protocol, 38 39 91 shortlisted them for writing the review and cross-checked each other. The review followed 40 on 41 92 the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 42 93 guidelines (Appendix 1). 43 44 94 ly 45 46 95 Eligibility criteria 47 96 The eligibility criteria were: 48 49 97 • Types of studies: cross sectional studies, cohort studies, randomized trials and survey 50 51 98 designs comparing an intervention of interest to a comparator on at least one facet of 52 99 extent, impact on behavior and attitude. Excluded were narrative reviews, case 53 54 100 reports, opinion polls, letters to the editor and systematic reviews. 55 56 101 • Types of participants: physicians, pharmaceutical representatives, physicians in 57 102 training/residents. We did not consider medical students or other health professionals. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 32 BMJ Open 5 1 2 3 103 • Types of exposure: any type of interaction between physicians and the 4 5 104 pharmaceutical industry where there is direct interaction with the physician, such as 6 105 meeting with drug representatives, participating in pharmaceutical-sponsored CME 7 8 106 event, receiving travel funding, free drug samples, industry-provided meals, gifts to 9 10 107 the individual and active presentation of industry-related information to the 11 108 physician. 12 13 109 • Types of outcome: knowledge of physicians (e.g. accuracy of knowledge related to a 14 15 110 specific medication), beliefs and/or attitudes of physicians regarding physician- Fo 16 111 industry interactions (e.g. perceived influence of information from the pharmaceutical 17 18 112 company on their behavior), behavior of physicians (e.g. prescribing 19 rp 20 113 quantity/frequency).Type of control: either not interaction or a lower level of 21 114 interaction. 22 23 115 • Exclusion criteria were: qualitative, ecological, econometric studies, editorials, letters ee 24 25 116 to the editor, studies on medical students, small samples sizes, studies assessing non- 26 117 targeted or indirect interactions (e.g. journal advertisement) and research funding. 27 rr 28 118 29 30 119 We did not exclude studies based on risk of bias. We took risk of bias into account when ev 31 120 grading the quality of evidence using GRADE approach. 32 33 121 34 ie 35 122 Search strategy 36 123 The search strategy included Pubmed, Embase, Cochrane library and Google scholar w 37 38 124 electronic databases (January 1992 to August 2016). Databases were not searched before 39 27 40 125 1992, as these studies were already investigated in an earlier review . The search combined on 41 126 terms for physicians and pharmaceutical, and included both free text words and medical 42 43 127 subject heading relevant to the topic. We did not use a search filter. The supplementary 44 ly 45 128 information file provides the full details of the search strategies. Additional search strategies 46 129 included a search of the grey literature (theses and dissertations). Also, we reviewed the 47 48 130 references lists of included and relevant papers 27-29. 49 50 131 51 132 Assessment of risk of bias in included studies 52 53 133 Two reviewers assessed in duplicate and independently the risk of bias in each eligible study. 54 55 134 They resolved disagreements by discussion or with the help of a third reviewer. We used the 56 135 recommendations outlined in the Cochrane Handbook to assess the risk of bias in randomized 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 32 6 1 2 3 136 studies. We graded each potential source of bias and rated the studies as high, low or unclear 4 5 137 risk of bias. 6 138 7 8 139 Data analysis and synthesis 9 10 140 We assessed the agreement between reviewers for full-text screening by calculating the kappa 11 141 statistic. We did not conduct a meta-analysis due to the heterogeneity of study design, types 12 13 142 of interventions, outcomes assessed, and outcome measures used. Instead, we summarized 14 15 143 the data narratively. We assessed the quality of evidence by outcome using the GRADE Fo 16 144 methodology 30. 17 18 145 19 rp 20 146 Results 21 22 147 We independently screened the titles and abstracts of the 2170 identified records for potential 23 ee 24 148 eligibility. Out of 2170, full text of 49 eligible citations, which matched the inclusion criteria, 25 149 were retrieved and used for qualitative assessment during the writing of the review (Figure 1, 26 27 150 Table 1). We excluded 2000 records as they were not relevant (n = 1641), not original rr 28 29 151 research (n=269), about medical students (n=4) and non-medical (e.g. ecological, 30 152 econometric; n=86). ev 31 32 33 153 Characteristics of included studies 34 ie 35 154 The identified studies were published between 1992 and August 2016. Most of the studies 36 155 included were cross-sectional studies 1, 9-13, 19, 21, 22, 31-55. Only two studies were cohort studies w 37 56, 57 38 156 , three were randomized trials 58-60 and one study was a case-control study 61. 39 40 157 on 41 158 Extent of interactions between physicians and the pharmaceutical industry 42 43 159 We found that PSR interactions are a regular feature in the daily lives of physicians across the 44 ly 45 160 world 9-11, 13, 42, 50. Most of the attending physicians and residents have at least one interaction 46 161 with the industry representatives per month 10, 21, 22, 36, 42 . The frequency of interactions or 47 48 162 gifts offered and accepted varies with private versus public hospital setting and the position 49 10, 13, 31, 38, 42, 43, 50, 58, 62 50 163 of the physicians in the medical hierarchy . Junior residents received 51 164 twice as much free drug samples from PSR interactions than senior residents 10 . PSR 52 13 53 165 interactions were significantly higher at the beginning of residency . The majority of 54 55 166 program directors of internal medicine residencies in USA allowed PSRs to meet with 56 167 residents during working hours and permitted PSR sponsorship of conferences 40. Attending 57 58 168 physicians and physician specialists have greater encounters with PSRs and received more 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 32 BMJ Open 7 1 2 9, 42 3 169 numbers of medical samples and promotional material than residents . Participants 4 5 170 working in private practice alone or in both sectors were more likely to receive gifts than 6 171 physicians working in the public sector 42, 50 . Physicians in academic or hospital-based 7 8 172 practice settings had less PSR interactions and significantly lower prescribing costs than 9 38 10 173 physicians in nonacademic and nonhospital practices . Most common gifts received were 11 174 medical samples 9, 21, 22, 31, 36, 37, 42, 63 , promotional material 9, 34, 42 invitations for dinners 9, 12 13 175 invitations for CMEs 22, 34, scientific journals 34 and free lunches 21, 37. 14 15 176 Fo 16 177 Attitude of physicians towards the interactions 17 1, 13, 19, 20, 22, 31, 32, 40, 49, 58, 64 18 178 We found that physicians have a positive attitude towards PSRs . 19 10, 22, 32, 43, 45, 46 rp 20 179 Physicians perceived PSRs as important sources of education and funding , 21 180 while some studies reporting skeptical attitudes about contribution of PSRs towards teaching 22 21, 36, 39, 40, 49 23 181 and education . Conference registration fees, informational luncheons, ee 24 25 182 sponsorship of departmental journal clubs, anatomical models, and free drug samples were 26 183 considered as appropriate gifts 19, 39, 51, 58 . Most of the physicians considered pharmaceutical 27 rr 28 184 information provided by PSRs, industry sponsored conferences and CME events as important 29 30 185 instruments for enhancing their scientific knowledge 22, 32, 45, 46. Compared to senior residents, ev 31 186 significantly more junior residents felt that pharmaceutical representatives have a valuable 32 10 33 187 teaching role . Most of the physicians considered themselves immune to the influence of 34 ie 1, 10, 32, 33, 35, 37, 43, 59 35 188 gifts . We found that better scores on knowledge and attitudes were 36 189 significantly associated with lesser number of interactions with representatives and their gifts w 37 19 38 190 . Most studies found that physicians do not believe that PSR interactions impact their 39 1, 9-13, 65, 66 40 191 prescribing behavoir , while other studies found that there was some extent of on 41 192 influence 21, 22, 34, 36, 37, 39, 43 . In addition, physicians considered their colleagues more 42 1, 20, 21, 37, 43 43 193 susceptible than themselves to PSR marketing strategies . There was a strong 44 ly 45 194 correlation between the amount of gifts and the belief that PSR interactions did not influence 46 195 their prescribing behavior 10. 47 48 196 49 50 197 Gifts 51 198 Most common gifts received were medical samples 9, 21, 22, 31, 36, 37, 42-44, 47 , promotional 52 53 199 material 9, 34, 42, 67 invitations for dinners 9 and scientific journals 34. 54 55 200 56 201 57 58 202 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 32 8 1 2 3 203 Drug samples 4 5 204 Most of the physicians who accepted drug samples had a positive attitude towards the 6 205 pharmaceutical representatives 9, 21, 22, 31, 36, 37, 42, 43. Accepting samples lead to higher branded 7 8 206 drug prescription rather than generic prescribing 22, 47. 9 10 207 Pharmaceutical representative speakers 11 12 208 Sponsored lectures/symposia of pharmaceutical companies influenced behavior of the 13 14 209 attendees leading to the attendees prescribing more drugs from the sponsoring companies 15 56, 57 210 without sufficient evidence supporting superiority of those drugs . The majority of Fo 16 17 211 attending physicians failed to identify inaccurate information about the company drug 18. This 18 19 212 might make them more prone to interactions of pharmaceutical sales representatives to rp 20 213 prescribe in favor of the company drug. 21 22 214 23 ee 24 215 Honoraria and Research Funding 25 216 Physicians who received money to attend pharmaceutical symposia or to perform research 26 27 217 requested formulary addition of the company’s drug more often than other physicians, This rr 28 29 218 association was independent of many confounding factors 61 (Table 2). Brief encounters with 30 219 PSRs and receipt of honoraria or research support were predictors of faculty requested ev 31 32 220 change in hospital formulary 68. 33 34 221 ie 35 36 222 Conference travel w 37 223 Pharmaceutical company sponsored conference travels to touristic locations have 38 39 224 quantifiable impact on the prescribing rational of attendees. A significant increase (three 40 on 41 225 times) in the prescribing rate of two company drugs was observed after the physicians 42 226 attended a company sponsored symposium with all their expenses covered. Despite this 43 44 227 significant difference in the prescribing patterns, physicians insisted there was no impact on ly 45 46 228 their prescribing behaviour 57. 47 229 48 49 230 Industry paid lunches 50 51 231 Most physicians received invitations for dinners 9 and free lunches 10, 21, 35, 43 . Clerks, interns 52 10 232 and junior residents attended more company sponsored lunches than senior residents . 53 39 54 233 Pharmaceutical companies also sponsored departmental lunches during journal clubs . 55 56 234 There was no significant association between attending industry paid lunches 37 and dinners 9 57 235 and formulary request for that company’s drug (Table 2). However, there was a significant 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 32 BMJ Open 9 1 2 3 236 association between attending industry paid lunches and increased prescription of branded 4 5 237 drugs 52, 53, 69. 6 238 7 8 239 CME sponsorship 9 10 240 Physicians who attended company sponsored CME events had more positive attitudes 11 241 towards and inclination to prescribe the branded drugs 28, 34, 43, 67, 70. We found that physicians 12 13 242 who refused CME sponsorship were seen to prescribe higher proportion of generics and 14 15 243 lower expenditure medicines when compared to physicians who attended CMEs 22. Fo 16 244 17 18 245 Discussion 19 rp 20 246 We report that there is widespread interaction between the pharmaceutical industry and 21 247 physicians 9-11, 13, 42, 50 . Interactions are in the form of personal communications, free gifts 22 23 248 such as drug samples, sponsored meals, sponsored conference travel, funding for research ee 24 9, 21, 22, 31, 36, 42 25 249 and CMEs and honoraria . The frequency of these interactions is comparable 26 250 between residents and physicians 10, 21, 22, 36, 42 . However, the amount and type of gifts vary 27 rr 28 251 with the position of the physician in medical hierarchy, specialization and location of practice 29 10, 13, 31, 38, 42, 43, 50, 58, 62 30 252 . In general, trainees (residents, interns) are treated with more drug ev 31 253 samples, stationery items and free meals than senior physicians 10, 13 . Senior physicians 32 33 254 usually avail of sponsored conferences/ trips, research funding, honoraria and CME events. 34 ie 35 255 The extent of these interactions varies with academic versus non-academic institutions: non- 36 256 academic hospitals record more interactions than others 31, 38, 42, 50, 55 . The majority of the w 37 1, 10, 32, 33, 35, 37, 43, 59 38 257 physicians do not believe that they are affected by PSR interactions . 39 40 258 However, a sizeable percentage in various surveys responded in the affirmative when asked on 41 259 whether they thought that their peers are vulnerable 1, 20, 21, 37, 43. It is further noted that there is 42 43 260 a trend towards non-physician clinicians interactions and prescribing, such as nurses whom, 44 ly 45 261 also, generally hold a positive attitude toward PSR-interactions. This further depicts the 46 262 extent of interactions and also might expose a risk of replicating irrational prescribing in non- 47 48 263 physicians 71. 49 50 264 51 265 We observe that there is a positive correlation between acceptance of gifts and physicians’ 52 12, 22, 47 53 266 urge to reciprocate favorably towards the benefactor . Considering that physicians 54 55 267 have a social contract with society at large to provide unbiased and altruistic service and also 56 268 the impact of these interactions on healthcare costs, this is an alarming observation. Countries 57 58 269 have put into effect legislation and policies to curb activities that abuse the role of physicians 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 32 10 1 2 3 270 as gatekeepers of society’s health, such as the The Sunshine Act which is the first 4 5 271 Congressional involvement in regulating the disclosure by physicians of payments by 6 272 pharmaceutical companies and manufacturers of drugs, federal health care programmes are 7 8 273 required to report certain payments and items of value given to physicians and teaching 9 10 274 hospitals (e.g. speaking fees, consulting arrangements, and free food) 72-74. The purpose is to 11 275 prevent undue influence and protect the public interest. Moreover, a 2005 joint report by the 12 13 276 WHO and Health Action International (HAI) reported on interventions to counter 14 75 15 277 promotional activities . The evidence presented in that report was not eligible for our Fo 16 278 systematic review, mostly because it related to interventions on students or doctors-in- 17 18 279 training. Nevertheless, the findings suggested that interventions such as industry self- 19 rp 20 280 regulation and guidelines for sales representatives are not effective, while education about 21 281 drug promotion might influence physician attitudes 76-78. 22 23 282 ee 24 25 283 Policies and educational intervention 26 284 The relationship of physicians with patients is of a fiduciary nature. Hence activities that 27 rr 28 285 might affect that relationship by altering physicians’ clinical behavior are not acceptable. 29 30 286 Physician-PSR interactions may put the trust of patients in physicians at risk. Interaction with ev 31 287 PSRs begins at medical school. Trainees are exposed to PSR marketing and promotional 32 33 288 techniques from the initial years of their medical education, which impact their prescribing 34 ie 35 289 behavior in future. Overall, trainees, i.e., residents and interns, are more vulnerable to PSR 36 290 interactions than senior physicians 11, 41, 62 . Physicians are susceptible to PSR interactions, w 37 38 291 which influences their clinical decision-making leading to greater prescriptions of branded 39 22, 47, 52, 53, 69 40 292 drugs over low cost generic medicines and increasing healthcare costs . In on 41 293 addition, this is accompanied by requests to add the benefactor company’s drug to existing 42 61 43 294 hospital formulary . Therefore, there is need to institute and implement stringent policies 44 ly 45 295 curtailing physician-PSR relationships, as well as educational programs to increase 46 296 awareness. Previous reports have indicated that implementing policies and conducting 47 48 297 educational programs are effective in increasing awareness of physician’s attitudes towards 49 50 298 PSR interactions 54, 59, 60, 76, 79-83. 51 299 52 53 300 Strengths and Limitations of the study 54 55 301 A major strength of this study is that is a large up-to-date systematic review of studies 56 302 exploring the effects of physician and pharmaceutical industry representative interactions and 57 58 303 their impact on attitudes, knowledge and prescribing behavior of practicing physicians and 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
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