Criticism of drug promotional literature(dpl)

HOW TO CRITICALLY APPRAISE A DPL

1. D r. sourav chakrabarty , Post-graduate trainee, Dept. Of Pharmacology , b.s. Medical College Criticism of Drug promotional literature(DPL)

2. Overview Introduction. Drug promotion & its methods. Sources of information for a physician. Regulatory codes & guidelines. Critical appraisal of DPL by a physician. Some recent works on review of DPL. Discussion. Bibliography . Exercise.

3. Introduction Advent of pharmaceutical sciences & globalisation of pharma industry good number of drugs (generic/brand) getting into market everyday. Every day … – ~ 46 randomized clinical trials are published – ~ 1000 new Medline articles – ~ 6,000 new articles in biomedical journals • Every year … – ~ 3 million articles published in ~ 30,000 journals Information explosion.

4. Most are “me too” product,no genuine innovation. Busy hectic professional life for a physician . No formal training of method of appraisal of medical literature during undergraduate MBBS courses . DPL- does Update knowledge OR develop wrong practices?

5. Drug promotion & its methods Drug promotion: “All informational and persuasive activities by manufacturers and distributors, the effect of which is to induce the prescription, supply, purchase, and/or use of medicinal drugs” (WHO 1988 ). $ 11 billion/year-for drug promotion and marketing, $ 5 billion/year –for sales representatives 8000-13000 $ per health care professional/year. Two types- Promotion to health care professional Promotion to general public.

6. Contd …………… Aids- literature: scientific paper,leaflet,brochure,drug reminder etc. Audio-visual aid. Gift item: pen ,paper weight,date calender,notepad . Media: television,internet . visual aid: banner,hording . Direct mailing. Newspaper & magazine. BUT most importantly, verbal presentation by medical representatives.

7. Written literature Protocols as evidence of clinical benefits Publication in non-peer reviewed / obscure journals Graphs with misleading axes! Surrogate end points Claims of superior potency Data from in-vitro studies, healthy volunteers Claims from emerging or scientific opinions Price comparisons Statistics

8. Contd ……….. Information- more for promoting the drug,rather than educating the physician. 11% of verbal statements are inaccurate. Only 25% of physicians are aware of that. Poor methodological quality of journal advertisements. But still………… an important medium for updation of knowledge for busy physicians,specially in remote areas.

9. Commonly misused shortcuts for choosing therapies Newer is better Experts know best If there is a mechanism for how a drug works, then it works If my peers are prescribing the drug then so should I. If the patient improves after the drug is prescribed, then the therapy must have worked. If the manufacturer gives gifts, I should support them in return

10. Sources of information for a physician A.Published literature: 1 .primary: original publication, research studies, case report, case series, letter to editor, review article. 2 .secondary : medline , pubmed , national library of medicine gateway, international pharmacy abstract,toxline , current content. 3 .tertiary: textbooks(Harrison’s principles of internal medicine),compendia (physician’s desk reference)

11. Contd …………. B.Internet C.CME: Scientific seminar/symposia/case presentation D.Drug promotional literature: scientific paper,,leaflet , brochure, drug reminder etc . E.From expert opinion.

12. Regulatory codes & guidelines Ethical criteria for medicinal drug promotion (WHO 1988) IFPMA Code of Practice (2012) OPPI Code of Pharmaceutical Practices(2012) National legislation: 1. Drugs and Cosmetics Act, 1940

13. Ethical criteria for medicinal drug promotion ( WHO 1988 ) At t he Forty-first World Health Assembly(13 may,1988). Objective: T o support and encourage the improvement of health care through the rational use of medicinal drugs. Applicability : Both prescription and non prescription medicinal drugs (" over-the-counter drugs"),also traditional medicines as appropriate, and to any other product promoted as a medicine. D o not constitute legal obligations.

14. Contd ………. medicinal drugs promotion should be reliable, accurate, truthful, informative, balanced,up -to-date , capable of substantiation and in good taste. No misleading or unverifible statements or omissions likely to induce medically unjustifiable drug use or to give rise to undue risks. The word "safe" should only be used if properly qualified. Comparison of products should be factual, fair and capable of substantiation. Do not disguise the real nature of a drug.

15. No financial or material benefit. Essential information criteria for DPL: A.Promotion to the physician: the name(s) of the active ingradient (s ) using either international nonproprietary names (INN) or the approved generic name of the drug ;) the brand name; content of active ingredient(s) per dosage form or regimen ; name of other ingredients known to cause problems ;

16. Contd ……. approved therapeutic uses; dosage form or regimen; side-effects and major adverse drug reactions; precautions, contra-indications and warnings; major interactions; name and address of manufacturer or distributor; reference to scientific literature as appropriate . @ (reminder advertisements ): the brand name, the international nonproprietary name or approved generic name, the name of each active ingradient,the name and address of the manufacturer/ distributor for the purpose of receiving further information.

17. B.Promotion to the general public: Advertisement’s claim must be substantiated . Not for scheduled narcotic and psychotropic drugs. lay language : information should be consistent with the approved scientific data sheet. Criteria : the name(s) of the active ingradient (s ) using either international nonproprietary names (INN) or the approved generic name of the drug; the brand name; major indication(s) for use; major precautions, contra-indications and warnings: name and address of manufacturer or distributor.

18. Free samples of legally available prescription drugs may be provided in modest quantities to prescribers, generally on request . Sponsorship of a symposia by a pharmaceutical manufacturer or distributor should be clearly stated in advance,at the meeting and in any proceedings. Post-marketing scientific studies and surveillance should not be misused as a disguised form of promotion.

19. Substantiated information on hazards associated with medicinal drugs should be reported to the appropriate national health authority . Adequate lnformation for patients= package inserts, leaflets and booklets- should provide information consistent with that approved by the country's drug regulatory authority.

20. IFPMA & OPPI code IFPMA ( International Federation of Pharmaceutical Manufacturers & Associations ) Code of Practice:2012. A dopted by OPPI( Organisation of Pharmaceutical Producers of India ) & published as OPPI Code of Pharmaceutical Practices(2012 ). Effective on 31 December, 2012. .

21. “ pharmaceutical product ”- all pharmaceutical or biological products (irrespective of patent status and/or whether they are branded or not) which are intended to be used on the prescription of, or under the supervision of, a healthcare professional and which are intended for use in the diagnosis, treatment or prevention of disease in humans, or to affect the structure or any function of the human body. Scope : Interactions with healthcare professionals , organizations/associations of healthcare professionals, medical institutions and patient organizations, promotion of pharmaceutical products.

22. Exclusion: Promotion of prescription only pharmaceutical products directly to the general public (i.e. direct to consumer advertising ). Promotion of self-medication products that are provided “over the counter ” without prescription . Pricing or other trade terms for the supply of pharmaceutical products. The engagement of a healthcare professional to provide legitimate consultancy or other legitimate services to a member company. The conduct of clinical trials (which are governed by separate GCP guidelines). The provision of non-promotional information by member companies

23. Ethical promotion Basis of interaction. Transparency of promotion. Independence of healthcare professionals: no financial benefit or benefit-in- kind Appropriate use Regulations. Pre-approval communications and off-label use: not allowed. BUT,should not restrict a full and proper exchange of scientific information.

24. STANDARDS OF PROMOTIONAL INFORMATION Consistency of Product Information Accurate and Not Misleading C apable of substantiation either by reference to the approved labeling or by scientific evidence. Printed promotional material:criteria the name of the product (normally the brand name );the active ingredients, using approved names where they exist; the name and address of the pharmaceutical company or its agent responsible for marketing the product; date of production of the advertisement; and “ abbreviated prescribing information” which should include an approved indication or indications for use together with the dosage and method of use, and a succinct statement of the contraindications , precautions and side effects

25. Electronic materials, including audiovisuals: same as literature. For websites: the identity of the pharmaceutical company and of the intended audience should be readily apparent; the content should be appropriate for the intended audience; the presentation (content, links, etc.) should be appropriate and apparent to the intended audience; and Information should comply with Drugs & Magic Remedies Act.

26. National legislation Drugs & Cosmetics Act 1940 and Rules 1945 , Drugs & Magic Remedies (OA) Act 1954 and Rules 1955 , Drugs (prices Control) Order 1995 (an Order made u/s . 3 of Essential Commodities Act 1955 ), Narcotic Drugs & Psychotropic Substances Act 1985

27. Critical appraisal of DPL by a physician Physician prescription strongly influenced by drug advertisements & DPL. What to look for? The disease The patient The need The comparator. Outcome of interest: disease oriented/patient oriented(morbidity/mortality/quality of life/cost) Methodology & statistics.: CI around the mean is a better parameter than p value in estimating the clinical outcome. Level of evidence.

28. Levels of Evidence for Therapy Question Level of Evidence Type of Study 1a Systematic reviews of randomized controlled trials ( RCTs ) 1b Individual RCTs with narrow confidence interval 2a Systematic reviews of cohort studies 2b Individual cohort studies and low-quality RCTs 3a Systematic reviews of case-control studies 3b Case-control studies 4 Case series and poor quality cohort and case-control studies 5 Expert opinion Levels of evidence (2001). Centre for Evidence Based Medicine. Retrieved 26 Aug 2008 from http://www.cebm.net/index.aspx?o=1025 Acquire

29. Stepwise Approach for Appraisal. Step 1. Consider the research hypothesis Is there a clear statement of the research hypothesis ? Does the study address a question that has clinical relevance?

30. Step 2. Consider the Study Design Is the study design appropriate for the hypothesis ? Does the design represent an advance over prior approaches ? Does the study use an experimental or an observational design?

31. Step 3. Consider the Outcome Variable Is the outcome being studied relevant to clinical practice ? What criteria are used to define the presence of disease ? Is the determination of the absence or presence of disease accurate?

32. Step 4. Consider the Predictor Variable How many exposures or risk factors are being studied? How is the presence or absence of exposure determined? Is the assessment of exposure likely to be precise and accurate? Is there an attempt to quantify the amount or duration of exposure? Are biological markers of exposure used in the study?

33. Step 5. Consider the Methods of Analysis Are the statistical methods employed suitable for the types of the variables ( nominal/ordinal/continuous ) in the study? Have the levels of type I and type II errors has been discussed appropriately? Is the sample size adequate to answer the research question? Have the assumptions underlying the statistical tests been met? Has chance been evaluated as a potential explanation of the results?

34. Step 6. Consider Possible source of Bias (Systematic Error) Is the method of selection of subjects likely to have biased results? Is the measurement of either the exposure or the disease likely to be biased? Have the investigators considered whether confounders could account for the observed results? In what direction would each potential bias influence the results?

35. Step 7. Consider the interpretation of the results. How large is the observed effect ? Is there evidence of a dose-response relationship ? Are the findings consistent with laboratory models ? Are the effect are biologically plausible ? If the findings are negative, was there sufficient statistical power to detect an effect?

36. Step 8. Consider how the results of the study can be used in practice. Are the findings consistent with other studies of the same questions ? Can the findings be generalized to other human populations ? Do the findings warrant a change in current clinical practice?

37. Critiquing quantitative research Likewise, if numbers need to treat (NNT) is not mentioned it may indicate that the treatment was not effective (i.e. you would need to treat too many patients to prevent one additional bad outcome) NNT=1/ARR [ARR=absolute risk reduction) Small confidence intervals indicate the likelihood of the same results recurring with a larger sample . TIP! For help critiquing quantitative research read: Harris, M. and Taylor, G. (2008) Medical statistics made easy, 2nd edn . Bloxham : Scion Harris.

38. CASP(Critical appraisal skills programme) tools CASP are the most commonly used checklists http://www.casp-uk.net Quantitative research tools Randomised controlled trial checklist Systematic review checklist Cohort study checklist Case control study checklist Diagnostic test checklist Qualitative research tools There is a single checklist for qualitative material.

39. Other critiquing tools Other critiquing tools include: Tools outlined in standard textbooks Best Bets critical appraisal tools CEMB critical appraisal sheets SIGN Checklists Tip! These are not meant to replace considered thought and judgement when reading a paper – they are simply there as guides and aide memoires.

40. Final appraisal How the benefit expressed as: relative risk ratio/absolute risk reduction/NNT./odd’s ratio. Safety of new drug Compliance Cost Supporting scientific material. Review of disclaimer & acknowledgement: whether funded by companies. General points of assesment: STEP ( safety,tolerability,efficacy & price)

41. Healthy scepticism 41

42. Criteria of a good advertisement

43. Are drug advertisements in Indian edition of  BMJ  unethical? BMJ  1997;  315, B Gitanjali , K.D.Tripathi . Trental 400 ( pentoxifylline ): “The advertisement makes unsubstantiated claims of improvement in mental function.” (This drug is marketed only for peripheral vascular disease in America and Britain; in India it is indicated for cerebrovascular disease as well.) Relaxyl (diclofenac) : “The claim 'gentle on the gastrointestinal tract' is not in accord with the reported high incidence of gastrointestinal side effects (up to 30% in Australian approved product information).” Alarsin products (Indian preparation ): “There is no information on active constituents, side effects, or contraindications, and the claims made are unsubstantiated.” Keflor ( c efaclor ): “Makes unsubstantiated claims such as 'respiratory specific.'” Fludac (fluoxetine): “This advertisement distorts the side effect profile by mentioning only the advantages it has over tricyclic antidepressants. There is no information on contraindications or dosage.”

44. Globac ( haemoglobin ferric ammonium citrate, copper sulphate , manganese sulphate , zinc sulphate ): “ No evidence for therapeutic effect is given, and there are no clear indications for use.” Mentat (Indian preparation): “There is no information on constituents, indications, precautions, or dosage. There is no evidence given for clinical efficacy, and the reference is to a study in an obscure (in house) journal.” Ciprodac (ciprofloxacin): “The claim 'super power in your hands' is meaningless. There is no mention of the generic name, constituents, contraindications, or side effects.” Ciprowin (ciprofloxacin): “Makes unsubstantiated superlative claims such as 'surgical infections: most effective and cost effective therapy' and 'LRTI: better than third generation cephalosporins .'” Ciprobid (ciprofloxacin): “ The claim 'superior to chloramphenicol, aminoglycosides, cephalosporins in … bronchopneumonia, osteomyelitis' is misleading

45. Some other studies Drug promotional literatures ( dpls ) evaluation as per world health organization (WHO) criteria : Jadav SS, Dumatar CB;Journal of applied pharmaceutical science vol. 4 (06), pp084-088, june , 2014. Assessment of promotional drug literature using world health organisation (who) guidelines ; Y ogesh a garje ,Baliram v Ghodke; Indian journal of applied research, Feb 2014. Volume : 4 | Issue : 2 Evaluation of promotional drug literature as p er world health organisation guideline ; Smita mali, IJP, jan 2011. Evaluation of drug promotional literatures using WHO guidelines ; Tejas Khakhkhar , Journal of Pharmaceutical Negative Results | Jan-Dec 2013 | Vol 4 | Issue 1.

46. Discussion. WHO guidelines were not followed by drug companies while promoting drug products. generic name of each active ingradient,recommended dosage form,brand name and approved therapeutic uses was mentioned in all DPLs. Information about ADRs, drug interactions and precautions- missing. Promising unsubstantiated claims, catchy phrase,irrelevant pictures,charts & tables- present. References either not cited or not recovered.

47. Contd …….. Manufacturer’s name and addresses were mentioned in almost half of the literatures.The cost of the drug was mentioned in only 10% of literatures. Dikshit and Dikshit found that the Indian issue of the Monthly Index of Medical Specialities (MIMS) did not seem to follow the code of the IFPMA. Steps can be taken by regional ethics comitee (Mumbai , New Delhi, Chennai, and Chandigarh) /drug controller authority.( Gopalakrishnan and Murali , 2002 ). Responsibilty of the physician to critically evaluate & properly report.

48. Bibliography 1.World Health Organization (WHO). 1988. Ethical criteria for medicinal drug promotion. Available at: http://www.who.int/medicinedocs/collect/edmweb/pdf/whozip08e/whozip08e.pdf . 2. Organization of Pharmaceutical Producers of India (OPPI ).2012 . OPPI code of pharmaceutical marketing practices. Available at: http :// www.indiaoppi.com/OPPI%20Code%20of%20Pharmaceutical%20Practices%20%20- %202012.pdf . 3. International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) . 2012. IFPMA code of practice. Available at: http:// www.ifpma.org/fileadmin/content/Publication/2012/IFPMA_Code_of_Practice_2012_new_logo.pdf 4. Gopalakrishnan S, Murali R. 2002. India: Campaign to tackle unethical promotion. Essential drugs monitor. [ONLINE]. Available at:http ://www.apps.who.int/medicinedocs/pdf/s4937e/s4937e.pdf.

49. Contd …….. 5. Rohra DK, Gilani AH, Memon IK, Perven G, Khan MT, Zafar H , Kumar R. Critical evaluation of claims made by pharmaceutical companies in drug promotional material in Pakistan. J Pharm Pharmaceut Sci , 2006; 9:50–9 . 6. Cooper RJ, Schriger DL. The availability of references and the sponsorship of original research cited in pharmaceutical advertisements.CMAJ , 2005; 172: 487–91 7. Oxford Centre for Evidence-based Medicine – Levels of Evidence. 8. Medhi B, Prakash A. 2010. Ideal characteristics of promotional literature . In: Medhi B and Prakash A, ed. Practical Manual of Experimental and Clinical Pharmacology. 1st edition. India: JBPMP 342-45.

50. Let us assess this dpl s ………………… Exercise……………

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