HOW TO CRITICALLY APPRAISE A DPL

1. Dr.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-
1. Promotion to health care professional
2. Promotion to general public.

6. Contd……………
 Aids-
1. literature: scientific paper,leaflet,brochure,drug
reminder etc.
2. Audio-visual aid.
3. Gift item:pen ,paper weight,date calender,notepad.
4. Media: television,internet.
5. visual aid:banner,hording.
6. Direct mailing.
7. 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 the Forty-first World Health Assembly(13 may,1988).
 Objective: To 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.
 Do 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.
 Adopted 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
 Capable 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?
1. The disease
2. The patient
3. The need
4. The comparator.
5. Outcome of interest: disease oriented/patient
oriented(morbidity/mortality/quality of life/cost)
6. Methodology & statistics.: CI around the mean is a better
parameter than p value in estimating the clinical outcome.
7. 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 (cefaclor): “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 ; Yogesh a garje ,Baliram v Ghodke;
Indian journal of applied research, Feb 2014. Volume : 4 | Issue : 2
 Evaluation of promotional drug literature as per 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
DPLs…………………
Exercise……………

51. 51