Abstracts

INTRODUCTION

The readability of the package leaflets is an essential issue for the safety and rational use of medicines after they are prescribed or dispensed in pharmacies. Patients may independently consult the package leaflets to clarify their doubts, such as information on medicine administration.²¹21 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030^,2222 March Cerdá JC, Prieto Rodríguez MA, Ruiz Azarola A, Lorda PS, Barrio Cantalejo I, Danet A. Mejora de la información sanitaria contenida en los prospectos de los medicamentos: expectativas de pacientes y de profesionales sanitarios. Aten Primaria. 2010;42(1):22-7. DOI:10.1016/j.aprim.2009.04.006^,2525 Shiffman S, Gerlach KK, Sembower MA, Rohay JM. Consumer understanding of prescription drug information: an illustration using an antidepressant medication. Ann Pharmacother. 2011;45(4):452-8. DOI:10.1345/aph.1P477

The inclusion of package leaflets inside all medicine packages is obligatory in the European Union.^aaEuropean Parliament and the Council. Directive 2001/83/EC: community code relating to medicinal products for human use. Brussels; 6 Nov 2001 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf In accordance with regulations,²⁹29 Wolf A, Fuchs J, Schweim HG. QRD template texts intended for package inserts: development from the first QRD template up to the new draft of July 2012. Pharm Ind. 2012;74(9):1540-9. the package leaflets must be organized in pre-defined sections^bb European Medicine Agency. Quality review of documents human product-information annotated template. Version 9. London; 2013 [cited 2013 Oct 13]. Available from:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000134.jspp and written in a clear and comprehensible way.^cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf

The European template on the content of the package leaflets is the Quality Review of Documents (QRD).^bb European Medicine Agency. Quality review of documents human product-information annotated template. Version 9. London; 2013 [cited 2013 Oct 13]. Available from:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000134.jspp This template was updated several times since the first version was published (1996).²⁹29 Wolf A, Fuchs J, Schweim HG. QRD template texts intended for package inserts: development from the first QRD template up to the new draft of July 2012. Pharm Ind. 2012;74(9):1540-9. According to the 9^thversion of QRD,^bb European Medicine Agency. Quality review of documents human product-information annotated template. Version 9. London; 2013 [cited 2013 Oct 13]. Available from:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000134.jspp the package leaflets should be organized as follows:

1. What X (X = name of the medicine) is and its indicated use;

2. What you need to know before you <take> <use> X;

3. How to <take> <use> X;

4. Possible side effects;

5. How to store X;

6. Contents of the pack and other information.

The results of legibility and usability^cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf tests are used to prove the simplicity, clarity, and comprehensibility of the information on the package leaflets for the medicine users.²¹21 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030^,2525 Shiffman S, Gerlach KK, Sembower MA, Rohay JM. Consumer understanding of prescription drug information: an illustration using an antidepressant medication. Ann Pharmacother. 2011;45(4):452-8. DOI:10.1345/aph.1P477 The guideline on the readability of the labeling and package leaflet of medicinal products for human use (European commission, 1998) was the first on this issue in Europe and is used by the European Medicine Agency.^cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf According to the general principles of these guideline,^aaEuropean Parliament and the Council. Directive 2001/83/EC: community code relating to medicinal products for human use. Brussels; 6 Nov 2001 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf^,cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf a questionnaire should be administered to at least 20 patients, preferentially from the population for which the medicinal product is intended. Healthcare professionals should not participate in legibility tests^cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf^,dd The Heads of Medicines Agencies, Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human. Position paper on user testing of package leaflet – consultation with target patient groups. 2011 [cited 2013 Oct 27]. Available from: http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Consulation_PatientsGroups/CMDh_234_2011.pdf so as to not bias the results. In contrast, it is advisable that geriatric and less proficient patients participate in these tests because these subjects usually present more difficulties in reading and interpreting documents.¹⁴14 Gazmarariana JA, Williams MV, Peelc J, Bakerd DW. Health literacy and knowledge of chronic disease. Patient Educ Couns. 2003;51(3):267-75. DOI:10.1016/S0738-3991(02)00239-2 The main topics of the package leaflets (indications or contraindications) are commonly selected to be examined.^cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf The aims of these tests are to identify problems with the location and comprehension of the information on package leaflets, and if necessary, to optimize the package leaflets^cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf and repeat the tests (retests).²¹21 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030^,2525 Shiffman S, Gerlach KK, Sembower MA, Rohay JM. Consumer understanding of prescription drug information: an illustration using an antidepressant medication. Ann Pharmacother. 2011;45(4):452-8. DOI:10.1345/aph.1P477 The package leaflets are considered acceptable when the participants obtain at least 90.0% of answers.^dd The Heads of Medicines Agencies, Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human. Position paper on user testing of package leaflet – consultation with target patient groups. 2011 [cited 2013 Oct 27]. Available from: http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Consulation_PatientsGroups/CMDh_234_2011.pdf

Although the medical authorities of each European country evaluate the legibility of package leaflets before their approval,²2 Calamusa A, Di Marzio A, Cristofani R, Arrighetti P, Santaniello V, Alfani S, et al. Factors that influence Italian consumers’ understanding of over-the-counter medicines and risk perception. Patient Educ Couns. 2012;87(3):395-401. DOI:10.1016/j.pec.2011.10.003 sometimes these documents are not adequately understood [e.g., dosage or adverse drug reactions (ADR)]. This is particularly bad for low-literate patients.²¹21 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030^,2525 Shiffman S, Gerlach KK, Sembower MA, Rohay JM. Consumer understanding of prescription drug information: an illustration using an antidepressant medication. Ann Pharmacother. 2011;45(4):452-8. DOI:10.1345/aph.1P477

The objective of the present study was to review studies on the readability of package leaflets of medicinal products for human use.

METHODS

Systematic review. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) criteria were used to organize the report on the selected studies.^ee Critérios Prisma - Transparent reporting of systematic reviews and meta-analysis; 2013 [cited 2013 Aug 16]. Available from: http://www.prisma-statement.org/ The studies were conducted between January 1, 2008 and February 24, 2013 (five years and two months), with the aim of including recent investigations and pharmaceutical regulatory updates.^cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf

The study keywords were “readability and package leaflet” or “readability and package insert” separated by the Boolean operator “and”. The selection of both designations followed from the fact that the designation “package leaflet” is more common in European countries^cc European Medicine Agency. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. London; 2009 [cited 2013 Aug 12]. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf^,dd The Heads of Medicines Agencies, Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human. Position paper on user testing of package leaflet – consultation with target patient groups. 2011 [cited 2013 Oct 27]. Available from: http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Consulation_PatientsGroups/CMDh_234_2011.pdf and “package insert” is used outside Europe.²⁰20 Leiderman DB. Risk management of drug products and the U.S. Food and Drug Administration: evolution and context. Drug Alcohol Depend. 2009;105(Suppl 1):S9-13. DOI:10.1016/j.drugalcdep.2009.02.007^,ff Australian Governament, Department of Health and Ageing, Therapeutic Good Administration. Mechanisms to maintain the currency of approved Product Information (PI) and Consumer Medicine Information (CMI): public consultation paper. Version 2013 [cited 2013 Aug 12]. Available from: https://www.google.pt/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=0CDsQFjAB&url=http%3A%2F%2Fwww.tga.gov.au%2Fword%2Fconsult%2Fconsult-opr-currency-pi-cmi-130513.docx&ei=fwdtUvenA_Op7Ab7ooHoDg&usg=AFQjCNHhjdYSrmN2s0muwVNMjwVS6UEu0w&sig2=Jtp7FfAdBJYD2oaORlX4zg&bvm=bv.55123115,d.ZG4&cad=rjtg

The search was performed using the academic search engine, Biblioteca do Conhecimento Online (b-on).^gg B On: Biblioteca do conhecimento online. Lisboa: Fundação para a Computação Nacional; 2013 [cited 2013 Aug 12]. Available from: http://www.b-on.pt/ This tool allows access to thousands of scientific journals and concurrent searches in different databases and bibliographic databases, including BioMed Central,^hh BMC: BioMed Central the open access publisher; 2014 [cited 2014 Dec 2]. Available from: http://www.biomedcentral.comBioOne,ⁱi BioOne online journals; 2014 [cited 2014 Dec 2]. Available from: http://www.bioone.org/ Bioline International,^jj Bioline International; 2014 [cited 2014 Dec 2]. Available from: http://www.bioline.org.br/ Directory of Open Access Journals,^kk DOAJ: Directory of Open Access Journals; 2014 [cited 2014 Dec 2]. Available from: http://doaj.org/ Medical Literature Analysis and Retrieval System Online (Medline),^ll MEDLINE: Medical Literature Analysis and Retrieval System Online. Bethesda (MD): US National Library of Medicine; [s.d.]. [cited 2014 Jul 28]. Available from:http://www.ncbi.nlm.nih.gov/IEB/ToolBox/SDKDOCS/MEDLINE.HTML United States National Library of Medicine National Institutes of Health (PubMed),^mm PubMed: the bibliographic database of the United States National Library of Medicine National Institutes of Health [Internet]. Bethesda (MD): National Library of Medicine. [1946] - [cited 2014 Jul 27]. Available from: http://www.ncbi.nlm.nih.gov/pubmed Scientific Electronic Library Online (Scielo Global),ⁿn SciELO: Scientific Electronic Library Online [Internet]. São Paulo (BR): Bireme/OPS/FAPESP/CNPq. [1998]. [cited 2014 Jul 28]. Available from: http://www.scielo.org/php/index.php?lang=en Elsevier^oo Elsevier; 2014 [cited 2014 Dec 2]. Available from: http://www.elsevier.com/ and SpringerLink.^pp SpringerLink; 2014 [cited 2014 Dec 2]. Available from: http://link.springer.com/ Moreover, two complementary searches were performed. One used PubMed to confirm the existence of additional results, and the other used the Cochrane Collaboration Reviews^qq Cochrane collaboration reviews; 2014 [cited 2014 Dec 2]. Available from:http://www.cochrane.org/cochrane-reviewsto confirm the existence of other reviews on this topic, which contributed to validate the interest and relevance of this review. All the review results are properly archived and available for future consultations. The inclusion and exclusion criteria are described in Table 1.

The repeated references were automatically identified using EndNoteWeb (a management references program).^rr EndnoteWeb. New York: Thomson Reuters; 2013 [cited 2013 Aug 12]. Available from:https://www.myendnoteweb.com/EndNoteWeb.html?SID=P2g6anKIJyF54XPliP4&returnCode=ROUTER.Success&SrcApp=CR&Init=Yes The main findings of the selected studies were summarized and organized into a tabular format (objectives, methods, results, and conclusions). The selected studies were divided into the following two categories. The first category comprised exploratory studies (studies with the participation of health professionals or patients), and the second was descriptive studies or studies involving non-enrolling participants (studies using legibility formulas or investigating the linguistic characteristics of texts). In particular, the studies on the readability of ADR were described and analyzed because of the importance of this issue for patient safety.²⁹29 Wolf A, Fuchs J, Schweim HG. QRD template texts intended for package inserts: development from the first QRD template up to the new draft of July 2012. Pharm Ind. 2012;74(9):1540-9. The selected studies were classified as follows:

1. Exploratory studies specifically enrolling health professionals;

2. Exploratory studies enrolling patients (or potential users of medicines), such as studies on comprehension of ADR (readability/usability tests) by patients;

3. Descriptive studies (studies using non-enrolled participants, i.e., all the non-experimental studies) on the readability of package leaflets, including studies that evaluate the number of words, length of phrases, or letter type.

Overall, the selected studies were comparatively analyzed. The main findings, potential limitations, and the opportunity for future work were evaluated and registered.

RESULTS AND DISCUSSION

Twenty-two studies out of the 202 were selected and comprised 16 full papers, three brief communications, and three indexed abstracts. The number of included and excluded studies are presented in Table 2 in addition to different keywords and search tools. The flowchart is organized using the PRISMA^ff Australian Governament, Department of Health and Ageing, Therapeutic Good Administration. Mechanisms to maintain the currency of approved Product Information (PI) and Consumer Medicine Information (CMI): public consultation paper. Version 2013 [cited 2013 Aug 12]. Available from: https://www.google.pt/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=0CDsQFjAB&url=http%3A%2F%2Fwww.tga.gov.au%2Fword%2Fconsult%2Fconsult-opr-currency-pi-cmi-130513.docx&ei=fwdtUvenA_Op7Ab7ooHoDg&usg=AFQjCNHhjdYSrmN2s0muwVNMjwVS6UEu0w&sig2=Jtp7FfAdBJYD2oaORlX4zg&bvm=bv.55123115,d.ZG4&cad=rjtg criteria, representing the exclusion reasons (Figure). None of the studies on the topics under review was found in the database of Cochrane Collaboration Reviews, confirming the interest in this review.

The main aspects (objectives, methods, results, and conclusions) of the selected studies are summarized in Table 3. The 22 selected studies were distributed as follows: two in Group A (exploratory studies enrolling health professionals), 12 in Group B (exploratory studies enrolling patients or potential patients who will use the medicines), and eight in Group C (descriptive studies).

Overall, few studies on the readability of the package leaflets were identified compared to a search in PubMed using the search term, “patient information”, which identified 6,357 search results on October 13, 2013.

Exploratory studies enrolling health professionals, patients or potential users of medicines

In the two exploratory studies (group A),⁵5 Cavaco A, Pires C. Improving package leaflet information: potential users and physicians opinions [abstract]. Res Soc Adm Pharm. 2012;8(6);e50-1. DOI:10.1016/j.sapharm.2012.08.117^,2222 March Cerdá JC, Prieto Rodríguez MA, Ruiz Azarola A, Lorda PS, Barrio Cantalejo I, Danet A. Mejora de la información sanitaria contenida en los prospectos de los medicamentos: expectativas de pacientes y de profesionales sanitarios. Aten Primaria. 2010;42(1):22-7. DOI:10.1016/j.aprim.2009.04.006 wherein healthcare professionals (physicians or pharmacists) participated, it was reported that the healthcare professionals were satisfied with the information in the leaflets. They considered the information in the package leaflets more important than did the actual patients (or potential patients) who required the medicines. In contrast, the patients (or potential patients) who would be using the medicines expressed their preferences for receiving personal explanations on the use of medicines during consultations. One reason for this was due to the high prevalence of technical terms in the package leaflets. Only two studies with healthcare professionals were identified in this revision, although these studies were important to validate the optimized package leaflets.⁵5 Cavaco A, Pires C. Improving package leaflet information: potential users and physicians opinions [abstract]. Res Soc Adm Pharm. 2012;8(6);e50-1. DOI:10.1016/j.sapharm.2012.08.117^,2222 March Cerdá JC, Prieto Rodríguez MA, Ruiz Azarola A, Lorda PS, Barrio Cantalejo I, Danet A. Mejora de la información sanitaria contenida en los prospectos de los medicamentos: expectativas de pacientes y de profesionales sanitarios. Aten Primaria. 2010;42(1):22-7. DOI:10.1016/j.aprim.2009.04.006

From the twelve exploratory studies with patients (or potential patients) receiving medicines (group B), ten were conducted to evaluate participant comprehension (usability and/or legibility tests,¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,22 Calamusa A, Di Marzio A, Cristofani R, Arrighetti P, Santaniello V, Alfani S, et al. Factors that influence Italian consumers’ understanding of over-the-counter medicines and risk perception. Patient Educ Couns. 2012;87(3):395-401. DOI:10.1016/j.pec.2011.10.003^,66 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019^,88 Dowse R, Ramela T, Browne SH. An illustrated leaflet containing antiretroviral information targeted for low-literate readers: development and evaluation. Patient Educ Couns. 2011;85(3):508-15. DOI:10.1016/j.pec.2011.01.013^,1111 Franck MCJ, Foulon V, Van Vaerenbergh L. ABOP, the automatic patient information leaflet optimizer: evaluation of a tool in development.Patient Educ Couns. 2011;83(3):411-6. DOI:10.1016/j.pec.2011.04.025^,1212 Fuchs J. The way forward in package insert user tests from a CRO’s perspective. Drug Inf J. 2010;44(2):119-29. DOI:10.1177/009286151004400203^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x^,2121 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030^,2525 Shiffman S, Gerlach KK, Sembower MA, Rohay JM. Consumer understanding of prescription drug information: an illustration using an antidepressant medication. Ann Pharmacother. 2011;45(4):452-8. DOI:10.1345/aph.1P477^,2626 Symonds T, Dean J, Coyne KS, Margolis MK, Hackett G, Edwards D, et al. The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials. J Sex Med. 2010;7(6):2217-25. DOI:10.1111/j.1743-6109.2010.01767.x or studies to specifically evaluate participant comprehension of the manner in which ADR were presented.¹⁸18 Knapp P, Raynor DK, Woolf E, Gardner PH, Carrigan N, McMillan B. Communicating the risk of side effects to patients: an evaluation of UK regulatory recommendations. Drug Safety. 2009;32(10):837-49. DOI:10.2165/11316570-000000000-00000^,1717 Knapp P, Gardner PH, Raynor DK, Woolf E, McMillan B. Perceived risk of tamoxifen side effects: a study of the use of absolute frequencies or frequency bands, with or without verbal descriptors. Patient Educ Couns. 2010;79(2):267-71. DOI:10.1016/j.pec.2009.10.002

The main problems identified in these 10 studies were patient (or potential patient) comprehension issues as some topics were poorly understood;²2 Calamusa A, Di Marzio A, Cristofani R, Arrighetti P, Santaniello V, Alfani S, et al. Factors that influence Italian consumers’ understanding of over-the-counter medicines and risk perception. Patient Educ Couns. 2012;87(3):395-401. DOI:10.1016/j.pec.2011.10.003^,1111 Franck MCJ, Foulon V, Van Vaerenbergh L. ABOP, the automatic patient information leaflet optimizer: evaluation of a tool in development.Patient Educ Couns. 2011;83(3):411-6. DOI:10.1016/j.pec.2011.04.025^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x^,2525 Shiffman S, Gerlach KK, Sembower MA, Rohay JM. Consumer understanding of prescription drug information: an illustration using an antidepressant medication. Ann Pharmacother. 2011;45(4):452-8. DOI:10.1345/aph.1P477^,2626 Symonds T, Dean J, Coyne KS, Margolis MK, Hackett G, Edwards D, et al. The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials. J Sex Med. 2010;7(6):2217-25. DOI:10.1111/j.1743-6109.2010.01767.x too complex texts, indicating the necessity of optimizing and simplifying the package leaflets;¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,1111 Franck MCJ, Foulon V, Van Vaerenbergh L. ABOP, the automatic patient information leaflet optimizer: evaluation of a tool in development.Patient Educ Couns. 2011;83(3):411-6. DOI:10.1016/j.pec.2011.04.025^,1212 Fuchs J. The way forward in package insert user tests from a CRO’s perspective. Drug Inf J. 2010;44(2):119-29. DOI:10.1177/009286151004400203^,2121 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030 and package leaflets not properly adapted for the low-literate patients, indicating the need to use simpler language.¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,66 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019^,88 Dowse R, Ramela T, Browne SH. An illustrated leaflet containing antiretroviral information targeted for low-literate readers: development and evaluation. Patient Educ Couns. 2011;85(3):508-15. DOI:10.1016/j.pec.2011.01.013^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x

The majority of the reviewed readability studies used package leaflets of specific medicines, including sildenafil, clozapine, acetaminophen, and diclofenac.¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,66 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x^,2626 Symonds T, Dean J, Coyne KS, Margolis MK, Hackett G, Edwards D, et al. The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials. J Sex Med. 2010;7(6):2217-25. DOI:10.1111/j.1743-6109.2010.01767.x It is likely that these package leaflets were selected for the following reasons: the straight therapeutic indices of some medicines such as clozapine,¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038over-the-counter medicines (no prescription necessary), such as diclofenac and acetaminophen, and highly utilized medicines such as acetaminophen.⁶6 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x The package leaflets of these medicines are more likely to be consulted. Therefore, it is difficult to generalize about or extend conclusions of these studies to the package leaflets of medicines with different active ingredients. The study on the automatic simplification of the technical terms was considered particularly relevant because an automatic methodology was used to simplify diverse package leaflets at the same time. In this study, an informatics tool was used, and the technical terms of the package leaflets were identified. More common and equivalent terms were then found in pre-defined lexical databases and finally, the original terms were automatically replaced by the more common terms.¹¹11 Franck MCJ, Foulon V, Van Vaerenbergh L. ABOP, the automatic patient information leaflet optimizer: evaluation of a tool in development.Patient Educ Couns. 2011;83(3):411-6. DOI:10.1016/j.pec.2011.04.025

Diverse limitations were identified in these studies¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,22 Calamusa A, Di Marzio A, Cristofani R, Arrighetti P, Santaniello V, Alfani S, et al. Factors that influence Italian consumers’ understanding of over-the-counter medicines and risk perception. Patient Educ Couns. 2012;87(3):395-401. DOI:10.1016/j.pec.2011.10.003^,66 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019^,88 Dowse R, Ramela T, Browne SH. An illustrated leaflet containing antiretroviral information targeted for low-literate readers: development and evaluation. Patient Educ Couns. 2011;85(3):508-15. DOI:10.1016/j.pec.2011.01.013^,11 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,1212 Fuchs J. The way forward in package insert user tests from a CRO’s perspective. Drug Inf J. 2010;44(2):119-29. DOI:10.1177/009286151004400203^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x^,2121 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030^,2525 Shiffman S, Gerlach KK, Sembower MA, Rohay JM. Consumer understanding of prescription drug information: an illustration using an antidepressant medication. Ann Pharmacother. 2011;45(4):452-8. DOI:10.1345/aph.1P477^,22 Calamusa A, Di Marzio A, Cristofani R, Arrighetti P, Santaniello V, Alfani S, et al. Factors that influence Italian consumers’ understanding of over-the-counter medicines and risk perception. Patient Educ Couns. 2012;87(3):395-401. DOI:10.1016/j.pec.2011.10.003⁶6 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019and were categorized as follows: high diversity of methods, limited number of participants, lack of certain assessments (such as the evaluation of participant literacy, humor, cognitive state, and satisfaction), lack of multicenter or longitudinal studies, lack of studies on specific topics such as contra-indications and precautions, study of the package leaflets from a limited number of medicines and active ingredients,¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,66 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x^,2626 Symonds T, Dean J, Coyne KS, Margolis MK, Hackett G, Edwards D, et al. The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials. J Sex Med. 2010;7(6):2217-25. DOI:10.1111/j.1743-6109.2010.01767.x and lack of pictograms (useful for low-literate patients) or other illustrations.⁸8 Dowse R, Ramela T, Browne SH. An illustrated leaflet containing antiretroviral information targeted for low-literate readers: development and evaluation. Patient Educ Couns. 2011;85(3):508-15. DOI:10.1016/j.pec.2011.01.013^,2424 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087 A few authors reported that the study limitations were contrary to good clinical practices, increasing the difficulty of precisely analyzing the results.

Studies on comprehension of adverse drug reactions

The presentation of ADR was particularly relevant in two studies (group B) because the patient comprehension of ADR strongly depended on the way ADR were presented.¹⁸18 Knapp P, Raynor DK, Woolf E, Gardner PH, Carrigan N, McMillan B. Communicating the risk of side effects to patients: an evaluation of UK regulatory recommendations. Drug Safety. 2009;32(10):837-49. DOI:10.2165/11316570-000000000-00000^,1717 Knapp P, Gardner PH, Raynor DK, Woolf E, McMillan B. Perceived risk of tamoxifen side effects: a study of the use of absolute frequencies or frequency bands, with or without verbal descriptors. Patient Educ Couns. 2010;79(2):267-71. DOI:10.1016/j.pec.2009.10.002 ADR were described in different manners in these studies. These ADR were described using qualitative descriptors (very common ADR) or quantitative descriptors (adverse reactions with a likelihood of 1.0%-10.0%).¹⁸18 Knapp P, Raynor DK, Woolf E, Gardner PH, Carrigan N, McMillan B. Communicating the risk of side effects to patients: an evaluation of UK regulatory recommendations. Drug Safety. 2009;32(10):837-49. DOI:10.2165/11316570-000000000-00000 Further, it was found that patients preferred numerically expressed ADR (using absolute frequencies)¹⁸18 Knapp P, Raynor DK, Woolf E, Gardner PH, Carrigan N, McMillan B. Communicating the risk of side effects to patients: an evaluation of UK regulatory recommendations. Drug Safety. 2009;32(10):837-49. DOI:10.2165/11316570-000000000-00000^,1717 Knapp P, Gardner PH, Raynor DK, Woolf E, McMillan B. Perceived risk of tamoxifen side effects: a study of the use of absolute frequencies or frequency bands, with or without verbal descriptors. Patient Educ Couns. 2010;79(2):267-71. DOI:10.1016/j.pec.2009.10.002 and considered the use of fractions (≥ 1/100) to be difficult to understand when the ADR frequency³3 Carrigan N, Raynor DK, Knapp P. Adequacy of patient information on adverse effects: an assessment of patient information leaflets in the UK.Drug Safety. 2008;31(4):305-12. DOI:10.114-5916/08/0004-0305/$548.00/0^,1717 Knapp P, Gardner PH, Raynor DK, Woolf E, McMillan B. Perceived risk of tamoxifen side effects: a study of the use of absolute frequencies or frequency bands, with or without verbal descriptors. Patient Educ Couns. 2010;79(2):267-71. DOI:10.1016/j.pec.2009.10.002^,1818 Knapp P, Raynor DK, Woolf E, Gardner PH, Carrigan N, McMillan B. Communicating the risk of side effects to patients: an evaluation of UK regulatory recommendations. Drug Safety. 2009;32(10):837-49. DOI:10.2165/11316570-000000000-00000^,2727 Wallace LS, Keenum AJ, Roskos SE, Blake GH, Colwell ST, Weiss BD. Suitability and readability of consumer medical information accompanying prescription medication samples. Patient Educ Couns. 2007;70(3):420-5. DOI:10.1016/j.pec.2007.11.017 was presented in this manner.

In general, the section of the package leaflets on ADR was compliant with the recommendations of the QRD.³3 Carrigan N, Raynor DK, Knapp P. Adequacy of patient information on adverse effects: an assessment of patient information leaflets in the UK.Drug Safety. 2008;31(4):305-12. DOI:10.114-5916/08/0004-0305/$548.00/0^,11 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038⁷7 Dale E, Chall J. A formula for predicting readability. Educ Res Bull. 1948;27(1):11-20, 37-54.^,1818 Knapp P, Raynor DK, Woolf E, Gardner PH, Carrigan N, McMillan B. Communicating the risk of side effects to patients: an evaluation of UK regulatory recommendations. Drug Safety. 2009;32(10):837-49. DOI:10.2165/11316570-000000000-00000^,2929 Wolf A, Fuchs J, Schweim HG. QRD template texts intended for package inserts: development from the first QRD template up to the new draft of July 2012. Pharm Ind. 2012;74(9):1540-9.^,bb European Medicine Agency. Quality review of documents human product-information annotated template. Version 9. London; 2013 [cited 2013 Oct 13]. Available from:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000134.jspp According to the requirements of the QRD template, ADR are presented in an ordered list of values (from the more to less frequent ADR). For example, a “common” ADR may affect up to 1 in 10 people, and “uncommon” ADR may affect up to 1 in 100 people.²⁹29 Wolf A, Fuchs J, Schweim HG. QRD template texts intended for package inserts: development from the first QRD template up to the new draft of July 2012. Pharm Ind. 2012;74(9):1540-9.

The number of studies specifically concerned with the most appropriate way to present ADR and the number of participants enrolled in these studies were limited.

Descriptive studies

The eight descriptive studies³3 Carrigan N, Raynor DK, Knapp P. Adequacy of patient information on adverse effects: an assessment of patient information leaflets in the UK.Drug Safety. 2008;31(4):305-12. DOI:10.114-5916/08/0004-0305/$548.00/0^,44 Cavaco AM, Várzea D. Contribuição para o estudo da leitura de folhetos informativos nas farmácias portuguesas. Rev Port Saude Publica. 2010;28(2):179-86. DOI:10.1016/S0870-9025(10)70009-2^,1313 Fuchs J, Werner S, Scheunpflug C, Götze EA, Elstermann K, Scheffel K, et al. Excessive medical information increase in package inserts. Int J Clin Pharmacol Ther. 2010;48(12):781-90. DOI:10.5414/CPP48781^,2323 Pinero-Lopez MA, Modamio P, Lastra CF, Marino EL. Readability levels of patient package inserts for biopharmaceuticals [abstract]. Int J Clin Pharm. 2011;33(4):715-6. DOI:10.1007/s11096-011-9523-0^,2424 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087^,2727 Wallace LS, Keenum AJ, Roskos SE, Blake GH, Colwell ST, Weiss BD. Suitability and readability of consumer medical information accompanying prescription medication samples. Patient Educ Couns. 2007;70(3):420-5. DOI:10.1016/j.pec.2007.11.017^,2828 Weiss SM, Smith-Simone SY. Consumer and health literacy: the need to better design tobacco-cessation product packaging, labels, and inserts.Am J Prev Med. 2010;38(3 Suppl):S403-13. DOI:10.1016/j.amepre.2009.11.020^,3030 Zite NB, Wallace LS. Do instructions for over-the-counter pre-coital female contraceptives promote “perfect use”? Contraception. 2008;79(3):211-5. DOI:10.1016/j.contraception.2008.10.002 (or studies with non-enrolled participants) on the usability of the package leaflets (group C) focused on the following aspects:³3 Carrigan N, Raynor DK, Knapp P. Adequacy of patient information on adverse effects: an assessment of patient information leaflets in the UK.Drug Safety. 2008;31(4):305-12. DOI:10.114-5916/08/0004-0305/$548.00/0^,44 Cavaco AM, Várzea D. Contribuição para o estudo da leitura de folhetos informativos nas farmácias portuguesas. Rev Port Saude Publica. 2010;28(2):179-86. DOI:10.1016/S0870-9025(10)70009-2^,1313 Fuchs J, Werner S, Scheunpflug C, Götze EA, Elstermann K, Scheffel K, et al. Excessive medical information increase in package inserts. Int J Clin Pharmacol Ther. 2010;48(12):781-90. DOI:10.5414/CPP48781^,2323 Pinero-Lopez MA, Modamio P, Lastra CF, Marino EL. Readability levels of patient package inserts for biopharmaceuticals [abstract]. Int J Clin Pharm. 2011;33(4):715-6. DOI:10.1007/s11096-011-9523-0^,2424 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087^,2727 Wallace LS, Keenum AJ, Roskos SE, Blake GH, Colwell ST, Weiss BD. Suitability and readability of consumer medical information accompanying prescription medication samples. Patient Educ Couns. 2007;70(3):420-5. DOI:10.1016/j.pec.2007.11.017^,2828 Weiss SM, Smith-Simone SY. Consumer and health literacy: the need to better design tobacco-cessation product packaging, labels, and inserts.Am J Prev Med. 2010;38(3 Suppl):S403-13. DOI:10.1016/j.amepre.2009.11.020^,3030 Zite NB, Wallace LS. Do instructions for over-the-counter pre-coital female contraceptives promote “perfect use”? Contraception. 2008;79(3):211-5. DOI:10.1016/j.contraception.2008.10.002 (i) use of legibility formulas, such as Flesch-Kincaid or Fry to calculate values on the association between the linguistic characteristic of texts and the education level of patients (linguistic metrics),⁴4 Cavaco AM, Várzea D. Contribuição para o estudo da leitura de folhetos informativos nas farmácias portuguesas. Rev Port Saude Publica. 2010;28(2):179-86. DOI:10.1016/S0870-9025(10)70009-2^,2323 Pinero-Lopez MA, Modamio P, Lastra CF, Marino EL. Readability levels of patient package inserts for biopharmaceuticals [abstract]. Int J Clin Pharm. 2011;33(4):715-6. DOI:10.1007/s11096-011-9523-0^,2424 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087^,2727 Wallace LS, Keenum AJ, Roskos SE, Blake GH, Colwell ST, Weiss BD. Suitability and readability of consumer medical information accompanying prescription medication samples. Patient Educ Couns. 2007;70(3):420-5. DOI:10.1016/j.pec.2007.11.017^,2828 Weiss SM, Smith-Simone SY. Consumer and health literacy: the need to better design tobacco-cessation product packaging, labels, and inserts.Am J Prev Med. 2010;38(3 Suppl):S403-13. DOI:10.1016/j.amepre.2009.11.020^,3030 Zite NB, Wallace LS. Do instructions for over-the-counter pre-coital female contraceptives promote “perfect use”? Contraception. 2008;79(3):211-5. DOI:10.1016/j.contraception.2008.10.002 (ii) identification of specific linguistic characteristics (e.g., number of difficult words or phrases) to obtain indirect indicators on the proper readability of texts;³3 Carrigan N, Raynor DK, Knapp P. Adequacy of patient information on adverse effects: an assessment of patient information leaflets in the UK.Drug Safety. 2008;31(4):305-12. DOI:10.114-5916/08/0004-0305/$548.00/0 and (iii) evaluation of graphical aspects that facilitate the understanding of information (e.g., letter size or presence of illustrations).²⁴24 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087^,2727 Wallace LS, Keenum AJ, Roskos SE, Blake GH, Colwell ST, Weiss BD. Suitability and readability of consumer medical information accompanying prescription medication samples. Patient Educ Couns. 2007;70(3):420-5. DOI:10.1016/j.pec.2007.11.017^,3030 Zite NB, Wallace LS. Do instructions for over-the-counter pre-coital female contraceptives promote “perfect use”? Contraception. 2008;79(3):211-5. DOI:10.1016/j.contraception.2008.10.002

Overall, the application of the descriptive methodologies confirmed a low readability of the package leaflets and the need to simplify the texts. The factors that decrease the readability of the package leaflets were evident in some studies and included the following: too complex texts (e.g., some package leaflets were classified as appropriate for readers with 10 or more years of education, instead of the five years recommended by Food and Drug Administration);^ss Food and Drug Administration: Guidance for Industry – Label comprehension studies for Nonprescription Drug Products; 2014 [cited 2010 Dec 2]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm143834.pdf omission of relevant technical information (e.g., maximum daily dose,³3 Carrigan N, Raynor DK, Knapp P. Adequacy of patient information on adverse effects: an assessment of patient information leaflets in the UK.Drug Safety. 2008;31(4):305-12. DOI:10.114-5916/08/0004-0305/$548.00/0^,44 Cavaco AM, Várzea D. Contribuição para o estudo da leitura de folhetos informativos nas farmácias portuguesas. Rev Port Saude Publica. 2010;28(2):179-86. DOI:10.1016/S0870-9025(10)70009-2^,1313 Fuchs J, Werner S, Scheunpflug C, Götze EA, Elstermann K, Scheffel K, et al. Excessive medical information increase in package inserts. Int J Clin Pharmacol Ther. 2010;48(12):781-90. DOI:10.5414/CPP48781^,2323 Pinero-Lopez MA, Modamio P, Lastra CF, Marino EL. Readability levels of patient package inserts for biopharmaceuticals [abstract]. Int J Clin Pharm. 2011;33(4):715-6. DOI:10.1007/s11096-011-9523-0^,2424 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087^,2727 Wallace LS, Keenum AJ, Roskos SE, Blake GH, Colwell ST, Weiss BD. Suitability and readability of consumer medical information accompanying prescription medication samples. Patient Educ Couns. 2007;70(3):420-5. DOI:10.1016/j.pec.2007.11.017^,2828 Weiss SM, Smith-Simone SY. Consumer and health literacy: the need to better design tobacco-cessation product packaging, labels, and inserts.Am J Prev Med. 2010;38(3 Suppl):S403-13. DOI:10.1016/j.amepre.2009.11.020^,3030 Zite NB, Wallace LS. Do instructions for over-the-counter pre-coital female contraceptives promote “perfect use”? Contraception. 2008;79(3):211-5. DOI:10.1016/j.contraception.2008.10.002 extensive use of technical words¹³13 Fuchs J, Werner S, Scheunpflug C, Götze EA, Elstermann K, Scheffel K, et al. Excessive medical information increase in package inserts. Int J Clin Pharmacol Ther. 2010;48(12):781-90. DOI:10.5414/CPP48781 or small letters (e.g., letters with a font size of < 11;²⁴24 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087^,2727 Wallace LS, Keenum AJ, Roskos SE, Blake GH, Colwell ST, Weiss BD. Suitability and readability of consumer medical information accompanying prescription medication samples. Patient Educ Couns. 2007;70(3):420-5. DOI:10.1016/j.pec.2007.11.017 and lack of illustrations.²⁴24 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087^,3030 Zite NB, Wallace LS. Do instructions for over-the-counter pre-coital female contraceptives promote “perfect use”? Contraception. 2008;79(3):211-5. DOI:10.1016/j.contraception.2008.10.002

We believe that the lack of readability formulae or other alternative linguistic metrics to evaluate texts specifically written in Portuguese⁷7 Dale E, Chall J. A formula for predicting readability. Educ Res Bull. 1948;27(1):11-20, 37-54.^,99 DuBay WH. The principles of readability. Costa Mes (Ca): Impact Information; 2004 [citado 2013 out 27]. Disponível em: http://www.impact-information.com/impactinfo/readability02.pdf
http://www.impact-information.com/impact... ^,1010 Flesch R. Marks of a readable style: a study in adult education. New York: Columbia University Teachers College; 1943. (Contributions to education, 897).^,1515 Gunning R. The technique of clear writing, New York: McGraw-Hill; 1952.^,1616 Klare GR. Measures of the readability of written communication: an evaluation. J Educ Psychol.1952;43(7):385-99. constitutes a limitation. The legibility concepts developed in the 1920s and have been continued by writers such as Rudolf Flesch,¹⁰10 Flesch R. Marks of a readable style: a study in adult education. New York: Columbia University Teachers College; 1943. (Contributions to education, 897).George Klare,¹⁶16 Klare GR. Measures of the readability of written communication: an evaluation. J Educ Psychol.1952;43(7):385-99. Edgar Dale, and Jeanne Chall.⁷7 Dale E, Chall J. A formula for predicting readability. Educ Res Bull. 1948;27(1):11-20, 37-54. The Gunning formula (1935)¹⁵15 Gunning R. The technique of clear writing, New York: McGraw-Hill; 1952. was one of the first, and according to the equation of this formula (suitable for English texts), the education level is equal to 0.4*(average size of phrases in number of words + the number of words with more than two syllables per 100 words).⁹9 DuBay WH. The principles of readability. Costa Mes (Ca): Impact Information; 2004 [citado 2013 out 27]. Disponível em: http://www.impact-information.com/impactinfo/readability02.pdf
http://www.impact-information.com/impact... There are currently several legibility formulas for diverse languages, such as Spanish, French, German, Swedish, Russian, Hebrew, Hindi, Chinese, Vietnamese, and Korean.⁹9 DuBay WH. The principles of readability. Costa Mes (Ca): Impact Information; 2004 [citado 2013 out 27]. Disponível em: http://www.impact-information.com/impactinfo/readability02.pdf
http://www.impact-information.com/impact... However, it is not known if legibility formulas specifically developed for the Portuguese language exist. Similar to other languages, Portuguese presents a specific combination of linguistic characteristics; thus, the development of legibility formulae specifically developed to evaluate the readability of Portuguese texts is recommended.⁴4 Cavaco AM, Várzea D. Contribuição para o estudo da leitura de folhetos informativos nas farmácias portuguesas. Rev Port Saude Publica. 2010;28(2):179-86. DOI:10.1016/S0870-9025(10)70009-2

In some studies, it was not possible to cross-check the results of different formulae (double verification)²⁴24 Roskos SE, Wallace LS, Weiss BD. Readability of consumer medication information for intranasal corticosteroid inhalers. Am J Health System Pharm. 2008;65(1):65-8 DOI:10.2146/ajhp070087^,2828 Weiss SM, Smith-Simone SY. Consumer and health literacy: the need to better design tobacco-cessation product packaging, labels, and inserts.Am J Prev Med. 2010;38(3 Suppl):S403-13. DOI:10.1016/j.amepre.2009.11.020^,3030 Zite NB, Wallace LS. Do instructions for over-the-counter pre-coital female contraceptives promote “perfect use”? Contraception. 2008;79(3):211-5. DOI:10.1016/j.contraception.2008.10.002 due to the fact that only one legibility formula was used.

Summary of the methodological limitations

In the studies of this review, the principal limitations identified are listed:

1. The inclusion of a limited number of patients or health professional in the readability and/or usability studies, particularly in the non-confirmatory studies;¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,55 Cavaco A, Pires C. Improving package leaflet information: potential users and physicians opinions [abstract]. Res Soc Adm Pharm. 2012;8(6);e50-1. DOI:10.1016/j.sapharm.2012.08.117^,66 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019^,88 Dowse R, Ramela T, Browne SH. An illustrated leaflet containing antiretroviral information targeted for low-literate readers: development and evaluation. Patient Educ Couns. 2011;85(3):508-15. DOI:10.1016/j.pec.2011.01.013^,1111 Franck MCJ, Foulon V, Van Vaerenbergh L. ABOP, the automatic patient information leaflet optimizer: evaluation of a tool in development.Patient Educ Couns. 2011;83(3):411-6. DOI:10.1016/j.pec.2011.04.025^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x^,2121 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030^,2222 March Cerdá JC, Prieto Rodríguez MA, Ruiz Azarola A, Lorda PS, Barrio Cantalejo I, Danet A. Mejora de la información sanitaria contenida en los prospectos de los medicamentos: expectativas de pacientes y de profesionales sanitarios. Aten Primaria. 2010;42(1):22-7. DOI:10.1016/j.aprim.2009.04.006^,2525 Shiffman S, Gerlach KK, Sembower MA, Rohay JM. Consumer understanding of prescription drug information: an illustration using an antidepressant medication. Ann Pharmacother. 2011;45(4):452-8. DOI:10.1345/aph.1P477^,2626 Symonds T, Dean J, Coyne KS, Margolis MK, Hackett G, Edwards D, et al. The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials. J Sex Med. 2010;7(6):2217-25. DOI:10.1111/j.1743-6109.2010.01767.x

2. The lack of certain evaluations before the study, such as the evaluation of the participants’ cognitive state, humor, satisfaction in participating in the test or opinion on the use of medicines and their package leaflets. These factors are likely to influence the interpretation of the results (interpretation bias);⁸8 Dowse R, Ramela T, Browne SH. An illustrated leaflet containing antiretroviral information targeted for low-literate readers: development and evaluation. Patient Educ Couns. 2011;85(3):508-15. DOI:10.1016/j.pec.2011.01.013

3. In majority of cases, participant literacy was also not evaluated, which probably influenced the accuracy of the study conclusions;¹⁴14 Gazmarariana JA, Williams MV, Peelc J, Bakerd DW. Health literacy and knowledge of chronic disease. Patient Educ Couns. 2003;51(3):267-75. DOI:10.1016/S0738-3991(02)00239-2

4. The non-use of the original packages of medicines or the absence of questions based on imaginary scenarios in several readability and/or usability tests, probably also influenced the accuracy of data collection;²¹21 Maat HP, Lentz L. Improving the usability of patient information leaflets. Patient Educ Couns. 2010;80(1):113-9. DOI:10.1016/j.pec.2009.09.030

5. The illustrations were scarcely used, namely pictograms,¹⁰10 Flesch R. Marks of a readable style: a study in adult education. New York: Columbia University Teachers College; 1943. (Contributions to education, 897). despite these graphic elements favoring the readability;

6. The selection of packages leaflets based on the composition of the medicines, (type of active ingredients)¹1 Brosnan S, Barron E, Sahm L, Sahm LJ. Health literacy and the clozapine patient. Perspect Public Health. 2012;132(1):39-42. DOI:10.1177/1757913911431038^,66 Cavaco A, Santos AL. Avaliação da legibilidade de folhetos informativos e literacia em saúde Rev Saude Publica. 2012;46(5):918-22. DOI:10.1590/S0034-89102012000500019^,1919 Lee IH, Lee HW, Je NK, Lee S. Examining the readability of two package inserts for self-medication in South Korea [abstract n.º 452, page 214].Pharmacoepidemiol Drug Saf. 2012;21:(Suppl 3):1-481. DOI:10.1111/j.1399-5448.2012.03324.x^,2626 Symonds T, Dean J, Coyne KS, Margolis MK, Hackett G, Edwards D, et al. The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials. J Sex Med. 2010;7(6):2217-25. DOI:10.1111/j.1743-6109.2010.01767.x may influence their selection (selection bias) because in general, the package leaflets with the worst linguistic characteristics were not selected, such as the longer package leaflets or the those containing more sentences per paragraph, abbreviations, or acronyms;

7. Few studies on patient comprehension of ADR³3 Carrigan N, Raynor DK, Knapp P. Adequacy of patient information on adverse effects: an assessment of patient information leaflets in the UK.Drug Safety. 2008;31(4):305-12. DOI:10.114-5916/08/0004-0305/$548.00/0^,1717 Knapp P, Gardner PH, Raynor DK, Woolf E, McMillan B. Perceived risk of tamoxifen side effects: a study of the use of absolute frequencies or frequency bands, with or without verbal descriptors. Patient Educ Couns. 2010;79(2):267-71. DOI:10.1016/j.pec.2009.10.002^,2626 Symonds T, Dean J, Coyne KS, Margolis MK, Hackett G, Edwards D, et al. The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials. J Sex Med. 2010;7(6):2217-25. DOI:10.1111/j.1743-6109.2010.01767.x and absence of studies on patient comprehension of specific topics, such as precautions, interactions, and contraindications;

8. The nonexistence of multicenter studies to study intra- and intercultural differences, such as dialectal differences;

9. The absence of longitudinal studies to investigate possible alterations over time, such as those caused by social changes, alterations on the pharmaceutical regulation or the appearance of new therapeutics;

10. Studies using only one legibility formula, which does not allow the comparison of different metrics. However, the results obtained through the application of legibility formulas are highly correlated according to some studies;⁹9 DuBay WH. The principles of readability. Costa Mes (Ca): Impact Information; 2004 [citado 2013 out 27]. Disponível em: http://www.impact-information.com/impactinfo/readability02.pdf
    http://www.impact-information.com/impact...

11. The lack of legibility formulae for Portuguese to calculate indicators on the simplicity of texts, similarly to the legibility formulas of other languages, such as English (e.g., Flesch formula).

Because of these methodological limitations, it is possible that the studied package leaflets were not accurately evaluated.

CONCLUSIONS

The studies on the readability of the package leaflets should be based on technical principles and be highly suitable with high quality scientific standards. Several points are strongly recommended for improving and standardizing the readability of package leaflets. These include minimizing or avoiding the previously discussed limitations, using larger and more varied samples of package leaflets, enrolling more participants, and development of new metrics and legibility formulas for specific languages (e.g., Portuguese).

In this review, diverse factors related with the readability of the package leaflets were highlighted (e.g., clear information, simple terms, and package leaflets with a proper design. The main methods for ensuring the intelligibility and comprehension of the package leaflets were the usability tests and the application of formulae and/or metrics to their texts.

The encountered readability/usability tests rely on the involvement of patients using the medication to test and confirm the readability of the informative materials. Ideally, these tests should also include patients with low literacy levels and health professionals to ensure the collection of reliable and efficient results.

The diverse methodological limitations identified should be avoided in future studies and considered in the assessment of results.

In general, the investigations on the readability of the package leaflets and their methods need more scientific contributions to assure the accuracy, reliability, and appropriateness of results in the social context and language of each country.

REFERENCES

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