Pharmaceutical products approved for marketing are generally accompanied by information targeted to health care prescribers and patients. The International Comparative Study on Drug Information (ICSODI) Collaborative Group has recently published an article in the European Journal of Clinical Pharmacology which documents the variability of written drug information in and within countries concerning the indications, side effects and cautions of three selected drugs: ciprofloxacin, fluoxetine and nifedipine. An original method to measure the degree of information agreement among different written materials, such as summaries of product characteristics, package inserts and data sheets, and a widely accepted reference text was developed (1).

Published studies addressing drug information in general (2-5) and readability of patient information materials (6-8) are available, but very little specifically address the issue of documenting differences in key aspects of drug information among different countries for the same drugs (9).

The selected drugs figured among the top thirty in terms of global sales in 2000 (10), and covered three therapeutic areas of high worldwide relevance in terms of mortality and morbidity (11).

A total of 483 written materials were obtained from 26 countries and analysed. Four variables: indications, dosage range in adults, side effects, and cautions were selected and a checklist of items was created using the British National Formulary as a reference text (12). The BNF was chosen because it is a complete, independent, and practice-oriented source of information and is widely used by professionals around the world, being easy to obtain and inexpensive.

Materials collected from each country, drug, and variable were compared with a checklist (see page 146). An indicator for the proportion of agreement was developed. The indicator was called “degree of information agreement” and was based on indications, side effects, and cautions for each country and drug. The proportion of checklist items found in the materials was calculated against the total number of relevant checklist items. The mean and confidence interval for the proportions were then calculated.

The same checklist and methodological approach used in the inter-country evaluation was applied to comparators among materials collected from each individual country.

Baseline characteristics of evaluated materials (26 countries)

BNF-derived checklist for assessing agreement of drug information material

A comparison was made between the information stated in the BNF and that found in the materials collected. Out of 26 countries, 11 had information that matched BNF indications for nifedipine. Only materials from Colombia and the UK listed all the indications included in the BNF for ciprofloxacin, and those from Canada, Estonia and the UK for fluoxetine. Concerning ciprofloxacin, materials from 3 countries are in disagreement with the dose range recommended by the BNF. This disagreement involved a total of 7 countries for nifedipine and 9 for fluoxetine, i.e. over one-third of the sample. None of the materials from the various countries reported all major side effects listed in the BNF for ciprofloxacin and fluoxetine.

Concerning nifedipine, only materials from Spain were found to report all the BNF side effects, while materials from Colombia did not report any of the 7 major side effects included in the BNF. Again, none of the materials from any of the countries report all the cautions included in the BNF. The findings of this study include extremes such as the presence of 1 caution statement out of the 19 listed in the BNF for ciprofloxacin in the Philippines, 1 out of 11 for fluoxetine in Argentina, and 3 out of 12 for nifedipine in Mozambique and Poland.

What did the analysis show?

Looking at inter-country comparisons, the degree of information agreement is surprisingly low for drugs that are routinely used in large numbers of patients. The disparity of dose ranges recommended by the different sources is especially surprising. Theoretically, prescribing information is based on the assessment of clinical studies and post marketing surveillance activities. In the majority of the cases studied, the materials collected were related to products of the same mother company thus leading to the assumption that the same basic facts should have been used to make the decisions concerning indications, dosage, side effects, and cautions. However, the results show that prescribers and patients are recommended substantially different things in different countries and this may be due to the fact that not all national authorities can conduct a full and systematic assessment of available worldwide data concerning clinical studies and drug monitoring data before approving prescribing information materials.

If intra-country comparisons are examined, the picture becomes even more difficult to understand: why should products have different indications, dosages, side effects and cautions simply because they have a different brand name?

While a plausible explanation cannot be offered for the differences found, it is possible that the implications at national level can be serious for patients and for those engaged in activities aimed at ensuring rational drug use. These implications can also involve communication problems between prescribers, regulatory authorities, companies, and patients. At the international level, there can be serious implications for travellers, or for health workers comparing drug utilization or developing therapeutic guidelines.

In the case of safety information, this was often presented as a list with no frequency indications or any specific guidance for prescribers or patients. Patients presented with such a list of side effects may be reluctant to continue taking a drug. The conclusion is that a list lacking practical guidance is not particularly useful to prescribers or patients. It is urgent for companies and regulatory authorities to understand that correctly presented safety information will assist in decision- making and can speed up identification of adverse reactions.

Responsibility for approving drug information materials lies with national regulatory authorities. Their task is difficult, especially when resources are limited and companies submit different materials in different countries. An effort should be made to identify sources of independent drug information that can be used as a complement to documentation submitted for approval thereby removing contradictory statements on drug information materials that have no reason to be different. Further training and continued education aimed at drug regulatory officials could play a role. Finally, measures to harmonize information materials at the national level, such as requiring the use of core information for pharmaceutically equivalent products, should be implemented.

References

1. The International Comparative Study on Drug Information (ICSODI) Collaborative Group. Prescribing information in 26 countries: a comparative study. European Journal of Clinical Pharmacology, Published online 21 May 2003. http://www.springer.com

2. Curran, C.F. A progress report: Drug information from 1970 to 2000. Drug Information Journal, 34(4):1355-1363 (2000).

3. Garattini, S. How to improve medical information on drugs. Lancet, 352:151-152 (1998).

4. Mindell, J., Kemp, T. Only two-fifths of advertisements cited published, peer reviewed references. British Medical Journal, 315: 1622 (1997).

5. Stryer, D., Bero, L.A. Characteristics of materials distributed by drug companies: An evaluation of appropriateness. Journal of Internal Medicine, 11(10):575-583 (1996).

6. Bradley, B., Singleton, M., Li Wan Po, A. Readability of patient information leaflets on over-the-counter (OTC) medicines. Journal of Clinical Pharmacology and Therapeutics, 19: 7-15 (1994).

7. Holt, G.A., Dorcheus, L., Hall, E.L. et al. Patient interpretation of label instructions. American Pharmacy, NS32: 58-62 (1992).

8. Gibbs, S., Waters, W.E., George, F.C. The benefits of prescription information leaflets (2). British Journal of Clinical Pharmacology, 28: 345-351 (1989).

9. Dikshit, R.K., Dikshit, N. Commercial source of drug information: comparison between the UK and India. British Medical Journal, 309: 990-991 (1994).

10. IMS World Review Report. IMS, USA.

11. World Health Organization. World Health Report 2002. Statistical Information System. http://www.who.int/whosis/menu.cfm.

12. The British Medical Association and the Royal Pharmaceutical Society of Great Britain. British National Formulary. London, UK; 2000.