Gaps in the evaluation and monitoring of new pharmaceuticals: proposal for a different approach
===============================================================================================

* Andreas Laupacis
* J. Michael Paterson
* Muhammad Mamdani
* Alaa Rostom
* Geoffrey M. Anderson

The marked increase in spending on drugs1 has led payers such as provincial governments to restrict funding for many drugs to specific clinical indications that are thought to be cost-effective.2,3 Some have argued that this unreasonably deprives patients of access to beneficial drugs.4 In this article we argue for a new approach to drug evaluation in Canada that combines the strengths of randomized trials and observational studies, and places more emphasis on the use of drug evaluation after marketing for decision-making.

At least 4 different types of clinical studies are required to inform rational drug policy: (1) randomized trials to determine efficacy and safety (which are required for licensing), (2) real-world randomized trials to determine effectiveness and safety in regular practice, (3) observational studies that use administrative databases and (4) targeted primary data collection (Table 1). Currently, most randomized trials are done to determine efficacy and safety under ideal conditions, whereas the other designs, which are less frequently used, attempt to determine a drug's pattern of use and effectiveness under real-world conditions. For some drugs, the results of randomized trials of efficacy will be so straightforward and the possibility of real-world use outside the conditions of the trial so small that no other study designs will be required. However, for other drugs there may be concern about the impact of the drug upon clinically important outcomes (e.g., if surrogate outcomes were used in the efficacy trials) or concern that the drug will be used for patients on whom it has not been studied or for whom it is cost-ineffective. In these circumstances, 2 or more of the study designs would be required to adequately assess the impact of the drug in the real world and to guide clinical and policy decisions.

View this table:
[Table1](http://www.cmaj.ca/content/169/11/1167/T1)

Table 1. 

A proposed model for optimal drug evaluation in Canada is shown in Fig. 1. We would suggest more large, head-to-head randomized trials to convincingly determine the relative benefits and risks of competing medications in regular practice. The greater use of observational studies and chart reviews after licensure would increase the use of real-world evidence to monitor the use of drugs. Payers might become more liberal in their initial decisions about paying for drugs if they knew that their decisions would be re-evaluated over time and that they could change their decision if the use of a drug seemed to be beyond that which the evidence would support.

![Figure1](http://www.cmaj.ca/https://www.cmaj.ca/content/cmaj/169/11/1167/F1.medium.gif)

[Figure1](http://www.cmaj.ca/content/169/11/1167/F1)

**Fig.1: A proposed model for drug evaluation in Canada. CEIPs = Centres of Excellence in Pharmacosurveillance.** 

Observational studies that use administrative data to link drug claims to physician and hospital use can play a key role in drug evaluation after marketing. Although work is underway to create a national drug-claims database5 this database will not link drug claims to other administrative data and will therefore be of limited use. Linked databases do exist in many provinces. Several research groups have the expertise and experience to use these databases for evaluation after marketing6,7,8,9,10,11,12,13 (for a list of these groups and Web sites, see the [online](http://www.cmaj.ca/cgi/content/full/169/11/1167/DC1) appendix at [www.cmaj.ca](http://www.cmaj.ca)). 

We refer to each of these groups as a Centre of Excellence in Pharmacosurveillance (CEIP). Ideally each CEIP should be affiliated with an academic institution or institutions to ensure independence and methodological rigour, and should work closely with provincial drug plan decision-makers and others to help identify priorities for research.

A national research infrastructure should be developed to allow researchers from a CEIP to access data from other provinces under appropriate conditions of security and confidentiality. If transfer of data between provinces is not possible analytical methods developed in one province could be used in other provinces (unpublished data). Collaboration among CEIPs would not only promote collegiality and shared methods, but also make it possible to increase sample size and detect rare outcomes. As well, analysis of natural experiments that occur when provinces make different formulary decisions (e.g., coverage for rofecoxib and celecoxib is restricted in British Columbia and Ontario, but unrestricted in Alberta and Quebec) could play an important role in informing drug policy.

The recent establishment of Health Canada's Marketed Health Products Directorate14 and the emergence of a national drug review process15 could provide a fresh emphasis on coordinated drug evaluations after marketing. In the United States, the Food and Drug Administration (FDA) uses signals from its adverse-event reporting system (AERS) as a trigger for targeted pharmacoepidemiological research conducted in academic centres with access to linked administrative databases.16,17 These studies, funded by the FDA, include support for focused efforts to collect primary data to supplement and validate the administrative data**.** Given efforts to establish a joint US–Canada AERS,18 we wonder why a similar network of CEIPs could not operate in Canada, perhaps in collaboration with the FDA. As well a forum and sufficient funding should be provided to permit all those involved in drug policy to meet formally to ensure that the most important questions are being examined, and that all available and appropriate methods and data sources (including clinical registries and electronic medical record databases) are being used to examine them. This new strategy will require more investment in research and outcomes assessment, and there will be considerable discussion about who should pay for what. However in the end the benefits generated by the more appropriate use of medications will be considerable.

Because of the societal importance of pharmaceuticals the act of writing a prescription, which used to be a private interaction between a physician and a patient, is now being scrutinized and manipulated by those who pay for drugs (to try to decrease the amount paid), by those who make drugs (to try to increase the amount paid) and by those who are interested in quality of care (to try to ensure that the right patients get the right drugs). Many of us wear more than one hat. The challenge for all of us is to ensure that drugs are used in the most appropriate, cost-effective manner possible. The large number of stakeholders involved and their conflicting self-interests make the development of effective drug policy difficult. The changes that must be made to the current system will require considerable courage and commitment on the part of all groups involved. Time will tell whether societal good will win over self-interest.

𝛃 See related article page [1170](http://www.cmaj.ca/lookup/volpage/169/1170)

## Footnotes

*   This article has been peer reviewed.
    
    *Contributors:* Andreas Laupacis and Michael Paterson prepared the initial draft of this article. All authors contributed to the conceptualization of this article, critically revised it and approved the final version of the manuscript.
    
    *Acknowledgements:* We thank Drs. David Juurlink and Paula Rochon for their comments on an earlier draft of this article.
    
    Dr. Laupacis is a Senior Scientist of the Canadian Institutes of Health Research (CIHR). Dr. Mamdani is supported by a New Investigator Award received through a CIHR Chronic Disease New Emerging Team (NET) program (grant no. 54010). Dr. Anderson holds the Liberty Health Chair in Health Management Strategies at the University of Toronto.
    
    The NET program is jointly funded by the Canadian Diabetes Association, the Kidney Foundation of Canada, the Heart and Stroke Foundation of Canada, and the CIHR Institutes of Nutrition, Metabolism and Diabetes, and Circulatory and Respiratory Health.
    
    The Institute for Clinical Evaluative Sciences (ICES) is a nonprofit research corporation sponsored by the Ontario Ministry of Health and Long-Term Care (OMHLTC). The opinions, results and conclusions expressed in this article are those of the authors. No endorsement by the OMHLTC or ICES is intended or should be inferred.
    
    *Competing interests:* None declared for Drs. Paterson and Anderson. Dr. Laupacis is a member of the Data Safety Monitoring Boards of 2 drugs manufactured by Novartis. Drs. Laupacis and Mamdani have received honoraria from the Drug Quality and Therapeutics Committee of the Ministry of Health and Long-Term Care. In 2001, Dr. Rostom presented a talk to rheumatologists at the University of Ottawa about the CLASS and VIGOR studies that was sponsored by Merck and Co.

## References

1.  1. Canadian Institute for Health Information (CIHI). *Drug expenditure in Canada 1985-2002*. Ottawa: The Institute; 2003.
    
    

2.  2. Laupacis A. Inclusion of drugs in provincial drug benefit programs: Who is making these decisions, and are they the right ones? CMAJ 2002;166(1):44-7.
    
    [FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czo4OiIxNjYvMS80NCI7czo0OiJhdG9tIjtzOjIyOiIvY21hai8xNjkvMTEvMTE2Ny5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

3.  3. Laupacis A, Anderson G, O'Brien B. Drug policy: making effective drugs available without bankrupting the healthcare system. Healthc Pap 2002; 3 (1):12-31.
    
    

4.  4. Dugal R, Mani A, Potvin K. Look beyond budgets to the broader benefits. Healthc Pap 2002;3(1):77-82.
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=12811115&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 

5.  5. Canadian Institute for Health Information. *National Prescription Drug Utilization Information System (NPDUIS)*. Ottawa: The Institute; 2002. Available: [www.cihi.ca/cihiweb/dispPage.jsp?cw\_page=indicators\_drug\_e](http://www.cihi.ca/cihiweb/dispPage.jsp?cw_page=indicators_drug_e) (accessed 2003 Aug 7).
    
    

6.  6. Mamdani M, Rochon P, Juurlink DN, Kopp A, Anderson GM, Naglie G, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325(7365):624.
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjEyOiIzMjUvNzM2NS82MjQiO3M6NDoiYXRvbSI7czoyMjoiL2NtYWovMTY5LzExLzExNjcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

7.  7. Schneeweiss S, Walker AM, Glynn RJ, Maclure M, Dormuth C, Soumerai SB. Outcomes of reference pricing for angiotensin-converting-enzyme inhibitors. N Engl J Med 2002;346(11):822-9.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1056/NEJMsa003087&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11893794&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000174328900006&link_type=ISI) 

8.  8. Bourgault C, Rainville B, Suissa S. Antihypertensive drug therapy in Saskatchewan: patterns of use and determinants in hypertension. Arch Intern Med 2001;161(15):1873-9.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1001/archinte.161.15.1873&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11493129&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000170236900011&link_type=ISI) 

9.  9. Benayoun S, Ernst P, Suissa S. The impact of combined inhaled bronchodilator therapy in the treatment of COPD. Chest 2001;119:85-92.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1378/chest.119.1.85&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11157588&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000166766300018&link_type=ISI) 

10. 10. Metge CJ, Blanchard JF, Peterson S, Bernstein CN. Use of pharmaceuticals by inflammatory bowel disease patients: a population-based study. Am J Gastroenterol 2001;96(12):3348-55.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1111/j.1572-0241.2001.05255.x&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11774948&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 

11. 11. Tamblyn R, Laprise R, Hanley JA, Abrahamowicz M, Scott S, Mayo N, et al. Adverse events associated with prescription drug cost-sharing among poor and elderly persons. JAMA 2001;285(4):421-9.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1001/jama.285.4.421&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11242426&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000166506000029&link_type=ISI) 

12. 12. Rahme E, Joseph L, Kong SX, Watson DJ, LeLorier J. Gastrointestinal health care resource use and costs associated with nonsteroidal antiinflammatory drugs versus acetaminophen: retrospective cohort study of an elderly population. Arthritis Rheum 2000;43(4):917-24.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1002/1529-0131(200004)43:4<917::AID-ANR25>3.0.CO;2-F&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=10765939&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000086398000025&link_type=ISI) 

13. 13. Burge F, Kephart G, Flowerdew G, Putnam W, Comeau DG, Whelan AM, et al. Physician characteristics in relation to cardiovascular drugs commonly prescribed for hypertension in Nova Scotia. Can J Clin Pharmacol 2001; 8(3): 139-45.
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11574896&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 

14. 14. Health Canada. Marketed Health Products Directorate. Ottawa: Health Canada; 2002. Available: [www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/mhpd-announce\_e.html](http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/mhpd-announce_e.html) (accessed 2003 Aug 7).
    
    

15. 15. Health Canada. *The common drug review*. *Proceedings of the Conference of Federal-Provincial-Territorial Ministers of Health*; 2002 Sept 2-5; Banff (AB). Available: [www.hc-sc.gc.ca/english/media/releases/2002/2002_58bk2.htm](http://www.hc-sc.gc.ca/english/media/releases/2002/2002_58bk2.htm) (accessed 2003 Aug 7).
    
    

16. 16. Strom BL, editor. *Pharmacoepidemiology*. 3rd ed. Sussex: John Wiley; 2000.
    
    

17. 17. Rodriguez EM, Staffa JA, Graham DJ. The role of databases in drug postmarketing surveillance. Pharmacoepidemiol Drug Saf 2001;10(5):407-10.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1002/pds.615&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11802586&link_type=MED&atom=%2Fcmaj%2F169%2F11%2F1167.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000172704600011&link_type=ISI) 

18. 18. Health Canada. *Response to the recommendations to Health Canada of the Coroner's Jury Investigation into the death of Vanessa Young*. Ottawa: Health Canada; 2002. Available: [www.hc-sc.gc.ca/english/protection/vanessa\_young/key\_initiatives.html](http://www.hc-sc.gc.ca/english/protection/vanessa_young/key_initiatives.html) (accessed 2003 Aug 7).