- Email: [email protected]
A comparison of new drug availability in Canada and the United States and potential therapeutic implications of differences
Health Policy 79 (2006) 214–220
A comparison of new drug availability in Canada and the United States and potential therapeutic implications of differences Joel Lexchin a,b,c,∗ a
School of Health Policy and Management, York University, 4700 Keele St., Toronto, Ont., Canada M3J 1P3 b Emergency Department, University Health Network, Canada c Department of Family and Community Medicine, University of Toronto, Toronto, Ont., Canada
Abstract Background: Claims are made that new valuable drugs are not available in Canada at the time that they are marketed in the United States. This study uses a convenience sample of new drugs marketed in the United States and determines how many of these products are initially unavailable in Canada and their therapeutic value. Methods: Issues of the Canadian edition of The Medical Letter from May 12, 2003 to June 21, 2004 were hand searched for evaluations of new drugs and the following information was recorded: indication, availability in Canada and conclusions about therapeutic value. For drugs not available in Canada two clinical pharmacologists rated the therapeutic value of the products and the type of FDA review (standard or priority) was recorded. A database from the Therapeutic Products Directorate was searched to see if any of the drugs initially unavailable were subsequently marketed. Results: Thirty-two of 37 drugs were not available in Canada. Between 9 and 11 of these products were rated as offering moderate to significant therapeutic gains. Twelve of the 32 drugs eventually were marketed in Canada. Interpretation: Although the majority of new drugs marketed in the United States but not available in Canada do not offer any therapeutic advantage, between about a quarter and a third of may offer moderate to significant therapeutic gains. The reasons why these drugs are unavailable and how much their absence affects the treatment Canadians receive should be the subject of future research. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Therapeutic value; Canada; United States; Prescription medications; Therapeutic Products Directorate; Food and Drug Administration
1. Introduction Medications are one of the cornerstones of modern health care. If the introduction of new drugs is delayed ∗
Tel.: +1 416 736 2100x22119/964 7186; fax: +1 416 736 5227. E-mail addresses: [email protected], [email protected].
patients may potentially receive therapeutically inferior care. Currently, Canada takes significantly longer to approve new drugs than does either the United States or Sweden [1] and the pharmaceutical industry charges that delays in Canada keep important new products from reaching Canadians in a timely manner [2]. Organizations, such as the Fraser Institute, are arguing that internet sales from Canada to the United
0168-8510/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.healthpol.2005.12.015
J. Lexchin / Health Policy 79 (2006) 214–220
States might reduce international drug company profits to such an extent that the preferred alternative would be to forego Canadian sales and not market the product in Canada [3]. Finally, price limitations on patented medications, imposed by the Patented Medicine Prices Review Board, may discourage marketing in Canada [4]. At the same time, there are evaluations that suggest that most new drugs do not offer any significant therapeutic gain [5,6]. Even if some important new drugs have their approval delayed or companies decide never to submit them for approval in Canada, individual patients would still able to obtain them through Health Canada’s Special Access Programme [7]. This program allows doctors to obtain unapproved drugs on a patient-by-patient basis. However, this mechanism is clearly inferior to having products freely available through the normal prescription route. This study uses a convenience sample of new drugs marketed in the United States (U.S.) and determines how many of these products are unavailable in Canada and their potential therapeutic value.
2. Methods On May 12, 2003 The Medical Letter started publishing a Canadian edition. The Medical Letter evaluates virtually all new drugs marketed in the U.S. [8] with the Canadian edition giving Canadian prices and indicating whether the medication is approved in Canada. Issues of The Medical Letter from May 12, 2003 to June 21, 2004 (volume 45, no. 1156 to volume 46, no. 1185) were hand searched. The name of each individual drug that was evaluated was recorded along with the following information: indication, manufacturer and availability in Canada. Information in The Medical Letter about whether or not the drug was marketed in Canada was confirmed through the web site of the Therapeutic Products Directorate (TPD), the Canadian equivalent of the FDA [9]. The Medical Letter’s assessment of the therapeutic value of the new product was recorded. Evaluations from The Medical Letter were used because it is the oldest and most respected independent drug bulletin in North America.
215
Two clinical pharmacologists who are also practicing general internists and who have extensive experience in critical appraisal of drug research and writing prescribing guidelines were sent a list of the drugs that were not available in Canada along with The Medical Letter’s conclusion about the therapeutic value of these drugs. They were asked to use the conclusion to provide an overall evaluation of the value of the new drugs using the following scale: little or no therapeutic advantage over existing products (category 1); moderate therapeutic advantage compared to existing drugs (category 2); significant therapeutic advantage compared to existing drugs (category 3). This rating classification was chosen because it is similar to the one that is used by the Canadian Patented Medicine Prices Review Board [10]. Ratings were done independently and discrepancies resolved by consensus. Drugs submitted for approval to the U.S. Food and Drug Administration (FDA) receive either a standard or a priority review. Drugs that are thought to be potentially significant therapeutic advances are granted priority reviews. All other drugs receive a standard review [11]. As a check on the ratings by the clinical pharmacologists, the FDA review status [12] was recorded for each of the drugs that the clinical pharmacologists were asked to rate and a Kappa score was computed to compare the two sets of ratings. For the purpose of computing the Kappa score if the clinical pharmacologists put the drug into either categories 2 or 3 that was deemed to be equivalent to a priority review. Approval dates in the United States were obtain from the web site of the FDA [13]. The availability of drugs not initially marketed in Canada was checked as of July 29, 2005 through the web site of the TPD [9]. The delay between Canadian and American approval dates was calculated in days. Since The Medical Letter chooses which drugs to write about based on U.S. approvals its evaluations would be delayed for drugs first marketed in Canada and there would not be any assessment of drugs only available in Canada. To see if this was a concern the approval dates for all new active substances (drugs not marketed before in any form) and new combination products approved in Canada in 2003 were reviewed [9] and compared to dates in the U.S. [13]. Descriptive statistical analysis was done using Stat View 5.0.1 for Macintosh [14].
216
J. Lexchin / Health Policy 79 (2006) 214–220
3. Results From May 12, 2003 to June 21, 2004 The Medical Letter evaluated 37 new drugs marketed in the U.S. Table 1 lists the 32 products not available in Canada. The two clinical pharmacologists evaluated the therapeutic value of these 32 drugs (see Table 1). Nineteen were rated as little or no improvement (category 1), six were moderate improvements (category 2) and one was a significant improvement (category 3). In some cases the conclusions in The Medical Letter meant that the two expert reviewers could not come to a definite interpretation about the drugs. Two drugs were felt to be generally category 1 but, for their approved indications, in some selected populations or in certain circumstances they might be moderate advances (category 2). For another two, the data were not robust enough to distinguish between categories 2 and 3. Finally, the reviewers felt that it was too early in the lifecycle of two drugs to make any decisions. Eleven of the 32 drugs received a priority review from the FDA, including the two that the reviewers were unable to rate (Table 1). After removing the two unrated drugs from the analysis, the Kappa score for agreement on therapeutic value between the clinical pharmacologists and the FDA was 0.52 indicating moderate agreement. Assuming that the two cases where the reviewers were unable to rate the drugs represented a disagreement with the FDA assessment, the Kappa score drops to 0.42, a value at the low end of moderate agreement [15]. By late July 2005, 12 of the drugs that had not initially been available in Canada had been approved. The median delay between American and Canadian approval dates was 259 days (inter-quartile range 358 days). For the 20 drugs that were not yet approved in Canada, the median time since American approval was 714 days (inter-quartile range 196 days). In 2003 there were 31 new active substances and new combination products approved in Canada. Twentyfive had already been approved in the U.S., four were initially approved in Canada and two drugs marketed in Canada were not marketed in the U.S. although slight variations of the Canadian drugs were available in the U.S. and had been approved prior to the Canadian drugs. For the four drugs first marketed in Canada, U.S. delays were 65, 93, 175 and 309 days. The therapeutic significance of these products was not assessed by the
two clinical pharmacologists and the FDA ratings were not accessed.
4. Discussion Almost 90% (32/37) of the new drugs assessed by The Medical Letter over a 13 month period (May 12, 2003–June 21, 2004) were unavailable in Canada at the time of publication of The Medical Letter. Out of those 32, about two-thirds [19–20] were considered to offer little to no therapeutic advantage over existing products by both the clinical pharmacologists and the FDA. Nine to 11 may have been either moderate or significant therapeutic improvements based on the ratings given to them by the two sources. Twelve out of the 32 drugs were marketed in Canada as of July 29, 2005, the time of completion of the analysis done for this paper. Nine of these products were in category 1 based on the clinical pharmacologists’ ratings and 10 received a standard review by the FDA. The method of sampling used for this study did not necessarily give a full picture of the additional therapeutic value that may be achieved from drugs marketed in the U.S. but not in Canada. The therapeutic gain from products not assessed by The Medical Letter is unknown and the current sample may not be representative of all drugs approved by the FDA in terms of therapeutic gain. However, it is likely that drugs of greater therapeutic value were oversampled in this study. In the period 2001–2003, the FDA gave 16% of all the products it reviewed a priority review [16]. Out of the sample of 32 drugs that were considered in this study over one-third received a priority review. An alternative approach to this issue would have been to identify drugs approved by the FDA over a 13 month period. However, this approach would have yielded a smaller sample size. Over the past 5 years the FDA has been approving an average of 29 new molecular entities annually [12] which is smaller than the sample of 37 drugs used in this study. While there may be drugs with moderate to significant therapeutic benefit that are available in Canada but not in the U.S. the number of these products is likely to be very small based on the fact that 27 of the 31 new drugs approved in Canada in 2003 were already marketed in the U.S.
Table 1 Drugs assessed by The Medical Letter and their availability in Canada Name
Abarelix
Cetuximab
Cyclosporine 0.05% ophthalmic emulsion Daptomycin Efalizumab Emtricitabine Entacapone + levodopa/carbidopa Epinastine HCl 0.05% ophthalmic solution Eplerenone Nasally administered influenza vaccine (Flumist® )
Advanced symptomatic prostate cancer in patients who should not take luteinizing hormone-releasing hormone Fabry disease Panic disorder Protease inhibitor Rosacea Metastatic colon cancer in combination with a fluorouracil-based regimen Metastatic colon cancer in patients with epidermal growth factor receptor expressing tumour either in combination with irinotecan when cancer progressed on irinotecan-based therapy or as monotherapy for those who cannot tolerate irinoteccan Dry eye disease IV treatment of complicated skin and skin structure infections Moderate to severe chronic plaque psoriasis Nucleoside analogue reverse transcriptase inhibitor Parkinson’s disease with end-of-dose “wearing off” Prevention of itchiness associated with allergic conjunctivitis Hypertension; heart failure Influenza vaccine
FDA priority review
Clinical pharmacologists’ rating
Availability in Canada At time of Medical Letter evaluation
July 29, 2005
FDA approval date
Canadian approval date
Canadian delay (days)
Yes
Category 2
No
No
11/25/2003
Yes No Yes No Yes
Category 2 Category 1 Category 2 Category 1 Categories 2 or 3
No No No No No
Yes No Yes No No
4/24/2003 1/17/2003 6/20/2003 12/24/2002 1/26/2004
Yes
Category 1
No
No
2/12/2004
533a
Yes
Unrated
No
No
12/23/2002
949a
Yes
Category 1
No
No
9/12/2003
686a
No
Categories 1 or 2
No
No
10/27/2003
641a
No
Category 1
No
No
7/20/2003
740a
No
Category 2
No
No
6/11/2003
779a
No
Category 1
No
No
10/16/2003
652a
No No
Categories 1 or 2 Category 1
No No
No No
9/27/2002 2/11/2004
1036a 534a
612a
1/23/2004 12/5/2003
274a 924a 168 948a 550a
J. Lexchin / Health Policy 79 (2006) 214–220
Agalsidase beta Alprazolam-extended release Atazanavir Azelaic acid 15% gel Bevacizumab
Indication
217
218
Gatifloxacin 0.3% ophthalmic drops Memantine Moxifloxacin 0.5% ophthalmic drops Olanzapine/fluoxetine Omalizumab
Pemetrexed Pentavalent vaccine (Pediarix® ) Recombinant human alpha-l-iduronidase Seasonale® Sertaconazole 2% cream Testosterone 1% gel Testosterone buccal tablet Tositumomab + radiolabeled Iodine-131 tositumomab (Bexxar® ) Vardenafil Zolmitriptan nasal spray a
Delay as of July 29, 2005.
No
Category 1
No
Yes
3/28/2003
8/30/2004
521
Alzheimer’s disease Bacterial conjunctivitis
No No
Category 1 Category 1
No No
Yes Yes
10/16/2003 4/15/2003
12/8/2004 5/11/2003
419 26
Depressive episodes associated with bipolar disorder Moderate to severe persistent asthma in those who have shown reactivity to an allergan and whose symptoms are inadequately controlled by an inhaled corticosteroid Overactive bladder Prevention of acute and delayed nausea and vomiting due to moderately and highly emetogenic cancer chemotherapy Malignant pleural mesothelioma Pediatric vaccine Enzyme replacement in mucopolysaccharidosis type I Extended cycle oral contraceptive Interdigital tinea pedis Hypogonadism Hypogonadism Relapsed follicular non-Hodgkin’s lymphoma refractory to rituximab
Yes
Category 1
No
No
12/24/2003
No
Category 1
No
Yes
6/20/2003
11/18/2004
517
No No
Category 1 Category 2
No No
Yes No
2/26/2003 7/25/2003
10/22/2004
604 735a
No Yes Yes
Category 2 Categories 2 or 3 Category 3
No No No
Yes Yes No
2/4/2004 12/13/2002 4/30/2003
5/21/2004 8/13/2003
107 243 821a
No No No No Yes
Category 1 Category 1 Category 1 Category 1 Unrated
No No No No No
No No Yes No No
9/5/2003 12/10/2003 2/28/2000 6/19/2003 6/27/2003
2/6/2002
693a 597a 709 771a 763a
Erectile dysfunction Migraine
No No
Category 1 Category 1
No No
Yes Yes
8/19/2003 9/30/2003
3/17/2004 3/2/2004
211 154
583a
J. Lexchin / Health Policy 79 (2006) 214–220
Oxybutynin (transdermal) Palonesetron
Bacterial conjunctivitis
J. Lexchin / Health Policy 79 (2006) 214–220
The two pharmacologists who rated the drugs were asked to rely on material from The Medical Letter. Under other circumstances they would have used a wider range of information in coming to their conclusions. Furthermore, they did not consider cost in categorizing the drugs. Other people using the same information may have reached different conclusions. Adding more information may have changed their conclusions, but The Medical Letter evaluations are already based on an extensive assessment including a review of the published and unpublished literature, the expert opinions of 10–20 investigators who have clinical and experimental experience with the drug, the FDA, the Centers for Disease Control and Prevention, the first authors of all the articles cited in The Medical Letter review, and the pharmaceutical companies making the drugs under review [8]. There was only moderate agreement between the drugs rated as moderate to significant improvements by the two reviewers and the ones given a priority review by the FDA. This finding is not necessarily unexpected as the evaluations of the drugs were taking place at different periods in the drugs’ life cycle: the FDA assessment was done before the drugs were marketed while the reviewers were looking at information about the drugs partly gathered in the post-marketing phase. The eventual value of drugs can change either positively [17] or negatively [18] as they move through their life cycle. Moreover, according to both sets of ratings about a third of the drugs not available in Canada had added therapeutic value; either categories 2 or 3 or a priority review. On average, the drug approval process in the United States is 7.8 months faster than in Canada [2]. This difference would explain the median 259-day delay in marketing the 12 drugs that subsequently became available in Canada. However, after a median of 714 days, more than three times the usual regulatory delay, the other 20 drugs were still not available in Canada suggesting that there are a number of other reasons for the unavailability besides longer Canadian approval times. Differences in filing dates between Canada and the U.S. may contribute to Canadian unavailability but are not the sole factor. Companies usually submit their drugs to Health Canada 6–9 months after they file with the FDA [19]. There is no publicly accessible database for the filing dates of individual drugs in Canada so this explanation cannot be explored any further.
219
Companies may choose not to market some of their products in Canada. The much larger American market with its higher prices makes it more economically attractive. A small Canadian market and/or limitations on introductory prices imposed by the Patented Medicine Prices Review Board may mean that expected sales are too low to warrant the costs of getting a drug approved and then promoting it in Canada. Drugs approved in the U.S. may have been rejected in Canada but the TPD does not release the names of products it rejects so whether or not this is a factor in the 20 unmarketed drugs is unknown. Finally, having new drugs available early is not always a benefit. There are a number of drugs that were sold in the U.S. that had to be withdrawn for safety reasons before they were on the Canadian market [20]. Whether or not the fact that Canadians were not exposed to these products offsets the absence of drugs that have moderate to major therapeutic benefits is an open question. The findings from this report indicate that most new drugs available in the United States but not marketed in Canada do not represent much in the way of therapeutic gains. A substantial minority may offer moderate to significant therapeutic advantages over existing therapies. The reasons why these drugs are unavailable and how much their absence affects the treatment Canadians receive needs to be investigated.
Acknowledgements Drs. Anne Holbrook and Mitchell Levine evaluated the therapeutic value of the drugs and provided valuable comments on the manuscript.
References [1] Rawson N. Timeliness of review and approval of new drugs in Canada from 1999 through 2001: is progress being made? Clinical Therapeutics 2003;25:1230–47. [2] Canada’s Research-Based Pharmaceutical Companies. Drug approval times in Canada. http://www.canadapharma.org/ Industry Publications/Fact Sheets/drugapprovaltimes 01 e.pdf; 2001 [accessed March 27, 2005]. [3] Graham JR. Prescription drug prices in Canada and the United States—Part 4: Canadian prescriptions for American patients are not the solution. Vancouver: Fraser Institute; September 2003.
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[4] Patented Medicine Prices Review Board. PMPRB annual report 2003. Ottawa: PMPRB; 2004. [5] Patented Medicine Prices Review Board. Annual report 2001. Ottawa: PMPRB; 2002. [6] Drugs in 2001: a number of ruses unveiled. Prescrire International 2002;11:58–60. [7] Therapeutic Products Directorate: TPD-Web. Special access programme-drugs; 2002. http://www.hc-sc.gc.ca/hpfb-dgpsa/ tpd-dpt/sap factsheet2002 e.html [accessed February 18, 2005]. [8] Who we are. The Medical Letter. http://www.medletter. com/html/who.htm; 2005 [accessed December 21, 2005]. [9] Therapeutic Products Directorate: TPD-Web. Notice of compliance listings. http://www.hc-sc.gc.ca/hpfb-dgpsa/tpddpt/index drugs noc e.html - 2004; 2005 [accessed March 15, 2005]. [10] Patented Medicine Prices Review Board. Legislation, regulations and guidelines: compendium of guidelines, policies and procedures; 2004. http://www.pmprb-cepmb.gc.ca/ english/View.asp?x=135&mp=73 [accessed March 27, 2005]. [11] Center for Drug Evaluation and Research. Manual of policies and procedures (MaPPs). Food and Drug Administration. http://www.fda.gov/cder/regulatory/default.htm; 2005 [accessed March 27, 2005]. [12] Food and Drug Administration. FY 2003 performance report to the president and the congress. Appendix B:
[13]
[14] [15] [16]
[17]
[18] [19]
[20]
list of approved applications. http://www.fda.gov/oc/pdufa/ report2003/appendixb2003.html; 2005 [accessed February 18, 2005]. Center for Drug Evaluation and Research. Drugs @ FDA. Food and Drug Administration. http://www.accessdata. fda.gov/scripts/cder/drugsatfda/index.cfm?CFID=5590034& CFTOKEN=16354048; 2005 [accessed March 27, 2005]. Stat View 5.0.1. Cary, NC: SAS Institute Inc.; 1999. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74. Center for Drug Evaluation and Research. NDAs approved in calendar years 1990–2003 by therapeutic potentials and chemical types; 2004. http://www.fda.gov/cder/rdmt/pstable.htm [accessed February 14, 2005]. Yasuda SU, Woosley RL. The clinical value of FDA class C drugs approved from 1981 to 1988. Clinical Pharmacology and Therapeutics 1992;52:577–82. Ursodeoxycholic acid. Primary biliary cirrhosis: dashed hopes. Prescrire International 2002;11:67–9. Tomalin A. A quick trip to the market: ten simple steps to hasten approval times for new drugs in Canada. Canadian Pharmaceutical Marketing 2000;winter:27–9. Rawson NSB, Kaitin KI. Canadian and US drug approval times and safety considerations. Annals of Pharmacotherapy 2003;37:1403–8.
A comparison of new drug availability in Canada and the United States and potential therapeutic implications of differences Joel Lexchin a,b,c,∗ a
School of Health Policy and Management, York University, 4700 Keele St., Toronto, Ont., Canada M3J 1P3 b Emergency Department, University Health Network, Canada c Department of Family and Community Medicine, University of Toronto, Toronto, Ont., Canada
Abstract Background: Claims are made that new valuable drugs are not available in Canada at the time that they are marketed in the United States. This study uses a convenience sample of new drugs marketed in the United States and determines how many of these products are initially unavailable in Canada and their therapeutic value. Methods: Issues of the Canadian edition of The Medical Letter from May 12, 2003 to June 21, 2004 were hand searched for evaluations of new drugs and the following information was recorded: indication, availability in Canada and conclusions about therapeutic value. For drugs not available in Canada two clinical pharmacologists rated the therapeutic value of the products and the type of FDA review (standard or priority) was recorded. A database from the Therapeutic Products Directorate was searched to see if any of the drugs initially unavailable were subsequently marketed. Results: Thirty-two of 37 drugs were not available in Canada. Between 9 and 11 of these products were rated as offering moderate to significant therapeutic gains. Twelve of the 32 drugs eventually were marketed in Canada. Interpretation: Although the majority of new drugs marketed in the United States but not available in Canada do not offer any therapeutic advantage, between about a quarter and a third of may offer moderate to significant therapeutic gains. The reasons why these drugs are unavailable and how much their absence affects the treatment Canadians receive should be the subject of future research. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Therapeutic value; Canada; United States; Prescription medications; Therapeutic Products Directorate; Food and Drug Administration
1. Introduction Medications are one of the cornerstones of modern health care. If the introduction of new drugs is delayed ∗
Tel.: +1 416 736 2100x22119/964 7186; fax: +1 416 736 5227. E-mail addresses: [email protected], [email protected].
patients may potentially receive therapeutically inferior care. Currently, Canada takes significantly longer to approve new drugs than does either the United States or Sweden [1] and the pharmaceutical industry charges that delays in Canada keep important new products from reaching Canadians in a timely manner [2]. Organizations, such as the Fraser Institute, are arguing that internet sales from Canada to the United
0168-8510/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.healthpol.2005.12.015
J. Lexchin / Health Policy 79 (2006) 214–220
States might reduce international drug company profits to such an extent that the preferred alternative would be to forego Canadian sales and not market the product in Canada [3]. Finally, price limitations on patented medications, imposed by the Patented Medicine Prices Review Board, may discourage marketing in Canada [4]. At the same time, there are evaluations that suggest that most new drugs do not offer any significant therapeutic gain [5,6]. Even if some important new drugs have their approval delayed or companies decide never to submit them for approval in Canada, individual patients would still able to obtain them through Health Canada’s Special Access Programme [7]. This program allows doctors to obtain unapproved drugs on a patient-by-patient basis. However, this mechanism is clearly inferior to having products freely available through the normal prescription route. This study uses a convenience sample of new drugs marketed in the United States (U.S.) and determines how many of these products are unavailable in Canada and their potential therapeutic value.
2. Methods On May 12, 2003 The Medical Letter started publishing a Canadian edition. The Medical Letter evaluates virtually all new drugs marketed in the U.S. [8] with the Canadian edition giving Canadian prices and indicating whether the medication is approved in Canada. Issues of The Medical Letter from May 12, 2003 to June 21, 2004 (volume 45, no. 1156 to volume 46, no. 1185) were hand searched. The name of each individual drug that was evaluated was recorded along with the following information: indication, manufacturer and availability in Canada. Information in The Medical Letter about whether or not the drug was marketed in Canada was confirmed through the web site of the Therapeutic Products Directorate (TPD), the Canadian equivalent of the FDA [9]. The Medical Letter’s assessment of the therapeutic value of the new product was recorded. Evaluations from The Medical Letter were used because it is the oldest and most respected independent drug bulletin in North America.
215
Two clinical pharmacologists who are also practicing general internists and who have extensive experience in critical appraisal of drug research and writing prescribing guidelines were sent a list of the drugs that were not available in Canada along with The Medical Letter’s conclusion about the therapeutic value of these drugs. They were asked to use the conclusion to provide an overall evaluation of the value of the new drugs using the following scale: little or no therapeutic advantage over existing products (category 1); moderate therapeutic advantage compared to existing drugs (category 2); significant therapeutic advantage compared to existing drugs (category 3). This rating classification was chosen because it is similar to the one that is used by the Canadian Patented Medicine Prices Review Board [10]. Ratings were done independently and discrepancies resolved by consensus. Drugs submitted for approval to the U.S. Food and Drug Administration (FDA) receive either a standard or a priority review. Drugs that are thought to be potentially significant therapeutic advances are granted priority reviews. All other drugs receive a standard review [11]. As a check on the ratings by the clinical pharmacologists, the FDA review status [12] was recorded for each of the drugs that the clinical pharmacologists were asked to rate and a Kappa score was computed to compare the two sets of ratings. For the purpose of computing the Kappa score if the clinical pharmacologists put the drug into either categories 2 or 3 that was deemed to be equivalent to a priority review. Approval dates in the United States were obtain from the web site of the FDA [13]. The availability of drugs not initially marketed in Canada was checked as of July 29, 2005 through the web site of the TPD [9]. The delay between Canadian and American approval dates was calculated in days. Since The Medical Letter chooses which drugs to write about based on U.S. approvals its evaluations would be delayed for drugs first marketed in Canada and there would not be any assessment of drugs only available in Canada. To see if this was a concern the approval dates for all new active substances (drugs not marketed before in any form) and new combination products approved in Canada in 2003 were reviewed [9] and compared to dates in the U.S. [13]. Descriptive statistical analysis was done using Stat View 5.0.1 for Macintosh [14].
216
J. Lexchin / Health Policy 79 (2006) 214–220
3. Results From May 12, 2003 to June 21, 2004 The Medical Letter evaluated 37 new drugs marketed in the U.S. Table 1 lists the 32 products not available in Canada. The two clinical pharmacologists evaluated the therapeutic value of these 32 drugs (see Table 1). Nineteen were rated as little or no improvement (category 1), six were moderate improvements (category 2) and one was a significant improvement (category 3). In some cases the conclusions in The Medical Letter meant that the two expert reviewers could not come to a definite interpretation about the drugs. Two drugs were felt to be generally category 1 but, for their approved indications, in some selected populations or in certain circumstances they might be moderate advances (category 2). For another two, the data were not robust enough to distinguish between categories 2 and 3. Finally, the reviewers felt that it was too early in the lifecycle of two drugs to make any decisions. Eleven of the 32 drugs received a priority review from the FDA, including the two that the reviewers were unable to rate (Table 1). After removing the two unrated drugs from the analysis, the Kappa score for agreement on therapeutic value between the clinical pharmacologists and the FDA was 0.52 indicating moderate agreement. Assuming that the two cases where the reviewers were unable to rate the drugs represented a disagreement with the FDA assessment, the Kappa score drops to 0.42, a value at the low end of moderate agreement [15]. By late July 2005, 12 of the drugs that had not initially been available in Canada had been approved. The median delay between American and Canadian approval dates was 259 days (inter-quartile range 358 days). For the 20 drugs that were not yet approved in Canada, the median time since American approval was 714 days (inter-quartile range 196 days). In 2003 there were 31 new active substances and new combination products approved in Canada. Twentyfive had already been approved in the U.S., four were initially approved in Canada and two drugs marketed in Canada were not marketed in the U.S. although slight variations of the Canadian drugs were available in the U.S. and had been approved prior to the Canadian drugs. For the four drugs first marketed in Canada, U.S. delays were 65, 93, 175 and 309 days. The therapeutic significance of these products was not assessed by the
two clinical pharmacologists and the FDA ratings were not accessed.
4. Discussion Almost 90% (32/37) of the new drugs assessed by The Medical Letter over a 13 month period (May 12, 2003–June 21, 2004) were unavailable in Canada at the time of publication of The Medical Letter. Out of those 32, about two-thirds [19–20] were considered to offer little to no therapeutic advantage over existing products by both the clinical pharmacologists and the FDA. Nine to 11 may have been either moderate or significant therapeutic improvements based on the ratings given to them by the two sources. Twelve out of the 32 drugs were marketed in Canada as of July 29, 2005, the time of completion of the analysis done for this paper. Nine of these products were in category 1 based on the clinical pharmacologists’ ratings and 10 received a standard review by the FDA. The method of sampling used for this study did not necessarily give a full picture of the additional therapeutic value that may be achieved from drugs marketed in the U.S. but not in Canada. The therapeutic gain from products not assessed by The Medical Letter is unknown and the current sample may not be representative of all drugs approved by the FDA in terms of therapeutic gain. However, it is likely that drugs of greater therapeutic value were oversampled in this study. In the period 2001–2003, the FDA gave 16% of all the products it reviewed a priority review [16]. Out of the sample of 32 drugs that were considered in this study over one-third received a priority review. An alternative approach to this issue would have been to identify drugs approved by the FDA over a 13 month period. However, this approach would have yielded a smaller sample size. Over the past 5 years the FDA has been approving an average of 29 new molecular entities annually [12] which is smaller than the sample of 37 drugs used in this study. While there may be drugs with moderate to significant therapeutic benefit that are available in Canada but not in the U.S. the number of these products is likely to be very small based on the fact that 27 of the 31 new drugs approved in Canada in 2003 were already marketed in the U.S.
Table 1 Drugs assessed by The Medical Letter and their availability in Canada Name
Abarelix
Cetuximab
Cyclosporine 0.05% ophthalmic emulsion Daptomycin Efalizumab Emtricitabine Entacapone + levodopa/carbidopa Epinastine HCl 0.05% ophthalmic solution Eplerenone Nasally administered influenza vaccine (Flumist® )
Advanced symptomatic prostate cancer in patients who should not take luteinizing hormone-releasing hormone Fabry disease Panic disorder Protease inhibitor Rosacea Metastatic colon cancer in combination with a fluorouracil-based regimen Metastatic colon cancer in patients with epidermal growth factor receptor expressing tumour either in combination with irinotecan when cancer progressed on irinotecan-based therapy or as monotherapy for those who cannot tolerate irinoteccan Dry eye disease IV treatment of complicated skin and skin structure infections Moderate to severe chronic plaque psoriasis Nucleoside analogue reverse transcriptase inhibitor Parkinson’s disease with end-of-dose “wearing off” Prevention of itchiness associated with allergic conjunctivitis Hypertension; heart failure Influenza vaccine
FDA priority review
Clinical pharmacologists’ rating
Availability in Canada At time of Medical Letter evaluation
July 29, 2005
FDA approval date
Canadian approval date
Canadian delay (days)
Yes
Category 2
No
No
11/25/2003
Yes No Yes No Yes
Category 2 Category 1 Category 2 Category 1 Categories 2 or 3
No No No No No
Yes No Yes No No
4/24/2003 1/17/2003 6/20/2003 12/24/2002 1/26/2004
Yes
Category 1
No
No
2/12/2004
533a
Yes
Unrated
No
No
12/23/2002
949a
Yes
Category 1
No
No
9/12/2003
686a
No
Categories 1 or 2
No
No
10/27/2003
641a
No
Category 1
No
No
7/20/2003
740a
No
Category 2
No
No
6/11/2003
779a
No
Category 1
No
No
10/16/2003
652a
No No
Categories 1 or 2 Category 1
No No
No No
9/27/2002 2/11/2004
1036a 534a
612a
1/23/2004 12/5/2003
274a 924a 168 948a 550a
J. Lexchin / Health Policy 79 (2006) 214–220
Agalsidase beta Alprazolam-extended release Atazanavir Azelaic acid 15% gel Bevacizumab
Indication
217
218
Gatifloxacin 0.3% ophthalmic drops Memantine Moxifloxacin 0.5% ophthalmic drops Olanzapine/fluoxetine Omalizumab
Pemetrexed Pentavalent vaccine (Pediarix® ) Recombinant human alpha-l-iduronidase Seasonale® Sertaconazole 2% cream Testosterone 1% gel Testosterone buccal tablet Tositumomab + radiolabeled Iodine-131 tositumomab (Bexxar® ) Vardenafil Zolmitriptan nasal spray a
Delay as of July 29, 2005.
No
Category 1
No
Yes
3/28/2003
8/30/2004
521
Alzheimer’s disease Bacterial conjunctivitis
No No
Category 1 Category 1
No No
Yes Yes
10/16/2003 4/15/2003
12/8/2004 5/11/2003
419 26
Depressive episodes associated with bipolar disorder Moderate to severe persistent asthma in those who have shown reactivity to an allergan and whose symptoms are inadequately controlled by an inhaled corticosteroid Overactive bladder Prevention of acute and delayed nausea and vomiting due to moderately and highly emetogenic cancer chemotherapy Malignant pleural mesothelioma Pediatric vaccine Enzyme replacement in mucopolysaccharidosis type I Extended cycle oral contraceptive Interdigital tinea pedis Hypogonadism Hypogonadism Relapsed follicular non-Hodgkin’s lymphoma refractory to rituximab
Yes
Category 1
No
No
12/24/2003
No
Category 1
No
Yes
6/20/2003
11/18/2004
517
No No
Category 1 Category 2
No No
Yes No
2/26/2003 7/25/2003
10/22/2004
604 735a
No Yes Yes
Category 2 Categories 2 or 3 Category 3
No No No
Yes Yes No
2/4/2004 12/13/2002 4/30/2003
5/21/2004 8/13/2003
107 243 821a
No No No No Yes
Category 1 Category 1 Category 1 Category 1 Unrated
No No No No No
No No Yes No No
9/5/2003 12/10/2003 2/28/2000 6/19/2003 6/27/2003
2/6/2002
693a 597a 709 771a 763a
Erectile dysfunction Migraine
No No
Category 1 Category 1
No No
Yes Yes
8/19/2003 9/30/2003
3/17/2004 3/2/2004
211 154
583a
J. Lexchin / Health Policy 79 (2006) 214–220
Oxybutynin (transdermal) Palonesetron
Bacterial conjunctivitis
J. Lexchin / Health Policy 79 (2006) 214–220
The two pharmacologists who rated the drugs were asked to rely on material from The Medical Letter. Under other circumstances they would have used a wider range of information in coming to their conclusions. Furthermore, they did not consider cost in categorizing the drugs. Other people using the same information may have reached different conclusions. Adding more information may have changed their conclusions, but The Medical Letter evaluations are already based on an extensive assessment including a review of the published and unpublished literature, the expert opinions of 10–20 investigators who have clinical and experimental experience with the drug, the FDA, the Centers for Disease Control and Prevention, the first authors of all the articles cited in The Medical Letter review, and the pharmaceutical companies making the drugs under review [8]. There was only moderate agreement between the drugs rated as moderate to significant improvements by the two reviewers and the ones given a priority review by the FDA. This finding is not necessarily unexpected as the evaluations of the drugs were taking place at different periods in the drugs’ life cycle: the FDA assessment was done before the drugs were marketed while the reviewers were looking at information about the drugs partly gathered in the post-marketing phase. The eventual value of drugs can change either positively [17] or negatively [18] as they move through their life cycle. Moreover, according to both sets of ratings about a third of the drugs not available in Canada had added therapeutic value; either categories 2 or 3 or a priority review. On average, the drug approval process in the United States is 7.8 months faster than in Canada [2]. This difference would explain the median 259-day delay in marketing the 12 drugs that subsequently became available in Canada. However, after a median of 714 days, more than three times the usual regulatory delay, the other 20 drugs were still not available in Canada suggesting that there are a number of other reasons for the unavailability besides longer Canadian approval times. Differences in filing dates between Canada and the U.S. may contribute to Canadian unavailability but are not the sole factor. Companies usually submit their drugs to Health Canada 6–9 months after they file with the FDA [19]. There is no publicly accessible database for the filing dates of individual drugs in Canada so this explanation cannot be explored any further.
219
Companies may choose not to market some of their products in Canada. The much larger American market with its higher prices makes it more economically attractive. A small Canadian market and/or limitations on introductory prices imposed by the Patented Medicine Prices Review Board may mean that expected sales are too low to warrant the costs of getting a drug approved and then promoting it in Canada. Drugs approved in the U.S. may have been rejected in Canada but the TPD does not release the names of products it rejects so whether or not this is a factor in the 20 unmarketed drugs is unknown. Finally, having new drugs available early is not always a benefit. There are a number of drugs that were sold in the U.S. that had to be withdrawn for safety reasons before they were on the Canadian market [20]. Whether or not the fact that Canadians were not exposed to these products offsets the absence of drugs that have moderate to major therapeutic benefits is an open question. The findings from this report indicate that most new drugs available in the United States but not marketed in Canada do not represent much in the way of therapeutic gains. A substantial minority may offer moderate to significant therapeutic advantages over existing therapies. The reasons why these drugs are unavailable and how much their absence affects the treatment Canadians receive needs to be investigated.
Acknowledgements Drs. Anne Holbrook and Mitchell Levine evaluated the therapeutic value of the drugs and provided valuable comments on the manuscript.
References [1] Rawson N. Timeliness of review and approval of new drugs in Canada from 1999 through 2001: is progress being made? Clinical Therapeutics 2003;25:1230–47. [2] Canada’s Research-Based Pharmaceutical Companies. Drug approval times in Canada. http://www.canadapharma.org/ Industry Publications/Fact Sheets/drugapprovaltimes 01 e.pdf; 2001 [accessed March 27, 2005]. [3] Graham JR. Prescription drug prices in Canada and the United States—Part 4: Canadian prescriptions for American patients are not the solution. Vancouver: Fraser Institute; September 2003.
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[4] Patented Medicine Prices Review Board. PMPRB annual report 2003. Ottawa: PMPRB; 2004. [5] Patented Medicine Prices Review Board. Annual report 2001. Ottawa: PMPRB; 2002. [6] Drugs in 2001: a number of ruses unveiled. Prescrire International 2002;11:58–60. [7] Therapeutic Products Directorate: TPD-Web. Special access programme-drugs; 2002. http://www.hc-sc.gc.ca/hpfb-dgpsa/ tpd-dpt/sap factsheet2002 e.html [accessed February 18, 2005]. [8] Who we are. The Medical Letter. http://www.medletter. com/html/who.htm; 2005 [accessed December 21, 2005]. [9] Therapeutic Products Directorate: TPD-Web. Notice of compliance listings. http://www.hc-sc.gc.ca/hpfb-dgpsa/tpddpt/index drugs noc e.html - 2004; 2005 [accessed March 15, 2005]. [10] Patented Medicine Prices Review Board. Legislation, regulations and guidelines: compendium of guidelines, policies and procedures; 2004. http://www.pmprb-cepmb.gc.ca/ english/View.asp?x=135&mp=73 [accessed March 27, 2005]. [11] Center for Drug Evaluation and Research. Manual of policies and procedures (MaPPs). Food and Drug Administration. http://www.fda.gov/cder/regulatory/default.htm; 2005 [accessed March 27, 2005]. [12] Food and Drug Administration. FY 2003 performance report to the president and the congress. Appendix B:
[13]
[14] [15] [16]
[17]
[18] [19]
[20]
list of approved applications. http://www.fda.gov/oc/pdufa/ report2003/appendixb2003.html; 2005 [accessed February 18, 2005]. Center for Drug Evaluation and Research. Drugs @ FDA. Food and Drug Administration. http://www.accessdata. fda.gov/scripts/cder/drugsatfda/index.cfm?CFID=5590034& CFTOKEN=16354048; 2005 [accessed March 27, 2005]. Stat View 5.0.1. Cary, NC: SAS Institute Inc.; 1999. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74. Center for Drug Evaluation and Research. NDAs approved in calendar years 1990–2003 by therapeutic potentials and chemical types; 2004. http://www.fda.gov/cder/rdmt/pstable.htm [accessed February 14, 2005]. Yasuda SU, Woosley RL. The clinical value of FDA class C drugs approved from 1981 to 1988. Clinical Pharmacology and Therapeutics 1992;52:577–82. Ursodeoxycholic acid. Primary biliary cirrhosis: dashed hopes. Prescrire International 2002;11:67–9. Tomalin A. A quick trip to the market: ten simple steps to hasten approval times for new drugs in Canada. Canadian Pharmaceutical Marketing 2000;winter:27–9. Rawson NSB, Kaitin KI. Canadian and US drug approval times and safety considerations. Annals of Pharmacotherapy 2003;37:1403–8.