How long do new medicines take to reach Canadian patients after companies file a submission: A cohort study.

INTRODUCTION: Studies of the delay between when companies file a New Drug Submission (NDS) and when drugs reach Canadian patients typically focus on the time in the regulatory review process and do not analyze the time between when approval is granted and the drug is available for purchase (company decision time). This study looks at the length of the two different time periods. Secondarily, it examines whether there is a difference in these time periods for drugs that received a standard review and those that received an expedited review.
METHODS: A list of all New Active Substances approved in Canada between January 1, 2014 and December 31, 2018 was compiled and the dates when the companies applied for a NDS, the dates when the drugs received a market authorization (Notice of Compliance, NOC) and whether the drugs received a standard review or an expedited review were recorded. The date of original marketing comes from Health Canada's Drug Product Database. Times in days were calculated between NDS and NOC (review time), between NOC and the marketing date (company decision time) and between NDS and the marketing date (total time). The company decision time as a percent of the total time was calculated for all drugs. Times were compared between standard and expedited review drugs using a two-tailed t-test.
RESULTS: One hundred and fifty-seven drugs were analyzed, 98 had a standard review and 59 had a priority review. Over 18% of the total time was due to company decisions. All three times were significantly lower for expedited review drugs versus standard review drugs as was the percent of total time due to company decision- 14.4% (95% CI 11.0, 17.8) versus 21.2% (95% CI 17.6, 24.8), p = 0.0102 (t-test).
CONCLUSIONS: Over 18% of the total time between when companies file for drug approval until the drug is available is due to decisions made by companies. Company decision times are shorter for drugs with expedited approvals compared to drugs with standard approvals.

Introduction

The time between when drug companies file a New Drug Submission (NDS) to get permission to market a new active substance (NAS, a molecule never marketed before in Canada) and when the drug is actually available for purchase has two components. The first is the time taken in the regulatory process until the drug receives a Notice of Compliance (NOC, market authorization). The second is the time between the NOC and when the drug appears on pharmacy shelves. The first period is largely determined by the activities of the Therapeutic Products Directorate (TPD) and the Biologics and Genetic Therapies Directorates (BGTD), the arms of Health Canada that approve small molecule drugs and biologics, respectively [1]. The second period is determined by internal decisions by the company marketing the drug. Some of these decisions may include whether to wait until a recommendation on provincial/territorial funding has been made, how to position the drug with respect to potential competitors, training sales staff in promotion, etc.

Studies of the delay between when companies file a NDS and when drugs reach Canadian patients typically focus on the time in the regulatory review process and do not analyze the company decision time [2, 3]. The lack of differentiation between the two times can potentially lead to a misplaced focus on what types of reforms are necessary should it be necessary to expedite the marketing of new drugs.

This study looks at the length of the two different time periods and the percent of total time from NDS to marketing taken up by company time. Secondarily, it examines whether there is a difference in these time periods for drugs that received a standard review and those that received either of two expedited reviews–priority review or a Notice of Compliance with conditions–review processes designed to ensure that promising therapies for serious, life-threatening or debilitating illnesses reach Canadians in a timely manner [4, 5]. Finally, because companies may wait for a recommendation about public funding before marketing their products, the marketing date is compared to the date when the funding recommendation is made.

Methods

Data sources

A list of all NAS approved in Canada between January 1, 2014 and December 31, 2018 was compiled from the annual reports of the TPD and BGTD. (Reports are available by directly contacting the directorates at publications@hc-sc.gc.ca) The brand and generic names of the drugs were recorded in an Excel spreadsheet along with the dates when the companies applied for a NDS, the dates when the drugs received a NOC, whether the drugs received a standard review (300 days) or an expedited review (priority review– 180 days, NOC/c review– 200 days) and whether they were small molecule drugs or biologics. The annual reports are regarded as the authoritative sources of such information. Health Canada does not provide information about when companies apply for new indications to existing products or when it makes decisions about these applications. Therefore, this study only examines NAS and not new indications for drugs already marketed.

Health Canada’s Drug Product Database (DPD) [6] gives the date when a product is originally marketed, defined on the website as the “earliest marketed date recorded in the Drug Product Database”. The DPD was initially searched on February 7, 2020 and the search was repeated on July 9, 2020 and the marketing date was recorded on the same Excel spreadsheet.

The Common Drug Review (https://www.cadth.ca/about-cadth/what-we-do/products-services/cdr/reports) and the pan-Canadian Oncology Drug Review (https://www.cadth.ca/pcodr/find-a-review), both arms of the Canadian Agency for Drugs and Technology in Health, make publicly available the timelines for the drugs that they review. The date of the final recommendation was recorded.

Data analysis

Mean times in days over the entire 5-year time period were calculated between NDS and NOC (review time), between NOC and the marketing date (company decision time) and between NDS and the marketing date (total time) for all drugs and then for drugs with a standard review and an expedited review, for small molecule drugs versus biologics and for drugs with a priority review versus those that went through the Notice of Compliance with conditions pathway. The marketing date and the date of the final recommendation on funding were compared to see which one came first. Finally, median times in days for each of review time, company decision time and overall time for the entire sample of drugs were also calculated for individual years. The company decision time as a percent of the total time was calculated for all drugs, drugs with a standard review and drugs with an expedited review. Times were compared between standard and expedited review drugs using a two-tailed t-test. Repeating the analyses using medians and the Mann-Whitney test did not change the outcomes and so only means are reported. Review times, company decision times and overall times over each of the 5 years were separately compared for all drugs using the Kruskal-Wallis test. All calculations were done with Prism 8.3.1 (GraphPad Software).

Results

From January 1, 2014 to December 31, 2018 there were 176 NAS approved in Canada. The original marketing dates were available for 157 of these and the analysis is based on this group. Over the 5-year period, 83% to 96% of drugs approved were eventually marketed, depending on the year. Ninety-eight drugs had a standard review and 59 had an expedited review. S1 File contains the complete data.

The mean total time for all drugs was 537 days (95% confidence interval (CI) 490, 583), the review time was 403 days (95% CI 374, 433) and the company time was 133 days (95% CI 101, 165) (Table 1). Over 18.5% of the total time was due to company decisions (Table 1). All three times were significantly lower for expedited review drugs versus standard review drugs as was the percent of total time due to company decision– 14.4% (95% CI 11.0, 17.8) versus 21.2% (95% CI 17.6, 24.8), p = 0.0102 (t-test) (Table 1).

Table 1

Time from New Drug Submission to marketing of new active substances.

	Time from NDS to marketing (total time) in days (mean, 95% confidence interval)	Time from NDS to NOC in days (review time) (mean, 95% confidence interval)	Time from NOC to marketing (company decision time) in days (mean, 95% confidence interval)	Company decision time as percent of total time (mean, 95% confidence interval)
All drugs	537 (490, 583)	403 (374, 433)	133 (101, 165)	18.5 (15.9, 21.1)
Standard review	646 (585, 708)*	467 (429, 505)*	179 (131, 228)†	21.2 (17.6, 24.8)‡
Expedited review	354 (313, 395)*	298 (264, 332)*	56 (38, 74)†	14.4 (11.0, 17.8)‡

NDS = New Drug Submission

NOC = Notice of Compliance

*Statistically significant difference, p < 0.0001 (t-test)

†Statistically significant difference, p = 0.0002 (t-test)

‡ Statistically significant difference, p = 0.0102 (t-test)

The date when the funding recommendation was finalized was available for 114 products. The market date occurred before the funding recommendation date for 104 (91.2%) products and on the same date for one product.

There was no statistically significant difference in median review time (p = 0.2386, Kruskal-Wallis test), median company decision time (p = 0.7226, Kruskal-Wallis test) or median overall time (p = 0.2804, Kruskal-Wallis test) over the 5-year period (Table 2).

Table 2

Review time, company decision time, total time: 2014–2018.

Median review time (IQR) (days)*					Median company time (IQR) (days)†					Median overall time (IQR) (days)‡
2014	2015	2016	2017	2018	2014	2015	2016	2017	2018	2014	2015	2016	2017	2018
388 (222, 665)	356 (330, 451)	349 (280, 406)	349 (261, 415)	349 (213, 454)	41 (15, 102)	68 (28, 151)	51 (23, 145)	62 (31, 113)	57 (35, 120)	512 (309, 781)	479 (368, 820)	430 (311, 562)	411 (283, 527)	405 (307, 588)

IQR = interquartile range

*No statistically significant difference, p = 0.0947 (Kruskal-Wallis test)

†No statistically significant difference, p = 0.8738 (Kruskal-Wallis test)

‡No statistically significant difference, p = 0.1683 (Kruskal-Wallis test)

Total time and review times were statistically significantly longer for drugs that went through the NOC/c pathway compared to those that received a priority review while company time was not statistically significantly different. All three times were not statistically significantly different when small molecules and biologics were compared. (Data not shown.)

Discussion

Almost one fifth of the time between when companies file a new drug submission to the time when doctors are able to prescribe a drug is due to company decisions. This figure drops to 13.9% for drugs that received an expedited review compared to 21.5% for drugs with a standard review indicating that companies move more rapidly in making these drugs available. Shorter company decision time could be a reflection of the therapeutic value of the drugs, the revenue that companies expect from sale of the drugs or a combination of both. However, there is no difference in company decision time when biologics are compared to small molecules or when drugs with a priority review are compared to those that went through the NOC/c pathway. Priority review times were shorter than review times in the NOC/c pathway.

In the vast majority of cases, companies marketed their products before the final funding recommendation was made suggesting that the time taken for the funding recommendation was not a factor in delaying marketing. There are no other studies that have explored these two time periods so the Canadian data cannot be compared to data from other countries.

Neither Health Canada’s review time nor the company decision time about when to actually put the medicine on pharmacy shelves changed over the 5-years. The absence of any change in these two metrics means that over the time period there was no change in company time as a percent of total time from filing of an NDS to the time the drug was actually marketed.

The reason behind the time that companies take to make a decision about when to market a drug was not explored in this study but it is probably due to a combination of factors such as distribution of the drug across the country, preparing marketing materials, competition from other similar products and remaining patent time.

Median Canadian review times in 2017 were about 100 days longer than those in the United States, although 70 days shorter than in the European Union [7]. The shorter American time may be a reflection of greater use of expedited review processes or it may be because Health Canada is less efficient than the Food and Drug Administration. Depending on the balance of the two factors there may be an opportunity to shorten Canadian review times and market drugs more quickly. However, this study also shows that drugs could be brought to market faster if companies are able to improve their decision making time once drugs have been approved. Treating standard review drugs in a similar manner to priority review ones would result in them reaching the market 123 days earlier.

This study relied on the accuracy of the information on Health Canada websites and in Health Canada reports and there was no way of verifying the accuracy of that information.

Conclusion

Over 18% of the total time between when companies file for drug approval until the drug is available is due to decisions made by companies. The time taken for a funding recommendation to be made does not appear to be a factor in when companies decide to market their drugs. Company decision times are shorter for drugs with expedited approvals compared to drugs with standard approvals.

Complete data.

(XLSX)

Click here for additional data file.

27 Aug 2020

PONE-D-20-04228

How long do new medicines take to reach Canadian patients after companies file a submission: a cohort study

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Reviewer #1: Summary of the research and your overall impression

The manuscript claims that the company decision time takes a certain part of the time between the submission of a New Drug Submission (NDS) and first date that it is on the market.

The strength of this manuscript is the use of solely publicly available information. A weakness is that the publicly available information can not be verified. Different dates of ‘Date of NDS submitted’ and ‘Date of Notice of Compliance’ are mentioned in the reports compared to dates mentioned on the website (https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-result.php?lang=en&term=#).

Discussion of specific areas for improvement

Major issues

1. The author has done extensive research, however something crucial has been missed: The first marketing date in the Health Canada’s Drug Product Database (DPD) is not always the earliest date of marketing. Therefore the ‘data of marketing’ does not always match the earliest date of marketing. I strongly advise the author to check the dates on the earliest date of marketing again, specifically for:

- Praluent;

- Bosulif;

- Invokana;

- Ferriprox;

- Nitisinone (here it appears that the marketing data of MDK-nitisinone was used);

- Ibrance;

- Mictoryl;

- Kevzara, and

- Cosentyx.

2. Although most of the ‘date NDS submitted’ data in the supplementary data are correct, there seems to be a few dates accidentally copied wrong, namely:

- Dymista – 4 November 2013;

- Tremfya – 25 November 2016, and

- Tegsedi – 7 March 2018.

3. Although most of the ‘Date of Notice of Compliance’ data in the supplementary data are correct, however there seems to be one date accidentally copied wrong, namely:

- Ravicti – 18 March 2016.

4. The introduction should be expanded and clarified to ensure that readers understand exactly why this research question is interesting/ why this is a problem.

5. The author is off to a good, interesting start. It is beneficial to this study to add two sub-analyses: 1) the influence of the two expedited reviews: priority review versus Notice of Compliance with conditions; and 2) The difference in time between the TPD and BGTD.

6. While the author appears to have a solid discussion, it appears to me it misses a clear take-home message to the discussion: why is it important to know what the company-decision time is?

Minor issues

1. Although the introduction is clear, no references were used in the first paragraph. The author should add one or more references here (line 56).

2. The author should clarify the definition of internal decisions by the company in the introduction (line 56) to avoid confusion: does this for example include the choice to wait with pricing regulation/ submitting to the HTA body till after receipt of NOC or NOC/c?

3. The author should move the aim of the paper to the last paragraph of the introduction. Subsequently should the aim also be addressed in the discussion.

4. A good addition to the methods section would be to specify that this study only looks at New Active Substances and not at extensions of the indication.

5. The author’s mentioning of the time which a standard review and an expedited review should take (line 76 and 77) creates the idea that the time from NDS to NOC is too long. This should be clarified/discussed in the discussion. The extra time can (partly) be explained by the time the regulatory authority has to wait on the additional data from the company to make up for the deficiency in the application.

6. The author should add a reference to the TPD and BGTD reports (line 73).

7. The author should add abbreviations under Table 1.

8. The discussion should be expanded and be put into context of previously published research on this topic: Is the time in regulatory process better or worse in comparison to these articles?

9. The author should add a reference to line 119 and 124.

- Unfortunately, I do not have the expertise to consider the statistics.

Although this paper needs some revisions, I really appreciate the issue the author poses: the time between the submission of the NDS till the drug is available for the patients depends not only on the regulatory authority, but also on the decision(s) of the company. If this issue is better defined this will be a great publication which is easy to read and to reproduce!

**********

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29 Aug 2020

August 29, 2020

To the Editor:

Thank you and the reviewer for the comments and the opportunity to revise my manuscript. Below I indicate how I have responded to the various comments.

Reviewer #1: Summary of the research and your overall impression

The manuscript claims that the company decision time takes a certain part of the time between the submission of a New Drug Submission (NDS) and first date that it is on the market.

The strength of this manuscript is the use of solely publicly available information. A weakness is that the publicly available information can not be verified. Different dates of ‘Date of NDS submitted’ and ‘Date of Notice of Compliance’ are mentioned in the reports compared to dates mentioned on the website (https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-result.php?lang=en&term=# [hpr-rps.hres.ca]).

The fact that the information cannot be verified is already mentioned in the manuscript.

It is now stated that the annual reports from the TPD and the BGTD are regarded of the authoritative sources of information about the date of NDS and NOC for individual products.

Discussion of specific areas for improvement

Major issues

1. The author has done extensive research, however something crucial has been missed: The first marketing date in the Health Canada’s Drug Product Database (DPD) is not always the earliest date of marketing. Therefore the ‘data of marketing’ does not always match the earliest date of marketing. I strongly advise the author to check the dates on the earliest date of marketing again, specifically for:

- Praluent;

- Bosulif;

- Invokana;

- Ferriprox;

- Nitisinone (here it appears that the marketing data of MDK-nitisinone was used);

- Ibrance;

- Mictoryl;

- Kevzara, and

- Cosentyx.

I am not sure what other database is available to check the date of marketing but if the reviewer can supply that information, I would be happy to look at the marketing dates in that database. In the meantime, I have checked the DPD for the drugs that the reviewer names. All of the dates listed in the DPD were correctly recorded except for those for Nitisinone and Cosentyx and those have been corrected.

2. Although most of the ‘date NDS submitted’ data in the supplementary data are correct, there seems to be a few dates accidentally copied wrong, namely:

- Dymista – 4 November 2013;

- Tremfya – 25 November 2016, and

- Tegsedi – 7 March 2018.

The dates of NDS submitted for these three drugs were checked against the dates given in the annual reports from the TPD and BGTD and the dates have been corrected.

3. Although most of the ‘Date of Notice of Compliance’ data in the supplementary data are correct, however there seems to be one date accidentally copied wrong, namely:

- Ravicti – 18 March 2016.

The date has been corrected.

4. The introduction should be expanded and clarified to ensure that readers understand exactly why this research question is interesting/ why this is a problem.

The following sentence has been added to the Introduction: “The lack of differentiation between the two times can potentially lead to a misplaced focus on what types of reforms are necessary should it be necessary to expedite the marketing of new drugs.”

5. The author is off to a good, interesting start. It is beneficial to this study to add two sub-analyses: 1) the influence of the two expedited reviews: priority review versus Notice of Compliance with conditions; and 2) The difference in time between the TPD and BGTD.

These additional comparisons have been done and the results are reported.

6. While the author appears to have a solid discussion, it appears to me it misses a clear take-home message to the discussion: why is it important to know what the company-decision time is?

The following passage has been inserted into the Discussion based on the reviewer’s comment: “Median Canadian review times in 2017 were about 100 days longer than those in the United States, although 70 days shorter than in the European Union.(6) The shorter American time may be a reflection of greater use of expedited review processes or it may be because Health Canada is less efficient than the Food and Drug Administration. Depending on the balance of the two factors there may be an opportunity to shorten Canadian review times and market drugs more quickly. However, this study also shows that drugs could be brought to market faster if companies are able to improve their decision making time once drugs have been approved. Treating standard review drugs in a similar manner to priority review ones would result in them reaching the market 123 days earlier.”

Minor issues

1. Although the introduction is clear, no references were used in the first paragraph. The author should add one or more references here (line 56).

A reference has been inserted.

2. The author should clarify the definition of internal decisions by the company in the introduction (line 56) to avoid confusion: does this for example include the choice to wait with pricing regulation/ submitting to the HTA body till after receipt of NOC or NOC/c?

The following section has been added to the Introduction: “Some of these decisions may include whether to wait until a recommendation on provincial/territorial funding has been made, how to position the drug with respect to potential competitors, training sales staff in promotion, etc.”

3. The author should move the aim of the paper to the last paragraph of the introduction. Subsequently should the aim also be addressed in the discussion.

The aim has been moved to the end of the Introduction. The Discussion already begins with a statement of the finding about how long companies take, on average, to make their marketing decisions.

4. A good addition to the methods section would be to specify that this study only looks at New Active Substances and not at extensions of the indication.

The following passage has been added to the end of the first paragraph in the Methods section: “Health Canada does not provide information about when companies apply for new indications to existing products or when it makes decisions about these applications. Therefore, this study only examines NAS and not new indications for drugs already marketed.”

5. The author’s mentioning of the time which a standard review and an expedited review should take (line 76 and 77) creates the idea that the time from NDS to NOC is too long. This should be clarified/discussed in the discussion. The extra time can (partly) be explained by the time the regulatory authority has to wait on the additional data from the company to make up for the deficiency in the application.

I respectfully disagree with the reviewer on this point. The length of time for the various review processes is just a statement of fact and there is no implication that these times are too long. The Summary Basis of Decision document lists the dates between when a Screening Deficiency Notice is issued, if there is one, and when a Screening Acceptance Letter is issued, but does not appear to give the times used in the review process waiting for responses to Clarification Requests. Therefore, the total amount of time taken up waiting for companies to respond to Health Canada requests is not known. As a result, I have not made any changes with respect to this point.

6. The author should add a reference to the TPD and BGTD reports (line 73).

These reports are not posted on the Health Canada website but the email address to request them is already provided in the manuscript.

7. The author should add abbreviations under Table 1.

NDS and NOC are spelled out below Table 1.

8. The discussion should be expanded and be put into context of previously published research on this topic: Is the time in regulatory process better or worse in comparison to these articles?

The Discussion already notes that there is no previously published research comparing review times and company decision times in other countries. The new reference 7 briefly mentions review times in the United States and the European Union.

9. The author should add a reference to line 119 and 124.

“(Table 1)” was added to the end of the sentence that started on line 119 (now line 157) to indicate the source of the figures cited in the preceding sentence. “(Table 1)” already appeared at the end of the sentence on line 124 (now line 159) to indicate the source of the figures cited in the preceding sentence.

- Unfortunately, I do not have the expertise to consider the statistics.

Although this paper needs some revisions, I really appreciate the issue the author poses: the time between the submission of the NDS till the drug is available for the patients depends not only on the regulatory authority, but also on the decision(s) of the company. If this issue is better defined this will be a great publication which is easy to read and to reproduce!

I thank the reviewer for the compliment.

Submitted filename: Response to Reviewer.docx

Click here for additional data file.

7 Oct 2020

How long do new medicines take to reach Canadian patients after companies file a submission: a cohort study

PONE-D-20-04228R1

Dear Dr. Lexchin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Reviewers' comments:

22 Oct 2020

PONE-D-20-04228R1

How long do new medicines take to reach Canadian patients after companies file a submission: a cohort study

Dear Dr. Lexchin:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

Dr. Maarten Postma

Academic Editor

PLOS ONE