REGULATORY
SERIES
A Comparison of Regulatory Approval Times for New Chemical Entities in Australia, Canada, Sweden, the United Kingdom, and the United States Elizabeth
A. Pieterson,
MSc
Regulatory approval times of new chemical entities (NCEs) in Australia, Canada, Sweden, the United Kingdom (UK), and the United States (US) were compared. The approval times of a set of common 25 NCEs and a larger set of unmatched NCEs were very similar in Australia, Canada, Sweden, and the US, with median approval times from 23 to 29 months. The median approval time in the UK was approximately 11 months. Analysis of the data showed that the approval times in Australia, Sweden, and the UK were not significantly affected by the therapeutic classification of the drug, the amount of additional data requested and received, or the submission date. In Canada, the date the drug submission was received and the frequency of additional data requests significantly affected the approval times. In the US, the date the drug submission was received and the frequency of additional data received significantly affected the approval times. The therapeutic classification of the drug did not significantly affect the approval time in Canada or the US.
T
he length of time taken by regulatory agencies to approve new drugs for marketing is frequently criticized in many countries by the pharmaceutical industry, health professionals, and consumers. The timeliness of drug approvals impacts on the financial compensation the pharmaceutical industry receives for its investment in a drug’s development. For the health professional and consumer, regulatory approval times determine when they will have access to drugs that may improve health status and quality of life, or possibly save lives. In Canada, critics of the drug approval process compare Canadian drug availability unfavorably with that in other countries, particularly the United States. Many studies have compared a measure of approval times between two countries, but there has not been a comparison of approval times for the same drug substances in several countries. The major objective of this report is to compare the approval times for the same drug substances in Australia, Canada,
From the Bureau of Pharmaceutical Surveillance, Drugs Directorate, Health and Welfare Canada. Address for reprints: Elizabeth Pieterson, MSc, Bureau of Pharmaceutical Surveillance, Finance Annex, Room 250, Tunney’s Pasture, Ottawa. Ontario Canada KIA 0L2.
.1ClIn Pharmacol
1992;32:889-896
Sweden, the United Kingdom (UK), and the United States (US). Approval time is defined as the total number of calendar days from the receipt of the application to the issuance of marketing approval. Factors that may affect the approval times are also considered to provide topics for future study and cornparison. METHODS Information was requested from the national drug regulatory agencies in Australia, Sweden, the UK, and the US on 70 new chemical entities (NCEs) that were given marketing approval in Canada from 1985 to 1989. An NCE for this study is defined as a chemical or biologic substance not previously approved for sale in Canada. It has been assumed that by collecting data on the same drug products, the complexity of the substance can be eliminated as a variable. It has been recognized that the drug approval process and regulatory requirements differ in the countries included in this study. The total approval time is nonetheless meaningful. Also, trends in approval times in some countries have been noted in recent years. It is assumed that these trends will not significantly affect the median approval times calculated in
889
PIETERSON
this report because the span of approval years for each country is large. It should be noted that the number of NCEs included in the data from each country does not indicate the number of NCEs approved in that country from 1985 to 1989. Because data on only specific products were sought and obtained for comparison, data on any other NCEs that were approved are not included in this study. Information on NCEs was used based on two assumptions: First, the complexity of this type of drug submission is usually the highest and therefore the review time is longest; and secondly, the availability of these products presents the greatest interest to all stakeholders. The following information on the new chemical entities was requested: 1.
The
proval
in all five countries (Table 1). Of the 70 drugs in Canada between 1985 and 1989, 57 were approved in the US, 43 in Australia, 48 in Sweden, and 54 in the UK. Approval times were calculated as the total number of calendar days from the date of receipt of the application to the date of marketing approval. The median, 25th, and 75th percentile regulatory approval times for the set of all data received from each country is shown in Table 2 and in Figure 1. The following median approval times were found: approved
TABLE I NCEs
Marketing
Approval
manufacturer
2. The date
the submission was received by the regulatory agency 3. The date the product was given marketing approval 4. The number of review days, (i.e., the number of days the submission was under review; this excludes processing, waiting, and manufacturer time) 5. The number of additional data (AD) requests made by the regulatory agent and the number of additional data (AD) submissions received by the regulatory agency 6. The number of investigational drug submissions conducted in the country and the date of the first investigational drug submission. An investigational drug submission provides approval to conduct a clinical trial. Additional data requested was defined as the total number of times that the regulatory agency requested significant AD from the manufacturer. Additional data received was defined as the total number of AD submissions received by the regulatory agency, including those specifically requested, those voluntarily sent by the manufacturer, and adverse drug reactions reported before marketing approval. Manufacturer time is the time elapsed while waiting for the manufacturer to respond to requests for AD. The American Food and Drug Administration’s therapeutic classification system was used. A drug is designated “A” if the gain is important, “B” if the gain is moderate, and “C” if there is little or no therapeutic gain.
From the list of 70 NCEs, information on a set of 25 NCEs that had received
#{149} J Clin Pharmacol
* * * *
Acebutolol HCI Alfentanil HCI Altretamine Aminosalicylic Acid Amiodarine HCI Atracurium Besylate Auranofin Betaxolol Bitolterol Budesonide Buserelin Buspirone
*
1992;32:889-896
was obtained marketing ap-
*
Leuprolide Acetate Levobunolol HCI Levonorgestrel
*
Loratadine Lovastati n Mesna
Nitrate *
Cefixime
* *
HCI Pentahydrate Sodium Disodium
Cyproterone
*
Pentamidine Pivmecillianam Propafenone Recombinant VAC Ribavirin
Acetate
Domperidone * Enalapril Maleate Epirubicin HCI * Famotidine Flecainide Acetate Fluoxetine HCI *Ganciclovir Sodium Glipizide
Goserelin
*
*
Cisapride
D
Hemophilus B Diphtheria Hepatitis B Immune Globulin
NCEs approved
in all countries:
HCI HCI
Isethionate HCI HCI Hepatitis
Sulconazole Nitrate Terazone HCI Tetrahydrocanabinol
Polysaccharide
*
2A 2B
Sometrem Somatropin
Acetate
Hemophilus
Mexiletine Midazolam Misoprostol Nimodipine Nizatidine Norfloxacin Octreotide Omeprazole
*
Ciprofloxacin
*
*
*
Carboplatin Cefmenoxime Ceftazidime Ceftizoxime Ceftriaxone
Ifosfamide Imipenem/Cilastatin Sodium lohexol lopamidol Interferon Alpha Interferon Alpha
*
Acetate HCI
Butoconazole *
*
*
Human Lymphoblastoid Interferon
RESULTS
890
Given
in Cana da (1985-1989)
*
Australia,
Tiaprofenic Acid Tissue Plasminogen Activa Tocainide HCI Trilostane Vecuronium Bromide Canada,
Sweden,
UK. US.
REGULATORY
APPROVAL
TIMES
TABLE II Comparison
MEDIAN
Canada
USA
57
Australia
Sweden
70
(months) 25th percentile (months) 75th percentile (months) *Years of
29.4
25.5
25.3
27.3
11.7
17.2
18.5
19.2
18.5
6.7
43.3
36.2
34.7
43.7
21.7
76-90
79-90
43
48
The range
OF
NCEs
54
50th percentile
approval
TIMES
UK
N Median
*
APPROVAL
of Regulatory Approval Times: All Data Collected
85-89 of years in which
76-9
the NCEs were given marketing
1
approval
M 0 N T H S
72-90 AUSTRALIA n#{149}25
in each
CANADA n#{149}25
SWEDEN n.25
UK n-25
USA n26
country.
Figure
months for Canada, 27.3 months for Sweden, 25.3 months for Australia, 25.5 months for the US, and 11.7 months for the UK. The distribution of approval times in each country for this data set is shown in Figure 2. The median regulatory approval times, and the 25th and 75th percentile approval times, for the set of 25 common products are shown in Table 3 and in Figure 3. The median approval times are 27.1 months for Canada, 25.3 months for Australia, 24.6 months for Sweden, 23.0 months for the US, and 10.6 months for the UK. The distribution of approval times in each country is shown in Figure 4.
2. Median
approval
times
of NCEs.
29.4
MEDIAN
APPROVAL
TIMES
OF
The data presented in Tables 2 and 3, in Figures 1 and 2, and Figures 3 and 4 are very similar. The medians in Australia, Canada, Sweden and US for both the common data and the unmatched data are within a 4.1-month span, whereas the median in the UK is less than half the others. The distribution of approval times in Canada, US, Australia, and Sweden resemble a normal distribution, whereas the UK distribution is clustered to the left of the median and tails to the right of the median. To determine if the same NCE required a relatively similar length of approval time in each country, correlation coefficients were calculated for the
NCEs
TABLE Comparison
of Regulatory
Ill Approval
for the Same 25 New Chemical Canada N
M 0 N T H S
Median 50th percentile (months) 25th percentile (months) 75th percentile (months) *Years
Australia
Sweden
UK
25
25
25
25
25
27.1
23.0
25.3
24.6
11.4
17.1
18.5
17.7
17.8
6.4
30.5
33.9
29.7
32.0
14.9
82-89
79-90
68-90
72-90
of
approval *
USA
Times
Entitles
85-89
The range of years in which
the NCEs were given marketing
approval
in each
country. Figure
1. Median
REGULATORY
approval
SERIES
times
of NCEs.
891
PIETERSON
Figure
3. Distribution
of approval
times
for
NCEs.
of 25 NCEs between-country pairs. Countrycountry comparisons also were made on matched pairs with a larger data set, which included all data received minus any approval time greater than 5 years and any NCE application received before 1980. These exclusion criteria were made for the following two reasons: the Canadian data is biased because the years of approval are 1985 to 1989, and by decreasing the range of approval years in the other countries, some of this bias will be removed; secondly, those applications taking longer than 5 years to approve are not representative of the approval times in each country. These exclusion criteria removed seven Canadian approval times, four Australian approval times, 11 Swedish approval times, nine UK approval times, and five US approval times. The correlation coefficients and the significance levels, as P values, are shown in Table 4. For the data set of 25 NCEs, there are three significant correlation coefficients (P < .05), between Canada-US, SwedenUK, and UK-US. Using the larger data set, the Canada-US and UK-US coefficients are significant. The coefficient values suggest a moderate magnitude of correlation in these five cases. To explain the variation of approval times within a country, linear multiple regression analysis was used with the following variables: therapeutic classification of the drug, the number of AD requests, the number of AD submissions received, and the date of the submission. The data set used in this analysis includes all data received minus those applications received before 1980 and those approval times greater than 5 years. set
892
#{149} J Clln Pharmacol
1992;32:889-896
The significance levels, as P values, determined in this analysis are shown in Table 5. A significant negative correlation (P < .05) was found between the submission date and the approval time in both Canada and the US. A significant positive correlation was found between AD requested and the approval time in Canada. A significant positive correlation was determined between the approval time and AD received in the US. The relationship between the therapeutic classification and the approval time was not significant in any country. The information collected on AD requested and AD received is presented in Tables 6 and 7, and the distributions are illustrated in Figures 5 and 6. Information on AD requested and AD received was not provided by the UK, nor were data provided on AD requested by the US. The frequency of AD requested was greatest in Sweden, with 66.7% (n = 48) and 48% (n = 25) of applications having more than five requests for AD. In Canada and Australia, AD was requested most frequently one or two times per application. Canada and Sweden received the greatest number of AD submissions. In Canada, 55.7% (n = 70) and 56% (n = 25) of the NCE applications received more than ten AD submissions. In the US and Australia, AD was received most frequently one to four times per application. Note that once again there is little difference in data on the set of 25 common NCEs and the set of all data received from each country. Information on the number of review days (the number of days the application was under review; this excludes processing, initial waiting time, and
DISTRIBUTION
OF APPROVAL 25 NCES
TIMES
FOR
F R E
0 U E
N C V
1%)
AUSTRALIA n25
CANADA
SWEDEN
UK
n25
n25
n’25
.1 YR 3-4
Figure
1-2 YR
4. Distribution
4-5
of approval
YR
USA n25 2-3
YR
‘S YR
YR
times
for
25 NCEs.
REGULATORY
APPROVAL
TABLE Comparison
of Approval
Australia
Australia
Times
IV
for Same
Canada r p
-
=
0.04
r
=
=
0.86
p
=
r = 0.08 p = 0.63 n=36
NCE Between
r = -0.04 p = 0.85 n=25
0.13 0.52
r p
n=25
r = 0.58 p = 0.0025 n=25
r = 0.48 p = 0.016* n=25
r = 0.38 p = 0.06 n=25
n=25 r
=
p
=
-
n=25 r = 0.16 p = 0.36 n=36
UK
r = 0.003 p = 0.99 n=29
r = 0.28 p = 0.07 n=41
r = 0.28 p = 0.14 n=30
USA
r = 0.13 p=O.47 n=32
r = 0.55 p=O.000P n=46
r = 0.16 p=0.40 n=31
P
5
46.5 11.6 2.3
n
Data
Requests
Canada and Sweden
Australia No. of AD requests
cific NCE in the country-country pairs suggests that the specific drug application is not a major factor in determining the length of the approval time. There are many factors that may influence the length of the review process in a country, including the regulations, policies, and guidelines in a country, the resources available to the regulatory agency, the philosophy, priorities, and procedures of the approval process of the agency, the availability of data from other regulatory agencies, and the review methods applied such as use of comprehensive summaries, and summarized data or raw data. Despite the known differences in these factors between the five countries, the approval times are similar in four, whereas the UK’s is less than half that in the others. The UK’s success at expediting drug approvals warrants further study of their review process and the factors affecting it. In Australia, Canada, Sweden, and the US, the review times reported here are similar. The data collected for this study allowed an examination of the effect of the therapeutic classification, submission data, AD requested, and AD received on the approval times. The results of the multiple regression analysis show that these factors do not appear to significantly affect the approval times in Australia, Sweden, and the UK. A larger data sample would provide a more meaningful analysis. The study shows that in Canada the approval times are affected by the submission date and the amount of AD requested. This finding agrees with the trend of decreasing review times in Canada over the last 5 years.1 The correlation between approval time and AD requested is expected because the amount of information requested has generally been considered a major cause of delay in the review process. The fact that the approval times minus manufacturer times, presented in Table 8, are not that much longer than the total approval times likely means that the manufacturers are responding
VI
Canada 25
=
32 60 8 0
n
=
70
n
20 58.6 14.3 7.1
Sweden =
25
16 68 12 4
n
48
=
0 8.3 25 66.7
n
=
25
0 12 40 48
of these applications to make an analysis and draw conclusions. Some general observations from the data collected can be made, however, which may be of interest. Of 40 NCE investigational applications that were made in both the US and Canada, only one was submitted in Canada first, nine were submitted in the same year in both countries, and 30 were submitted in the US first. Of 25 NCE investigational applications made in the US, the UK, and in Canada, 15 were submitted first in the US, four first in the UK, three in the US and UK in the same year, two in Canada and the US in the same year, and one in all three countries in the same year. DISCUSSION This study shows that the median approval times and the distribution of approval times for a group of 25 common NCEs and a larger unmatched group of NCEs are very similar in Canada, the US, Sweden, and Australia. The span of median approval times is approximately 23 to 29 months. The UK’s median approval time is considerably shorter, approximately II months. The insignificant or moderate correlations between the approval times and the spe-
TABLE Frequency
(%)
of Additional
Data
Australia No. of AD received
0 ito
4
n=43
VII
Received
in Australia,
Canada,
Canada n=25
n=70
Sweden,
and USA
Sweden n=25
0
n=48
USA n=25
n=57
n=25
37.2
36
0
0
26.3
24
60.5
72
17.1
16
10.4
16
50.9
56
0
5tolO
23
0
27.1
28
35.4
24
21.1
20
>10
0
0
55.7
56
54.2
60
1.8
0
894
#{149} J CIln Pharmacol
1992;32:889-896
REGULATORY
ADDITIONAL
DATA REQUESTED
F R C 0 U E N C V
1%)
AUSTRALIA
CANADA
fl.43
n-70
0/VR
1-2/YR
SWEDEN
3-4/VR
APPROVAL
TIMES
as compared with the Australian process, where AD is not accepted after a preliminary review period. A new policy was issued in 1991 by the Drugs Directorate in Canada that discourages the submission of unsolicited data. Although it is too early to measure the effects of this policy, future studies such as this should find a significant decrease in the amount of AD received. The American approval times used in this study show a significant relationship with the submission date. As in Canada, this reflects decreasing approval times over the last several years.”2 The relationship between approval time and AD received is interesting in that it was highlighted by the Food and Drug Administration that only significant AD were in-
‘5/VR
ADDITIONAL ADDITIONAL
DATA
DATA RECEIVED
REQUESTED
F R
50 40
F R E 0
U 30 C “
U E N C V
20
1%) 10
(%)
I
AUSTRALIA n#{149}43
n-25
0 VR
Figure
5. Additional
1-2
data
YR
SERIES
p.57
5-10/VR
1-4/YR
L ‘10/YR
n-25 3-4
VR
‘5 VR
ADDITIONAL
requested.
quickly to requests, but the additional information received from these requests lengthens the review process. Prompt responses to requests for AD also means that the manufacturer must have the data available in many instances; this raises the question of why it was not originally submitted. Although the data indicates that Canada receives the most AD, no significant relationship between AD received and approval time was found. It therefore must be the AD received in response to specific requests that lengthens the review process. The amount of AD received in each country demonstrates the policy and procedures of the regulatory agency. The large amount of AD received in Canada reflects the unstructured nature of the review process,
REGULATORY
fl#{149}45
n70
0/VR n25
I
CANADA
F
-
.
30 C V (%)
.
I I
-
gU
RECEIVED
l
50
R
DATA
I
5--
itE
20
10
AUSTRALIA
CANADA
n25
o25 0/YR
Figure
6. Additional
1-4/YR
data
SWEDEN n-25 5-10/YR
I’ L S
,,USA
n25
‘10/YR
received.
895
PIETERSON
TABLE VIII Approval
Times Minus Manufacturer Time for the Same 51 PICEs In Canada and US Canada
n Median approval manufacturer Median approval
time timeS
time
minus (Months) (Months)
* The approval time minus the number manufacturer/sponsor for AD.
US
51
51
28.9 29.9
23.0 25.9
of days awaiting
responses
from
the
cluded in the data provided for this category. This can be compared with the Canadian situation where AD requested lengthens the approval time. Again, the median approval time minus manufacturer time is similar to the total approval time likely because manufacturers respond promptly to the request but the total approval time is increased. It is noteworthy that the therapeutic class did not significantly affect the approval time in any country, Nhich means that a drug considered to be a major (herapeutic breakthrough is taking as long to reach the market as drugs considered to be less therapeutically important in all countries. This finding has been previously reported for American NCEs approved in 1985 and 1986. In Canada, a new policy has been implemented to give review priority to certain drugs considered to be therapeutically important.4 A similar policy has been recommended in Australia and is underway in the US. In a recent publication, drug availability in Canada from 1982 to 1989 was found to “lag” behind that in the US.5 The availability of a drug product is determined by the length of the approval process and also by the date the application is submitted. Based on the findings reported here, the explanation for the
896
#{149} J CIIn Pharmacol
1992;32:889-896
“lag” must be earlier submission dates and not differences in approval times. It is hoped that the increasing international cooperation in sharing of regulatory information, such as defined in the Scheme for the Mutual Recognition of Evaluation Reports on Pharmaceutical Products, will encourage manufacturers to submit applications to all countries at the same time. In the Baume report, a review of the Australian drug regulatory process, it is recommended that Australia increases the use of overseas evaluation reports to increase the efficiency of their review process.6 Similarly, such cooperation in now being encouraged between the US and Canada for therapeutically significant new drugs. The fact that, of 70 NCEs approved in Canada from 1985 to 1989, only 25 were approved in all five countries is an interesting finding in itself. For future research it would be worthwhile to explore the marketing, regulatory, or legislative reasons for such a wide variation in NCE availability. The
author
analysis
thanks
and
Eric
valuable
Ormsby
for providing
the statistical
comments.
REFERENCES 1.
Directorate,
Drugs
Health
and
Welfare
Canada,
unpublished
data. 2. 24 New Chemical Entities Introduced onto the UK Market in 1989. Center for Medicines Research News, 1990;8(2). 3. Kaitin KI, Richard BW, Lasangna L: Trends in drug development: The 1985-86 New Drug Approvals. J Clin Pharmacol 1987:27:542-548. 4. Health Protection Branch, Health and Welfare Canada: Drug Submission Evaluation. Information Letter No. 773, Feb. 2, 1990. 5. DiCerbo, PA, Richard BW, Lasagna L: Availability of new chemical entities: A comparison of Canada and the US. Boston: Center for
the
Study
6. Baume evaluation Family
and
of Drug
P: A question in Australia. Health
Development, of balance:
Tufts
Commissioned
Services,
University,
Report
Commonwealth
on
the
1991. future
for the Minister of Australia,
of drug
for Aged, 1991.
SERIES
A Comparison of Regulatory Approval Times for New Chemical Entities in Australia, Canada, Sweden, the United Kingdom, and the United States Elizabeth
A. Pieterson,
MSc
Regulatory approval times of new chemical entities (NCEs) in Australia, Canada, Sweden, the United Kingdom (UK), and the United States (US) were compared. The approval times of a set of common 25 NCEs and a larger set of unmatched NCEs were very similar in Australia, Canada, Sweden, and the US, with median approval times from 23 to 29 months. The median approval time in the UK was approximately 11 months. Analysis of the data showed that the approval times in Australia, Sweden, and the UK were not significantly affected by the therapeutic classification of the drug, the amount of additional data requested and received, or the submission date. In Canada, the date the drug submission was received and the frequency of additional data requests significantly affected the approval times. In the US, the date the drug submission was received and the frequency of additional data received significantly affected the approval times. The therapeutic classification of the drug did not significantly affect the approval time in Canada or the US.
T
he length of time taken by regulatory agencies to approve new drugs for marketing is frequently criticized in many countries by the pharmaceutical industry, health professionals, and consumers. The timeliness of drug approvals impacts on the financial compensation the pharmaceutical industry receives for its investment in a drug’s development. For the health professional and consumer, regulatory approval times determine when they will have access to drugs that may improve health status and quality of life, or possibly save lives. In Canada, critics of the drug approval process compare Canadian drug availability unfavorably with that in other countries, particularly the United States. Many studies have compared a measure of approval times between two countries, but there has not been a comparison of approval times for the same drug substances in several countries. The major objective of this report is to compare the approval times for the same drug substances in Australia, Canada,
From the Bureau of Pharmaceutical Surveillance, Drugs Directorate, Health and Welfare Canada. Address for reprints: Elizabeth Pieterson, MSc, Bureau of Pharmaceutical Surveillance, Finance Annex, Room 250, Tunney’s Pasture, Ottawa. Ontario Canada KIA 0L2.
.1ClIn Pharmacol
1992;32:889-896
Sweden, the United Kingdom (UK), and the United States (US). Approval time is defined as the total number of calendar days from the receipt of the application to the issuance of marketing approval. Factors that may affect the approval times are also considered to provide topics for future study and cornparison. METHODS Information was requested from the national drug regulatory agencies in Australia, Sweden, the UK, and the US on 70 new chemical entities (NCEs) that were given marketing approval in Canada from 1985 to 1989. An NCE for this study is defined as a chemical or biologic substance not previously approved for sale in Canada. It has been assumed that by collecting data on the same drug products, the complexity of the substance can be eliminated as a variable. It has been recognized that the drug approval process and regulatory requirements differ in the countries included in this study. The total approval time is nonetheless meaningful. Also, trends in approval times in some countries have been noted in recent years. It is assumed that these trends will not significantly affect the median approval times calculated in
889
PIETERSON
this report because the span of approval years for each country is large. It should be noted that the number of NCEs included in the data from each country does not indicate the number of NCEs approved in that country from 1985 to 1989. Because data on only specific products were sought and obtained for comparison, data on any other NCEs that were approved are not included in this study. Information on NCEs was used based on two assumptions: First, the complexity of this type of drug submission is usually the highest and therefore the review time is longest; and secondly, the availability of these products presents the greatest interest to all stakeholders. The following information on the new chemical entities was requested: 1.
The
proval
in all five countries (Table 1). Of the 70 drugs in Canada between 1985 and 1989, 57 were approved in the US, 43 in Australia, 48 in Sweden, and 54 in the UK. Approval times were calculated as the total number of calendar days from the date of receipt of the application to the date of marketing approval. The median, 25th, and 75th percentile regulatory approval times for the set of all data received from each country is shown in Table 2 and in Figure 1. The following median approval times were found: approved
TABLE I NCEs
Marketing
Approval
manufacturer
2. The date
the submission was received by the regulatory agency 3. The date the product was given marketing approval 4. The number of review days, (i.e., the number of days the submission was under review; this excludes processing, waiting, and manufacturer time) 5. The number of additional data (AD) requests made by the regulatory agent and the number of additional data (AD) submissions received by the regulatory agency 6. The number of investigational drug submissions conducted in the country and the date of the first investigational drug submission. An investigational drug submission provides approval to conduct a clinical trial. Additional data requested was defined as the total number of times that the regulatory agency requested significant AD from the manufacturer. Additional data received was defined as the total number of AD submissions received by the regulatory agency, including those specifically requested, those voluntarily sent by the manufacturer, and adverse drug reactions reported before marketing approval. Manufacturer time is the time elapsed while waiting for the manufacturer to respond to requests for AD. The American Food and Drug Administration’s therapeutic classification system was used. A drug is designated “A” if the gain is important, “B” if the gain is moderate, and “C” if there is little or no therapeutic gain.
From the list of 70 NCEs, information on a set of 25 NCEs that had received
#{149} J Clin Pharmacol
* * * *
Acebutolol HCI Alfentanil HCI Altretamine Aminosalicylic Acid Amiodarine HCI Atracurium Besylate Auranofin Betaxolol Bitolterol Budesonide Buserelin Buspirone
*
1992;32:889-896
was obtained marketing ap-
*
Leuprolide Acetate Levobunolol HCI Levonorgestrel
*
Loratadine Lovastati n Mesna
Nitrate *
Cefixime
* *
HCI Pentahydrate Sodium Disodium
Cyproterone
*
Pentamidine Pivmecillianam Propafenone Recombinant VAC Ribavirin
Acetate
Domperidone * Enalapril Maleate Epirubicin HCI * Famotidine Flecainide Acetate Fluoxetine HCI *Ganciclovir Sodium Glipizide
Goserelin
*
*
Cisapride
D
Hemophilus B Diphtheria Hepatitis B Immune Globulin
NCEs approved
in all countries:
HCI HCI
Isethionate HCI HCI Hepatitis
Sulconazole Nitrate Terazone HCI Tetrahydrocanabinol
Polysaccharide
*
2A 2B
Sometrem Somatropin
Acetate
Hemophilus
Mexiletine Midazolam Misoprostol Nimodipine Nizatidine Norfloxacin Octreotide Omeprazole
*
Ciprofloxacin
*
*
*
Carboplatin Cefmenoxime Ceftazidime Ceftizoxime Ceftriaxone
Ifosfamide Imipenem/Cilastatin Sodium lohexol lopamidol Interferon Alpha Interferon Alpha
*
Acetate HCI
Butoconazole *
*
*
Human Lymphoblastoid Interferon
RESULTS
890
Given
in Cana da (1985-1989)
*
Australia,
Tiaprofenic Acid Tissue Plasminogen Activa Tocainide HCI Trilostane Vecuronium Bromide Canada,
Sweden,
UK. US.
REGULATORY
APPROVAL
TIMES
TABLE II Comparison
MEDIAN
Canada
USA
57
Australia
Sweden
70
(months) 25th percentile (months) 75th percentile (months) *Years of
29.4
25.5
25.3
27.3
11.7
17.2
18.5
19.2
18.5
6.7
43.3
36.2
34.7
43.7
21.7
76-90
79-90
43
48
The range
OF
NCEs
54
50th percentile
approval
TIMES
UK
N Median
*
APPROVAL
of Regulatory Approval Times: All Data Collected
85-89 of years in which
76-9
the NCEs were given marketing
1
approval
M 0 N T H S
72-90 AUSTRALIA n#{149}25
in each
CANADA n#{149}25
SWEDEN n.25
UK n-25
USA n26
country.
Figure
months for Canada, 27.3 months for Sweden, 25.3 months for Australia, 25.5 months for the US, and 11.7 months for the UK. The distribution of approval times in each country for this data set is shown in Figure 2. The median regulatory approval times, and the 25th and 75th percentile approval times, for the set of 25 common products are shown in Table 3 and in Figure 3. The median approval times are 27.1 months for Canada, 25.3 months for Australia, 24.6 months for Sweden, 23.0 months for the US, and 10.6 months for the UK. The distribution of approval times in each country is shown in Figure 4.
2. Median
approval
times
of NCEs.
29.4
MEDIAN
APPROVAL
TIMES
OF
The data presented in Tables 2 and 3, in Figures 1 and 2, and Figures 3 and 4 are very similar. The medians in Australia, Canada, Sweden and US for both the common data and the unmatched data are within a 4.1-month span, whereas the median in the UK is less than half the others. The distribution of approval times in Canada, US, Australia, and Sweden resemble a normal distribution, whereas the UK distribution is clustered to the left of the median and tails to the right of the median. To determine if the same NCE required a relatively similar length of approval time in each country, correlation coefficients were calculated for the
NCEs
TABLE Comparison
of Regulatory
Ill Approval
for the Same 25 New Chemical Canada N
M 0 N T H S
Median 50th percentile (months) 25th percentile (months) 75th percentile (months) *Years
Australia
Sweden
UK
25
25
25
25
25
27.1
23.0
25.3
24.6
11.4
17.1
18.5
17.7
17.8
6.4
30.5
33.9
29.7
32.0
14.9
82-89
79-90
68-90
72-90
of
approval *
USA
Times
Entitles
85-89
The range of years in which
the NCEs were given marketing
approval
in each
country. Figure
1. Median
REGULATORY
approval
SERIES
times
of NCEs.
891
PIETERSON
Figure
3. Distribution
of approval
times
for
NCEs.
of 25 NCEs between-country pairs. Countrycountry comparisons also were made on matched pairs with a larger data set, which included all data received minus any approval time greater than 5 years and any NCE application received before 1980. These exclusion criteria were made for the following two reasons: the Canadian data is biased because the years of approval are 1985 to 1989, and by decreasing the range of approval years in the other countries, some of this bias will be removed; secondly, those applications taking longer than 5 years to approve are not representative of the approval times in each country. These exclusion criteria removed seven Canadian approval times, four Australian approval times, 11 Swedish approval times, nine UK approval times, and five US approval times. The correlation coefficients and the significance levels, as P values, are shown in Table 4. For the data set of 25 NCEs, there are three significant correlation coefficients (P < .05), between Canada-US, SwedenUK, and UK-US. Using the larger data set, the Canada-US and UK-US coefficients are significant. The coefficient values suggest a moderate magnitude of correlation in these five cases. To explain the variation of approval times within a country, linear multiple regression analysis was used with the following variables: therapeutic classification of the drug, the number of AD requests, the number of AD submissions received, and the date of the submission. The data set used in this analysis includes all data received minus those applications received before 1980 and those approval times greater than 5 years. set
892
#{149} J Clln Pharmacol
1992;32:889-896
The significance levels, as P values, determined in this analysis are shown in Table 5. A significant negative correlation (P < .05) was found between the submission date and the approval time in both Canada and the US. A significant positive correlation was found between AD requested and the approval time in Canada. A significant positive correlation was determined between the approval time and AD received in the US. The relationship between the therapeutic classification and the approval time was not significant in any country. The information collected on AD requested and AD received is presented in Tables 6 and 7, and the distributions are illustrated in Figures 5 and 6. Information on AD requested and AD received was not provided by the UK, nor were data provided on AD requested by the US. The frequency of AD requested was greatest in Sweden, with 66.7% (n = 48) and 48% (n = 25) of applications having more than five requests for AD. In Canada and Australia, AD was requested most frequently one or two times per application. Canada and Sweden received the greatest number of AD submissions. In Canada, 55.7% (n = 70) and 56% (n = 25) of the NCE applications received more than ten AD submissions. In the US and Australia, AD was received most frequently one to four times per application. Note that once again there is little difference in data on the set of 25 common NCEs and the set of all data received from each country. Information on the number of review days (the number of days the application was under review; this excludes processing, initial waiting time, and
DISTRIBUTION
OF APPROVAL 25 NCES
TIMES
FOR
F R E
0 U E
N C V
1%)
AUSTRALIA n25
CANADA
SWEDEN
UK
n25
n25
n’25
.1 YR 3-4
Figure
1-2 YR
4. Distribution
4-5
of approval
YR
USA n25 2-3
YR
‘S YR
YR
times
for
25 NCEs.
REGULATORY
APPROVAL
TABLE Comparison
of Approval
Australia
Australia
Times
IV
for Same
Canada r p
-
=
0.04
r
=
=
0.86
p
=
r = 0.08 p = 0.63 n=36
NCE Between
r = -0.04 p = 0.85 n=25
0.13 0.52
r p
n=25
r = 0.58 p = 0.0025 n=25
r = 0.48 p = 0.016* n=25
r = 0.38 p = 0.06 n=25
n=25 r
=
p
=
-
n=25 r = 0.16 p = 0.36 n=36
UK
r = 0.003 p = 0.99 n=29
r = 0.28 p = 0.07 n=41
r = 0.28 p = 0.14 n=30
USA
r = 0.13 p=O.47 n=32
r = 0.55 p=O.000P n=46
r = 0.16 p=0.40 n=31
P
5
46.5 11.6 2.3
n
Data
Requests
Canada and Sweden
Australia No. of AD requests
cific NCE in the country-country pairs suggests that the specific drug application is not a major factor in determining the length of the approval time. There are many factors that may influence the length of the review process in a country, including the regulations, policies, and guidelines in a country, the resources available to the regulatory agency, the philosophy, priorities, and procedures of the approval process of the agency, the availability of data from other regulatory agencies, and the review methods applied such as use of comprehensive summaries, and summarized data or raw data. Despite the known differences in these factors between the five countries, the approval times are similar in four, whereas the UK’s is less than half that in the others. The UK’s success at expediting drug approvals warrants further study of their review process and the factors affecting it. In Australia, Canada, Sweden, and the US, the review times reported here are similar. The data collected for this study allowed an examination of the effect of the therapeutic classification, submission data, AD requested, and AD received on the approval times. The results of the multiple regression analysis show that these factors do not appear to significantly affect the approval times in Australia, Sweden, and the UK. A larger data sample would provide a more meaningful analysis. The study shows that in Canada the approval times are affected by the submission date and the amount of AD requested. This finding agrees with the trend of decreasing review times in Canada over the last 5 years.1 The correlation between approval time and AD requested is expected because the amount of information requested has generally been considered a major cause of delay in the review process. The fact that the approval times minus manufacturer times, presented in Table 8, are not that much longer than the total approval times likely means that the manufacturers are responding
VI
Canada 25
=
32 60 8 0
n
=
70
n
20 58.6 14.3 7.1
Sweden =
25
16 68 12 4
n
48
=
0 8.3 25 66.7
n
=
25
0 12 40 48
of these applications to make an analysis and draw conclusions. Some general observations from the data collected can be made, however, which may be of interest. Of 40 NCE investigational applications that were made in both the US and Canada, only one was submitted in Canada first, nine were submitted in the same year in both countries, and 30 were submitted in the US first. Of 25 NCE investigational applications made in the US, the UK, and in Canada, 15 were submitted first in the US, four first in the UK, three in the US and UK in the same year, two in Canada and the US in the same year, and one in all three countries in the same year. DISCUSSION This study shows that the median approval times and the distribution of approval times for a group of 25 common NCEs and a larger unmatched group of NCEs are very similar in Canada, the US, Sweden, and Australia. The span of median approval times is approximately 23 to 29 months. The UK’s median approval time is considerably shorter, approximately II months. The insignificant or moderate correlations between the approval times and the spe-
TABLE Frequency
(%)
of Additional
Data
Australia No. of AD received
0 ito
4
n=43
VII
Received
in Australia,
Canada,
Canada n=25
n=70
Sweden,
and USA
Sweden n=25
0
n=48
USA n=25
n=57
n=25
37.2
36
0
0
26.3
24
60.5
72
17.1
16
10.4
16
50.9
56
0
5tolO
23
0
27.1
28
35.4
24
21.1
20
>10
0
0
55.7
56
54.2
60
1.8
0
894
#{149} J CIln Pharmacol
1992;32:889-896
REGULATORY
ADDITIONAL
DATA REQUESTED
F R C 0 U E N C V
1%)
AUSTRALIA
CANADA
fl.43
n-70
0/VR
1-2/YR
SWEDEN
3-4/VR
APPROVAL
TIMES
as compared with the Australian process, where AD is not accepted after a preliminary review period. A new policy was issued in 1991 by the Drugs Directorate in Canada that discourages the submission of unsolicited data. Although it is too early to measure the effects of this policy, future studies such as this should find a significant decrease in the amount of AD received. The American approval times used in this study show a significant relationship with the submission date. As in Canada, this reflects decreasing approval times over the last several years.”2 The relationship between approval time and AD received is interesting in that it was highlighted by the Food and Drug Administration that only significant AD were in-
‘5/VR
ADDITIONAL ADDITIONAL
DATA
DATA RECEIVED
REQUESTED
F R
50 40
F R E 0
U 30 C “
U E N C V
20
1%) 10
(%)
I
AUSTRALIA n#{149}43
n-25
0 VR
Figure
5. Additional
1-2
data
YR
SERIES
p.57
5-10/VR
1-4/YR
L ‘10/YR
n-25 3-4
VR
‘5 VR
ADDITIONAL
requested.
quickly to requests, but the additional information received from these requests lengthens the review process. Prompt responses to requests for AD also means that the manufacturer must have the data available in many instances; this raises the question of why it was not originally submitted. Although the data indicates that Canada receives the most AD, no significant relationship between AD received and approval time was found. It therefore must be the AD received in response to specific requests that lengthens the review process. The amount of AD received in each country demonstrates the policy and procedures of the regulatory agency. The large amount of AD received in Canada reflects the unstructured nature of the review process,
REGULATORY
fl#{149}45
n70
0/VR n25
I
CANADA
F
-
.
30 C V (%)
.
I I
-
gU
RECEIVED
l
50
R
DATA
I
5--
itE
20
10
AUSTRALIA
CANADA
n25
o25 0/YR
Figure
6. Additional
1-4/YR
data
SWEDEN n-25 5-10/YR
I’ L S
,,USA
n25
‘10/YR
received.
895
PIETERSON
TABLE VIII Approval
Times Minus Manufacturer Time for the Same 51 PICEs In Canada and US Canada
n Median approval manufacturer Median approval
time timeS
time
minus (Months) (Months)
* The approval time minus the number manufacturer/sponsor for AD.
US
51
51
28.9 29.9
23.0 25.9
of days awaiting
responses
from
the
cluded in the data provided for this category. This can be compared with the Canadian situation where AD requested lengthens the approval time. Again, the median approval time minus manufacturer time is similar to the total approval time likely because manufacturers respond promptly to the request but the total approval time is increased. It is noteworthy that the therapeutic class did not significantly affect the approval time in any country, Nhich means that a drug considered to be a major (herapeutic breakthrough is taking as long to reach the market as drugs considered to be less therapeutically important in all countries. This finding has been previously reported for American NCEs approved in 1985 and 1986. In Canada, a new policy has been implemented to give review priority to certain drugs considered to be therapeutically important.4 A similar policy has been recommended in Australia and is underway in the US. In a recent publication, drug availability in Canada from 1982 to 1989 was found to “lag” behind that in the US.5 The availability of a drug product is determined by the length of the approval process and also by the date the application is submitted. Based on the findings reported here, the explanation for the
896
#{149} J CIIn Pharmacol
1992;32:889-896
“lag” must be earlier submission dates and not differences in approval times. It is hoped that the increasing international cooperation in sharing of regulatory information, such as defined in the Scheme for the Mutual Recognition of Evaluation Reports on Pharmaceutical Products, will encourage manufacturers to submit applications to all countries at the same time. In the Baume report, a review of the Australian drug regulatory process, it is recommended that Australia increases the use of overseas evaluation reports to increase the efficiency of their review process.6 Similarly, such cooperation in now being encouraged between the US and Canada for therapeutically significant new drugs. The fact that, of 70 NCEs approved in Canada from 1985 to 1989, only 25 were approved in all five countries is an interesting finding in itself. For future research it would be worthwhile to explore the marketing, regulatory, or legislative reasons for such a wide variation in NCE availability. The
author
analysis
thanks
and
Eric
valuable
Ormsby
for providing
the statistical
comments.
REFERENCES 1.
Directorate,
Drugs
Health
and
Welfare
Canada,
unpublished
data. 2. 24 New Chemical Entities Introduced onto the UK Market in 1989. Center for Medicines Research News, 1990;8(2). 3. Kaitin KI, Richard BW, Lasangna L: Trends in drug development: The 1985-86 New Drug Approvals. J Clin Pharmacol 1987:27:542-548. 4. Health Protection Branch, Health and Welfare Canada: Drug Submission Evaluation. Information Letter No. 773, Feb. 2, 1990. 5. DiCerbo, PA, Richard BW, Lasagna L: Availability of new chemical entities: A comparison of Canada and the US. Boston: Center for
the
Study
6. Baume evaluation Family
and
of Drug
P: A question in Australia. Health
Development, of balance:
Tufts
Commissioned
Services,
University,
Report
Commonwealth
on
the
1991. future
for the Minister of Australia,
of drug
for Aged, 1991.
