N E W S & A N A LY S I S Nature Reviews Drug Discovery | AOP, published online 17 April 2015; doi:10.1038/nrd4621
BIOBUSINESS BRIEFS R E G U L AT O RY WAT C H
Impact of scientific advice from the European Medicines Agency Scientific advice (SA) provided by the European Medicines Agency (EMA) was initiated in 1996 as a tool to improve communication between sponsors and regulators throughout drug development. Its aim is to support sponsors to provide adequate data for benefit–risk assessment at the time of marketing authorization application (MAA), and thereby to facilitate the introduction of new, safe and effective medicines. SA is voluntary and non‑binding, and may be given on all aspects of drug development programmes by the Scientific Advice Working Party (SAWP) of the EMA’s Committee for Medicinal Products for Human Use (CHMP). Compliance with SA recommendations on clinical trial design has previously been shown to correlate with MAA success
SA during pivotal trials (28 products)
Total (118 products)
90 80 70 60 50 40 30 20 10 0
90 80 70 60 50 40 30 20 10 0
90 80 70 60 50 40 30 20 10 0
70/90 59/70 11/20
al
t To
b
nNo iant l p om
nt
lia
p om
C
SA submission
18/28 16/18 al
t To
c
SA assessment Acceptable (n = 39; 33%)
Total (n = 118)
2/10 nNo iant l p om
nt
lia
C
p om
MAA success rate (%)
(90 products)
MAA success rate (%)
MAA success rate (%)
a SA before pivotal trials
(Eur. J. Clin. Pharmacol. 66, 39–48; 2010). With this in mind, we analysed MAA submissions between 2008 and 2012 that received SA to investigate whether SA leads to changes in clinical trial design and whether the timing of and compliance with SA affect the regulatory assessment and its outcome (see Supplementary information S1 (box) for details of the analysis). Over the analysed period, the proportion of products at MAA that had received SA increased (up to 70% in 2012; Supplementary information S2 (table)), reflecting a growing demand for interaction with regulators prior to MAA submission. Analysing the timing of SA requests reveals that sponsors prefer early interactions, with the majority of SA applications (76%) being made prior to the start of pivotal trials (FIG. 1a).
c
MAA assessment Compliant* (n = 38; 97%)
Compliant (n = 50; 63%) Non acceptable (n = 79; 67%) Non-compliant (n = 29; 37%)
87/118 74/88 13/30 al
t To
nNo iant l p om
nt
lia
p om
C
c
MAA outcome Positive (n = 32; 84%) Negative (n = 6; 16%) Positive (n = 43; 86%) Negative (n = 7; 14%) Positive (n = 12; 41%) Negative (n = 17; 59%)
Figure 1 | Impact of scientific advice. a | Timing of scientific advice (SA), timing of compliance and the relationship with the success of marketing authorization applications (MAAs) for the Nature Reviews | Drug Discovery 118 MAAs that were submitted in 2008–2012 for which SA had been received and that could be assessed for compliance on the key variables, subdivided into groups depending on whether SA was provided before or during pivotal trial advancement. The number of MAAs as a proportion of the relevant total is shown within the bars. b | Evolution of clinical trial design from SA submission to MAA outcome. Clinical trial designs submitted for SA were evaluated for: their acceptability at future MAA; their compliance with SA recommendations at MAA; and their ultimate MAA success. The regulatory process from submission of a request for SA to MAA outcome is shown. *One product was acceptable and non-compliant; the sponsor changed the primary efficacy end point that was originally proposed and accepted by SA, and the MAA outcome was positive.
NATURE REVIEWS | DRUG DISCOVERY
Interestingly, earlier SA is subsequently associated with a higher MAA success rate (78%) when compared to products that received SA during the ongoing pivotal trial phase (64%; FIG. 1a). The rate of compliance with SA that was provided on three key variables — choice of primary efficacy end point, choice of comparator treatment and robustness of chosen statistical methodology — at the time of MAA was found to be 75% on average over the period of analysis (Supplementary information S2 (table)). Our analysis also confirmed previous findings demonstrating a positive association between compliance with SA recommendations on clinical trial design and a positive MAA outcome: programmes that complied with trial design recommendations achieved a MAA success rate of 84%, compared with 43% for non‑compliant programmes (FIG. 1a). A more detailed subanalysis identified that, at the time of the SA request, only 33% of programmes were deemed to have an acceptable clinical trial design with regard to their suitability for future MAA. Conversely, 67% of programmes were considered deficient, and the respective applicants were advised to modify their trial design. In view of this advice, the majority of these applicants (63%) changed their trial design. Both confirmation of an acceptable trial design at the time of SA and change of a deficient trial design to conform with SA recommendations equally increased the likelihood of a positive CHMP opinion, with MAA success rates of 84% and 86% respectively, compared with only 41% when a deficient clinical trial design was not adapted according to SA recommendations (FIG. 1b). Interestingly, applicants who requested SA during ongoing pivotal studies were found to be less compliant with SA at time of MAA more often than applicants who requested SA before initiating pivotal studies (64% versus 78%, respectively), and to have a lower MAA success rate (FIG. 1b). Our final analysis was aimed at elucidating further measurable effects of compliance with SA on attributes of the regulatory assessment that are seen as indicators for the acceptability and success of the drug and its development programme during the CHMP assessment. We found that compliance with SA on clinical trial design was associated with a reduction in major objections (MOs) raised in all categories during CHMP review and with an MAA procedure that was, on average, 61 days shorter (Supplementary information S3 (table)). Ultimately, a new drug is approved on the basis of an overall positive benefit–risk assessment that is established by the CHMP, ADVANCE ONLINE PUBLICATION | 1
© 2015 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S which is not bound by SA recommendations. This is reflected by the fact that not all development programmes that comply with SA concerning clinical trial design are successful, and vice versa. Nevertheless, MAA failure as a consequence of the inability to demonstrate drug efficacy is often interrelated with deficiencies in the clinical trial design (Eur. J. Clin. Pharmacol. 58, 573–580; 2002) and SA offers an opportunity to establish early scientific discussion on all aspects of drug development, including clinical trial design. This may provide an explanation as to why compliance with SA on clinical trial design is an important factor associated with MAA outcome. Although a positive association has been observed between compliance with SA and MAA success regardless of the timing of SA (that is, before or during the pivotal trial stage), there are obvious benefits to requesting SA early in drug development. Not only does it allow a sponsor to modify the clinical trial design of the pivotal studies, but early SA consultation can also support the design of informative studies in the learning phase, which has been demonstrated to be a determinant for future MAA success (Nature Rev. Drug Discov. 11, 903–904; 2012). Our finding that only one‑third of the clinical trial design proposals to SA are deemed acceptable, in conjunction with the higher compliance and MAA success rates that are observed when SA is obtained during the pre-pivotal development stage, indicates that early SA gives the sponsor the time and the opportunity to implement changes to the clinical development programme in order that trials provide adequate data for the regulatory benefit–risk assessment. Matthias P. Hofer, Christina Jakobsson, Nikolaos Zafiropoulos, Spiros Vamvakas, Thorsten Vetter and Jan Regnstrom are at the European Medicines Agency, 30 Churchill Place, Canary Wharf, London E14 5EU, UK. Robert J. Hemmings is at the Medicines and Healthcare Products Regulatory Agency, 151 Buckingham Palace Road, Victoria, London SW1W 9SZ, UK. Correspondence to J.R. e-mail: [email protected] doi:10.1038/nrd4621 The authors declare no competing interests. The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.
SUPPLEMENTARY INFORMATION See online article: S1 (box) | S2 (table) | S3 (table) ALL LINKS ARE ACTIVE IN THE ONLINE PDF
2 | ADVANCE ONLINE PUBLICATION
www.nature.com/reviews/drugdisc © 2015 Macmillan Publishers Limited. All rights reserved
BIOBUSINESS BRIEFS R E G U L AT O RY WAT C H
Impact of scientific advice from the European Medicines Agency Scientific advice (SA) provided by the European Medicines Agency (EMA) was initiated in 1996 as a tool to improve communication between sponsors and regulators throughout drug development. Its aim is to support sponsors to provide adequate data for benefit–risk assessment at the time of marketing authorization application (MAA), and thereby to facilitate the introduction of new, safe and effective medicines. SA is voluntary and non‑binding, and may be given on all aspects of drug development programmes by the Scientific Advice Working Party (SAWP) of the EMA’s Committee for Medicinal Products for Human Use (CHMP). Compliance with SA recommendations on clinical trial design has previously been shown to correlate with MAA success
SA during pivotal trials (28 products)
Total (118 products)
90 80 70 60 50 40 30 20 10 0
90 80 70 60 50 40 30 20 10 0
90 80 70 60 50 40 30 20 10 0
70/90 59/70 11/20
al
t To
b
nNo iant l p om
nt
lia
p om
C
SA submission
18/28 16/18 al
t To
c
SA assessment Acceptable (n = 39; 33%)
Total (n = 118)
2/10 nNo iant l p om
nt
lia
C
p om
MAA success rate (%)
(90 products)
MAA success rate (%)
MAA success rate (%)
a SA before pivotal trials
(Eur. J. Clin. Pharmacol. 66, 39–48; 2010). With this in mind, we analysed MAA submissions between 2008 and 2012 that received SA to investigate whether SA leads to changes in clinical trial design and whether the timing of and compliance with SA affect the regulatory assessment and its outcome (see Supplementary information S1 (box) for details of the analysis). Over the analysed period, the proportion of products at MAA that had received SA increased (up to 70% in 2012; Supplementary information S2 (table)), reflecting a growing demand for interaction with regulators prior to MAA submission. Analysing the timing of SA requests reveals that sponsors prefer early interactions, with the majority of SA applications (76%) being made prior to the start of pivotal trials (FIG. 1a).
c
MAA assessment Compliant* (n = 38; 97%)
Compliant (n = 50; 63%) Non acceptable (n = 79; 67%) Non-compliant (n = 29; 37%)
87/118 74/88 13/30 al
t To
nNo iant l p om
nt
lia
p om
C
c
MAA outcome Positive (n = 32; 84%) Negative (n = 6; 16%) Positive (n = 43; 86%) Negative (n = 7; 14%) Positive (n = 12; 41%) Negative (n = 17; 59%)
Figure 1 | Impact of scientific advice. a | Timing of scientific advice (SA), timing of compliance and the relationship with the success of marketing authorization applications (MAAs) for the Nature Reviews | Drug Discovery 118 MAAs that were submitted in 2008–2012 for which SA had been received and that could be assessed for compliance on the key variables, subdivided into groups depending on whether SA was provided before or during pivotal trial advancement. The number of MAAs as a proportion of the relevant total is shown within the bars. b | Evolution of clinical trial design from SA submission to MAA outcome. Clinical trial designs submitted for SA were evaluated for: their acceptability at future MAA; their compliance with SA recommendations at MAA; and their ultimate MAA success. The regulatory process from submission of a request for SA to MAA outcome is shown. *One product was acceptable and non-compliant; the sponsor changed the primary efficacy end point that was originally proposed and accepted by SA, and the MAA outcome was positive.
NATURE REVIEWS | DRUG DISCOVERY
Interestingly, earlier SA is subsequently associated with a higher MAA success rate (78%) when compared to products that received SA during the ongoing pivotal trial phase (64%; FIG. 1a). The rate of compliance with SA that was provided on three key variables — choice of primary efficacy end point, choice of comparator treatment and robustness of chosen statistical methodology — at the time of MAA was found to be 75% on average over the period of analysis (Supplementary information S2 (table)). Our analysis also confirmed previous findings demonstrating a positive association between compliance with SA recommendations on clinical trial design and a positive MAA outcome: programmes that complied with trial design recommendations achieved a MAA success rate of 84%, compared with 43% for non‑compliant programmes (FIG. 1a). A more detailed subanalysis identified that, at the time of the SA request, only 33% of programmes were deemed to have an acceptable clinical trial design with regard to their suitability for future MAA. Conversely, 67% of programmes were considered deficient, and the respective applicants were advised to modify their trial design. In view of this advice, the majority of these applicants (63%) changed their trial design. Both confirmation of an acceptable trial design at the time of SA and change of a deficient trial design to conform with SA recommendations equally increased the likelihood of a positive CHMP opinion, with MAA success rates of 84% and 86% respectively, compared with only 41% when a deficient clinical trial design was not adapted according to SA recommendations (FIG. 1b). Interestingly, applicants who requested SA during ongoing pivotal studies were found to be less compliant with SA at time of MAA more often than applicants who requested SA before initiating pivotal studies (64% versus 78%, respectively), and to have a lower MAA success rate (FIG. 1b). Our final analysis was aimed at elucidating further measurable effects of compliance with SA on attributes of the regulatory assessment that are seen as indicators for the acceptability and success of the drug and its development programme during the CHMP assessment. We found that compliance with SA on clinical trial design was associated with a reduction in major objections (MOs) raised in all categories during CHMP review and with an MAA procedure that was, on average, 61 days shorter (Supplementary information S3 (table)). Ultimately, a new drug is approved on the basis of an overall positive benefit–risk assessment that is established by the CHMP, ADVANCE ONLINE PUBLICATION | 1
© 2015 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S which is not bound by SA recommendations. This is reflected by the fact that not all development programmes that comply with SA concerning clinical trial design are successful, and vice versa. Nevertheless, MAA failure as a consequence of the inability to demonstrate drug efficacy is often interrelated with deficiencies in the clinical trial design (Eur. J. Clin. Pharmacol. 58, 573–580; 2002) and SA offers an opportunity to establish early scientific discussion on all aspects of drug development, including clinical trial design. This may provide an explanation as to why compliance with SA on clinical trial design is an important factor associated with MAA outcome. Although a positive association has been observed between compliance with SA and MAA success regardless of the timing of SA (that is, before or during the pivotal trial stage), there are obvious benefits to requesting SA early in drug development. Not only does it allow a sponsor to modify the clinical trial design of the pivotal studies, but early SA consultation can also support the design of informative studies in the learning phase, which has been demonstrated to be a determinant for future MAA success (Nature Rev. Drug Discov. 11, 903–904; 2012). Our finding that only one‑third of the clinical trial design proposals to SA are deemed acceptable, in conjunction with the higher compliance and MAA success rates that are observed when SA is obtained during the pre-pivotal development stage, indicates that early SA gives the sponsor the time and the opportunity to implement changes to the clinical development programme in order that trials provide adequate data for the regulatory benefit–risk assessment. Matthias P. Hofer, Christina Jakobsson, Nikolaos Zafiropoulos, Spiros Vamvakas, Thorsten Vetter and Jan Regnstrom are at the European Medicines Agency, 30 Churchill Place, Canary Wharf, London E14 5EU, UK. Robert J. Hemmings is at the Medicines and Healthcare Products Regulatory Agency, 151 Buckingham Palace Road, Victoria, London SW1W 9SZ, UK. Correspondence to J.R. e-mail: [email protected] doi:10.1038/nrd4621 The authors declare no competing interests. The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.
SUPPLEMENTARY INFORMATION See online article: S1 (box) | S2 (table) | S3 (table) ALL LINKS ARE ACTIVE IN THE ONLINE PDF
2 | ADVANCE ONLINE PUBLICATION
www.nature.com/reviews/drugdisc © 2015 Macmillan Publishers Limited. All rights reserved
