Analysis of integrated clinical trial protocols in early phases of medicinal product development

Abstract

Purpose: While in the past, most clinical trial applications (CTAs) following non-integrated (standard) protocols were used to investigate one primary objective concerning a (new) drug, nowadays, the use of integrated protocols investigating multiple objectives within the same CTA becomes more and more popular. The aims of the present study were to investigate the usage and the impact of integrated protocols on regulatory activities and to find the motivation for their increasing use.

Methods: Two thousand nine hundred sixty-nine phase I and I/II CTAs submitted to the German Federal Institute for Drugs and Medical Devices (BfArM) during the time period from August 1, 2004, until August 31, 2014, were analysed with regard to protocol and sponsor status, duration until initial authorisation and the number of substantial amendments and their respective approval times. Additionally, applicants who submitted integrated protocols to BfArM were interviewed with respect to their opinion on integrated protocols in an online survey.

Results: The percentage of integrated protocols has constantly increased by approximately 10% within the last 10 years from 17.9% in 2004 to 28.2% in 2014. It could be shown that authorisation procedures with single integrated protocols take significantly longer until initial authorisation (58 vs. 53 days) requires more substantial amendments (1.9 vs. 1.2 amendments per CTA) and the approval of the entirety of amendments takes longer to process as compared to standard protocols (22 vs. 14 days). Nevertheless, applicants prefer the use of integrated protocols due to higher time and cost economy for the entire phase I development process.

Conclusion: Although clinical trials (CTs) following integrated protocols are partly more time-consuming and costly, still, time and/or money may be saved during drug development due to the fact that overall, fewer CTs are needed than with standard protocols. Hence, the main reason for the increasing use of integrated protocols is improved time and cost efficiencies when conducting CTs.

Keywords: Early-phase clinical trials; Federal Institute for Drugs and Medical Devices (BfArM); Integrated protocol; Non-integrated (standard) protocol; Substantial amendment.

Fig. 1

Data set selection and survey participant selection. All clinical trial applications (CTA) submitted to the Federal Institute for Drugs and Medical Devices (BfArM) between August 2004 and August 2014 (N = 10,000) were collected from the PharmNet.Bund database as well as from the in-house archive of the BfArM. After exclusion of all CTAs other than phase I and I/II (N = 6950), further CTAs were removed from the data set (N = 81). In this regard, CTAs where the initial authorisation was still pending when the database analysis was performed (N = 22), CTAs that the BfArM rejected (N = 21), CTAs that were withdrawn by the applicant (N = 7), CTAs that were revoked by the BfArM (N = 3) and CTAs that were not associated with medicinal products (N = 28) were excluded from the analysis. The remaining phase I and I/II CTAs (N = 2969) were classified according to their protocol status. N = 671 met the criteria for an integrated protocol, and N = 2298 were identified as non-integrated protocols. Applicants who submitted at least one integrated protocol to BfArM were invited by e-mail to participate in the online survey (N = 332). As five e-mails were returned as undeliverable, a total of N = 327 applicants were invited to participate in the survey

Fig. 2

Classification of integrated protocols. According to their primary and secondary endpoints, the integrated protocols were classified into five major subgroups ‘SAD + additional endpoint(s)’, ‘MAD + additional endpoint(s)’, ‘SD/SS + additional endpoint(s)’, ‘PD trials’ and ‘Phase I/II oncology trials’. These subgroups partially consisted of further smaller subgroups which are displayed as supplemental information only. The total numbers as well as the percentage values are displayed. SAD single ascending dose trials, MAD multiple ascending dose trials, SD/SS trials using stable dose(s) (single or multiple) or steady-state conditions, PD trials with primary pharmacodynamic objectives

Fig. 3

Integrated protocols over time. a Percentage of integrated protocols (N = 671) in comparison to standard protocols (N = 2298) for the years 2004 to 2014. b Percentage of the five major subgroups of integrated protocols (‘SAD + additional endpoint(s)’, ‘MAD + additional endpoint(s)’, ‘SD/SS + additional endpoint(s)’, ‘PD trials’ and ‘Phase I/II oncology trials’) for the years 2004 to 2014 (N = 671). SAD single ascending dose trials, MAD multiple ascending dose trials, SD/SS trials using stable dose(s) (single or multiple) or steady-state conditions, PD trials with primary pharmacodynamic objectives

Fig. 4

Duration until initial authorisation over time. a Duration until initial authorisation of a clinical trial application displayed in days for integrated protocols (N = 671) in comparison to non-integrated protocols (N = 2298) for the years 2004 to 2014. Correlation of duration over the time for non-integrated protocols: r = − 0.76 (p = 0.007), for integrated protocols: not significant. b Duration until initial authorisation of an integrated trial application displayed for the five major subgroups of integrated protocols (‘SAD + additional endpoint(s)’, ‘MAD + additional endpoint(s)’, ‘SD/SS + additional endpoint(s)’, ‘PD trials’ and ‘Phase I/II oncology trials) for the years 2004 to 2014 (N = 671). SAD single ascending dose trials, MAD multiple ascending dose trials, SD/SS trials using stable dose(s) (single or multiple) or steady-state conditions, PD trials with primary pharmacodynamic objectives

Fig. 5

Survey results on duration of initial authorisation and clinical conduct, time-saving factors, and number of substantial amendments and major problems. Survey participants were asked to rate to what extent the duration of initial authorisation and clinical conduct of a CTA have changed when using integrated protocols compared to standard protocols. An ascending six-point scale ranging from ‘clearly shorter’ to ‘clearly longer’ was used. The first three options (‘clearly shorter’, ‘shorter’and ‘rather shorter’) were classified as faster initial authorisation and faster clinical conduct, whereas the last three options (‘rather longer’, ‘longer’ and ‘clearly longer’) were classified as slower initial authorisation and slower clinical conduct (bar nos. 1 and 2). Moreover, the survey participants were asked to rate the impact of the three aspects ‘Time gain during initial submission’, ‘Avoidance of substantial amendments’ and ‘Avoidance of rejection of the CTA during initial submission’ on time-saving when using integrated protocols. An ascending six-point scale ranging from ‘clearly saved time’ to ‘no time saved at all’ was used. The first three options (‘clearly saved time’, ‘saved time’ and ‘rather saved time’) were classified as time-saving factors, whereas the last three options (‘rather no time saved’, ‘no time saved’ and ‘no time saved at all’) were classified as no time-saving factors. Additionally, the participants could also choose the option ‘time delay’, when time was lost due to use of integrated protocols (bar nos. 3, 4 and 5). Finally, the survey participants were asked to rate to what extent the numbers of substantial amendments and major problems have changed when using integrated protocols compared to standard protocols. An ascending five-point scale ranging from ‘number has decreased clearly’ to ‘number has increased clearly’ was used. The first two options (‘number has decreased clearly’ and ‘number has decreased slightly’) were classified as decrease in substantial amendments and major problems, whereas the last two options (‘number has increased slightly’ and ‘number has increased clearly’) were classified as increase. Additionally, the participants could also choose the option ‘number largely unchanged’ when no relevant differences in the number of substantial amendments and major problems were observed (bar nos. 6 and 7)

Fig. 6

Survey results on motivation. Relevance ratings of motivational aspects for using integrated protocols. Survey participants were asked to rate to what extent ‘Financial aspects’, ‘Time aspects’, ‘Number of major problems’, ‘Number of substantial amendments’, ‘Expenditures for trial preparation’ and ‘Expenditure for trial conduct’ are relevant as motivation for using integrated protocols. An ascending six-point scale ranging from ‘very relevant’ to ‘not relevant at all’ was used. The first three options (‘very relevant’, ‘rather relevant’ and ‘slightly relevant’) were classified as relevant for motivation for using integrated protocols, whereas the last three options (‘slightly irrelevant’, ‘rather irrelevant’ and ‘not relevant at all’) were classified as not relevant for using integrated protocols