Strengths and limitations of this study This is the most up to date and complete study that considers trends in clinical development timelines for new drugs introduced into the UK.

The study used data from the European Medicines Agency, Medicines and Healthcare Products Regulatory Agency and British National Formulary to ensure that all relevant drugs were identified and regulatory dates were accurate.

However, this study considered only the clinical phase of development, from the initiation of clinical trials to regulatory approval and omits the time and resources needed for discovery and preclinical development, as well as postauthorisation activities.

This study did not consider new indications or the repurposing of existing licensed and marketed drugs.

Introduction Recent decades have seen the emergence and identification of several new viral infections of global significance,1 ,2 but they have also witnessed the development of highly innovative new antiviral drug therapies, which have, for example, dramatically improved the prognosis of those infected with HIV3 and now are radically changing the care of those infected by hepatitis C.4 However, concerns have been expressed about the increasing costs of developing new drugs and bringing them into clinical use.5–9 In broad terms, drug development begins with discovery and preclinical laboratory research, before moving on to clinical development, starting with first testing in humans (phase I clinical trials) and continuing until regulatory review and approval.5 ,6 ,10 ,11 Phase I to III clinical trials may be responsible for more than half the time and cost required to bring a new drug from discovery to regulatory approval.6 ,12 Therefore, trends in the time taken for clinical development may be an important driver of increasing total development costs as well as having implications for patient access to innovative new medicines. A number of authors have attempted to characterise the time taken to translate basic research findings into clinical practice; a review by Morris et al10 identified a number of studies reporting the time taken to translate health research, concluding that 17 years was the most likely estimate despite wide variation in definitions and marked differences in the time periods studied and approaches to data collection. However, few researchers have considered trends in drug development timeframes. Keyhani et al13 considered the time taken from the Investigational New Drug (IND) Application (a step required by the US Food and Drug Administration (FDA) prior to testing in humans14) to the filing of a New Drug Application15 and subsequent FDA approval (the latter time points representing the regulatory review process). For all new drugs approved in the USA from 1992 to 2001, the authors found no increase in the time taken to conduct clinical trials prior to filing a New Drug Application (median 5.1 years) and a decrease in the time taken for the subsequent regulatory review and approval. Kaitin and DiMasi16 considered a much longer time frame (1980–2009) and also found a decrease in time taken for regulatory review by the FDA. However, they found an increase in the clinical trial periods prior to filing (increasing from a mean 5.7 years for drugs approved in the USA 1980–1984, to 6.4 years for those approved 2005–2009) and concluded that this was due, in part, to increasing numbers of central nervous system and antineoplastic agents with very long average development times. However, the clinical trial periods prior to filing (ie, from IND application to filing a New Drug Application) for HIV antiviral agents also increased from a mean 2.3–5 years, and clinical trial periods for other anti-infective agents (including other antiviral drugs) increased from 4.2 to 6.6 years. More recent data on drug intervention trials registered with ClinicalTrials.gov suggests that trial lengths may have reduced in recent years (from 2 years for trials beginning in 2005 to 1.3 years for those beginning in 2009), but this trend was considerably less marked for industry sponsored trials, which are more likely to support the approval of new drugs.17 Similar data on trends in drug development have not been published for drugs launched in the UK. We sought to determine whether the overall time taken for the clinical development (clinical trial periods prior to filing and subsequent consideration by the regulator) of new drugs launched in the UK had changed over more than three decades, using data for antiviral drugs.

Methods All new drugs first licensed for use in the UK between 1981 and 2014 (inclusive) and specifically indicated for the treatment of viral disease were identified along with their initial approved indication(s) from relevant editions of the British National Formulary (BNF) and the European Medicines Agency (EMA) website. The BNF lists all preparations available for prescribing and/or dispensing in the UK, including prescription only and over-the-counter medicines. A new drug was defined as a new chemical entity or new biological product not previously licensed for use in the UK; new formulations and new indications for existing licensed drugs were omitted from the study, as were new combination products where all the active components were already licensed and available separately or in other combination products. Clinical development was defined as the period from the initiation of studies in humans (clinical trials) to the receipt of a Marketing Authorisation (MA or ‘licence’) applicable to the UK from the Medicines and Healthcare Products Regulatory Agency (MHRA) or the EMA as appropriate.5 This period was further subdivided by the date of Marketing Authorisation Application (MAA, regulatory submission or ‘filing’) into periods representing clinical trials (prior to filing) and subsequent regulatory approval. The initiation of clinical development was determined from searches of a commercial pharmaceutical R&D database (Pharmaprojects, Informa Group plc) and a bibliographic database of published biomedical literature (MEDLINE, US National Library of Medicine). The date of IND Application to the FDA was taken as the start of clinical development; where this was not available, we used the date that the first clinical trials were undertaken (taken from the published literature) or the date that the first report of clinical trials (typically phase I) was published instead. The dates of MAA and MA were obtained from the EMA website or direct from the MHRA. The duration of clinical development, as well as the clinical trial and regulatory approval periods, were calculated to the nearest month. Simple descriptive statistics were used to summarise these data and explore differences in durations according to the drug indication (viral disease) and year of licence (1981–1992, 1993–2003 and 2004–2014). The statistical significance of differences in mean duration were determined using unpaired t tests. Scatter plots were used to visualise trends in development timeframes by year of UK drug launch, and where relevant, Pearson's correlation coefficient and least-squares linear regression lines were calculated. Statistical analyses were conducted using SPSS (V.21.0, IBM).

Results There were 48 new drugs licensed for the treatment of viral diseases in the UK during the 34-year period from 1981 to 2014, representing a mean 1.4 new drugs per year (table 1). Almost half of these drugs were licensed in the middle period (1993–2003, 48%), while just 15% were licensed in the earlier period (1981–1992). Over half of new drugs (54%) were initially indicated for HIV infection. The next most frequent initial indication was hepatitis C infection (15%), followed by infection with cytomegalovirus (13%), hepatitis B (8%), herpes simplex virus (4%), influenza virus (4%) and respiratory syncytial virus (2%, full details provided in online supplementary file 1). Table 1 Duration of clinical development for antiviral drugs, in total and subdivided into clinical trials and regulatory approval periods, by year of first license and indication in the UK, 1981–2014 The overall mean duration of clinical development was 77.2 months, the majority of which was spent in clinical trials before the date of regulatory submission (84%, table 1). The total time in clinical development increased during the study period, from 58 months for drugs licensed 1981–1992, to 91.7 months for drugs licensed 2004–2014, a result that was statistically significant (p=0.048). This increase was accounted for by an increase in time spent in clinical trials before regulatory submission, which increased from 41.7 months for drugs licensed 1981–1992 to 78.4 months for drugs licensed 2001–2014 (p=0.027). No equivalent increase in time spent in the regulatory approval period was observed. A statistically significant upward linear trend in the total duration of clinical development (r=0.31, y=1.26×year—2442.01, p=0.034, figure 1) and the clinical trials period (r=0.34, y=1.38×year—2695.37, p=0.018) was observed for drugs licensed across the whole study period, suggesting that mean total clinical development and clinical trial durations increased by 12 months every 9.5 and 8.7-year period, respectively. In contrast, no significant linear trend was observed for the duration of the regulatory approval period (r=0.16, y=−0.12×year+253.36, p=0.32). Figure 1 Duration of clinical development for antiviral drugs by year of first license in the UK, 1981–2014. Considering the initial indications for new drugs, those licensed to treat hepatitis C infection had a longer duration of clinical development than those indicated for HIV infection or other viral infections (table 1), though this result was not statistically significant. A statistically significant upward linear trend was observed for total clinical development durations for drugs first licensed to treat HIV across the study period (r=0.54, y=1.84×year—3606.44, figure 2). The clinical development durations of drugs initially licensed to treat other viral infections increased at a slower rate, and the trend was not statistically significant (r=0.29, y=0.98×year—1882.40). Figure 2 Duration of clinical development for antiviral drugs indicated for HIV and other viral infections by year of first license in the UK, 1981–2014.