Zwiers Regulatory Consultancy Corresponding author: Alex Zwiers, alex.zwiers@az-regulatory.com 5349 AA Zwiers Regulatory Consultancy, Gasstraat 20, Oss, The Netherlands. Tel: 0031 (0)6 10489150 Key words: CONFLICT OF INTEREST The authors declared no competing interests for this work. FUNDING No funding was received for this work.
The FDA and the EMA offer expedited regulatory approval programs for drugs with high potential patient value applicable at different stages leading to marketing authorization: (i) drug development (fast track designation (FTD), breakthrough therapy designation (BTD), regenerative medicine advanced therapy designation in the United States (US), and priority medicines scheme in the European Union (EU)), (ii) review of marketing authorization application (priority review in the US and accelerated assessment in the EU), (iii) approval of drug (accelerated approval in the US and conditional approval in the EU). Typical clinical development time of 76 new anticancer drugs, for which the EMA gave a positive opinion between January 2010 and December 2019, was 6.7 years: 5.8 years for small molecules and 7.7 years for biotechnology-derived products. Drugs following only BTD (5.6 years) typically had a shorter clinical development time than drugs following only FTD (6.4 years) or both FTD and BTD (6.4 years), compared to drugs not following any expedited regulatory approval program at the drug development stage (7.7 years). Drugs following an expedited regulatory approval program at the stage of drug development and accelerated approval in the US (FDA1 (4.5 years) and FDA3 (5.6 years)), and drugs following the standard procedure at the stage of drug development and conditional approval in the EU (EMA5 (5.5 years) and EMA7 (4.5 years)) typically had a reduced clinical development time. These findings provide insight for the industry into combinations of expedited regulatory approval programs correlated with shorter clinical development time of new anticancer drugs.
In 2020, the Global Cancer Observatory (GLOBOCAN) estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths [1]. New anticancer drugs have been invented with the goal to treat the increasing number of cancer patients efficiently and safely, decrease the cost of the drugs for the patients, and decrease the cost of development and chance of failure to obtain marketing authorization for the pharmaceutical industry [2]. The cost of developing a new medicine is estimated to range between US$944m and US$2,826m (adjusted to 2019 prices), including the discovery and pre-clinical and clinical development [3]. The rate of failure to obtain marketing authorization decreases when a candidate drug advances from preclinical development phase into Phase 1 and subsequent phases of clinical development. Anticancer drugs in Phase 1, Phase 2 and Phase 3 of clinical development at the drug development stage, and at the stage of review of marketing authorization application (MAA) have been reported to have a 3.4%, 6.7%, 35.5% and 81.7 % chance of receiving regulatory approval in the United States (US), respectively [4]. The regulatory agencies in the US and the European Union (EU), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), respectively, offer expedited regulatory approval programs for drugs with high potential patient value, which (i) support the development of such drugs (i.e., fast track designation (FTD) (introduced in 1987) [5], breakthrough therapy designation (BTD) (introduced in 2012) [5] and regenerative medicine advanced therapy designation (RMATD) (introduced in 2017) [6] in the US, and priority medicines scheme (PRIME) (introduced in 2016) [7] in the EU), (ii) provide shorter review times of MAAs (i.e., priority review designation (introduced in 1992) [5] in the US, and accelerated assessment (introduced in 2005) [8] in the EU), or (iii) provide preliminary approval (i.e., accelerated approval (introduced in 1992) [5] in the US, and exceptional circumstances (introduced in 1995) [9] and conditional marketing authorization (introduced in 2006) [10] in the EU). We have recently shown the correlation between expedited regulatory approval programs offered by the FDA and the EMA, type of product (small molecule or biotechnology-derived product) or consulting scientific advisory committees and the regulatory review time of the MAAs for new anticancer drugs [11]. Here, a detailed analysis of the correlation between different expedited regulatory approval programs or type of product and the clinical development time of new anticancer drugs is presented.
New anticancer drugs for which the Committee for Medicinal Products for Human Use (CHMP) of the EMA gave a positive opinion between January 2010 and December 2019 were identified by Garsen et al. [12]. The construction of the dataset composed of 76 new anticancer drugs with both positive CHMP opinion and FDA approval was recently described by da Costa Gonçalves et al. [11]. The inclusion criteria were (i) article 8(3) full or full-mixed application as legal basis, (ii) new active substance, and (iii) products developed to treat cancer [12, 11].
Information on the type of product (small molecule or biotechnology-derived product), expedited regulatory approval program (PRIME, accelerated assessment and conditional approval) in the EU and clinical trial start date was extracted from the European Public Assessment Report (EPAR) and the summary of the CHMP opinion available on the EMA website. The dataset does not contain any drugs that underwent exceptional circumstances offered by the EMA. Information on the date of submission of MAA, date of approval of the drug by the FDA, type of MAA (new drug application (NDA) for small molecules and biologic license application (BLA) for biotechnology-derived products), expedited regulatory approval program (FTD, BTD, RMATD, priority review and accelerated approval) in the US and clinical trial start date was extracted from the FDA approval letters, administrative correspondence and FDA application review files available in the Drugs@FDA database.
Different stages leading to marketing authorization and applicable expedited regulatory approval programs at each stage were defined as: (i) drug development (FTD, BTD, and RMATD in the US, and PRIME in the EU), (ii) review of MAA (priority review in the US and accelerated assessment in the EU), and (iii) approval of drug (accelerated approval in the US and conditional approval in the EU) [11]. Each drug was classified to follow either a standard (i.e., no employment of expedited regulatory approval programs at any stage) or an expedited regulatory approval pathway (i.e., employment of at least one expedited regulatory approval program at least at one stage).
The databases ClinicalTrials.gov and the EU Clinical Trials Register were searched using the active ingredient of each drug as search term. Search results from each database were filtered to display only Early Phase 1 and/or Phase 1 studies, and were compared to select the earliest clinical trial start date. The clinical trial start date for an active ingredient was adjusted if an earlier date was encountered in an EPAR, FDA application review file (gemtuzumab ozogamicin (Clinical Review(s), Reference ID: 4138714, the first day of the month was selected due to lack of information)), or published manuscript (for alectinib [13], dinutuximab [14] (the first day of the year of publication was selected due to lack of information), and trifluridine and tipiracil hydrochloride [15] (the first day of the year of publication was selected due to lack of information)). Clinical development time was calculated as the number of days that elapsed from the earliest clinical trial start date to the date of submission of MAA in the US (Table S1).
Box plots were created using the web tool BoxPlotR [16].
Considering up to billions of dollars spent during drug development, it is important for the pharmaceutical industry to follow the best available regulatory strategy shortening the clinical development time and increasing the chance of regulatory approval. The regulatory agencies in the US and EU, the FDA and the EMA, respectively, offer expedited regulatory approval programs for drugs with high potential patient value that expedite the development and review time of the MAA of such drugs. Drugs following FTD, BTD, RMATD and PRIME are eligible for early and increased interaction and frequent meetings with the FDA and the EMA enabling continuous regulatory compliance and streamlining the development process [17], while accelerated approval and conditional marketing authorization enable early approval supported by limited data before the confirmatory clinical studies are completed [17]. In this study, the correlation between different expedited regulatory approval programs or type of product (i.e., small molecule or biotechnology-derived product) and the clinical development time of 76 new anticancer drugs, with positive CHMP opinion between January 2010 and December 2019 and FDA approval, is analysed.
We have previously shown that the date of submission of the MAAs for new anticancer drugs were comparable in the US and the EU, albeit mostly earlier in the US [11]. In this study, clinical development time was calculated as the number of days that elapsed from the earliest clinical trial (i.e., first in human study) start date to the date of submission of MAA in the US (Table S1). In some cases, the earliest clinical trial start date extracted from public databases ClinicalTrials.gov and the EU Clinical Trials Register might not correspond with the actual first in human study on the corresponding active ingredient, considering the reportedly missing registration of trials in the databases, date of entry into force of the laws requiring registrations, and registrations of some types of trials not required by law (e.g., registration of some Phase 1 clinical trials in the EU Clinical Trials Register) [18, 19]. It should also be noted that the clinical development time after the date of submission of MAA in the US, e.g., mandatory confirmatory clinical studies for the drugs approved via accelerated approval or conditional marketing authorization, was not included in the clinical development time in this study.
The typical clinical development time, calculated as the number of days that elapsed from the earliest clinical trial (i.e., first in human study) start date to the date of submission of MAA in the US, of new anticancer drugs was 6.7 years. While the type of product did not have a high impact on the review time of the MAAs [11], it had a high impact on the clinical development time (small molecules 5.8 years (median) vs biotechnology-derived products 7.7 years (median)) (Figure 1a).
Twenty-five drugs did not follow any expedited regulatory approval program at the drug development stage. Thirty-two, 28, three and two drugs underwent FTD, BTD, PRIME and RMATD, respectively, correlating with the duration these programs have been in effect (since 1987, 2012, 2016 and 2017, respectively). There are limited data on the effect of following PRIME and RMATD in clinical development time, and there is no drug in the dataset that followed only PRIME or only RMATD at the drug development stage. Drugs following only FTD, only BTD and both FTD and BTD at the drug development stage had a reduced clinical development time of 6.4 years (median), 5.6 years (median), and 6.4 years (median), respectively, compared to drugs not following any expedited regulatory approval program at the drug development stage (7.7 years (median)). Drugs following only BTD typically had a shorter clinical development time than drugs following only FTD or both FTD and BTD (Figure 1b). These results are in line with a previously published analysis of clinical development time (from Investigational New Drug (IND) application to FDA approval between January 2012 and December 2016) of 174 new drugs: 7.1 years (IQR 5.5-9.6) only FTD, 4.8 years (IQR 3.6-8.3) only BTD, and 5.0 years (IQR 2.9-7.7) both FTD and BTD [20].
New anticancer drugs following expedited regulatory approval programs at the stages of drug development (FTD, BTD and/or RMATD) and approval of drug (accelerated approval) in the US (FDA1 and FDA3), and the new anticancer drugs flowing the standard procedure at the stage of drug development and an expedited regulatory approval program at the stage of approval of drug (conditional approval) in the EU (EMA5 and EMA7) typically had a reduced clinical development time. These results confirm the strong correlation between undergoing BTD or accelerated approval in the US and reduced clinical development time (from initiation of first in human clinical studies to FDA approval between 2010 and 2020) of 405 innovative drugs previously shown in another study [21].
The regulatory pathways that correlated with the shortest clinical development time of 4.5 years (median) were FDA1 in the US (at least one expedited regulatory approval program at the stage of drug development, priority review of MAA and approval of drug) and EMA7 in the EU (only conditional approval at the stage of approval of drug) (Figure 2). Although the clinical development time of drugs following these regulatory pathways are typically the same, the MAAs of the drugs following FDA1 were previously shown to have the shortest review time in the US (172 days (median)), while the MAAs of the drugs following EMA7 were shown to have the longest review time in the EU (392 days (median)) [11].
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