Points of View Survey of Drug Development Time ～Do Differences in Modalities and Diseases Matter?

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Yosuke Takahashi, Senior Researcher, National Institute of Biomedical Innovation Policy

Introduction

In Policy Research Institute News No. 66, we conducted an analysis of the "probability of success" in pharmaceutical ^R&D1). In analyzing R&D productivity, not only "success probability" but also "R&D duration" and "R&D cost" are important factors, and by considering these factors as a whole, it is possible to estimate the amount of R&D investment assumed to be required to bring a single new drug to market. The R&D period not only affects the opportunity cost of bringing a new drug to market, but also affects the period of exclusivity during the patent protection period after the drug is launched, thus significantly affecting the present value-based profitability of the R&D investment. In this paper, we analyze the "research and development period" based on the information contained in the drug databases.

Methodology and Results

In this study, development time was evaluated by two methods: the first method is to calculate the time in each phase for each indication of each development candidate; the second method focuses on each development candidate (NME) and calculates the time from the date of the first clinical trial in some indication to the date of the first clinical trial in some indication (different indication from the start of the trial). The second method focuses on each NME and calculates the time from the date of the first clinical trial for a given indication (which can be a different indication than when the trial was initiated) to the date of the first approval for a given indication. The former method is useful for understanding the average development period of each phase and the average development period for each indication (therapeutic area), and is a general-purpose method when analyzing the R&D period of a drug, but it has the limitation of not being able to capture the development period focused on a single development candidate (NME). The second method takes this into consideration and calculates the development period for each NME, including all the twists and turns in the development process due to changes in indications and other factors.

In the series of research studies described in this paper, Evaluate Pharma, a pharmaceutical database, was used. First, the Phase 1, Phase 2, and Phase 3 periods, as well as the review period from application to approval (illustrated as Filed), were investigated using Method 1. Specifically, we used the timeline analysis of the Developmental Risk module to cover all data listed as of the survey date. It should be noted that in this database, the period of each phase is defined as the start date of the next phase from the start date of the ^phase2) and not the period of the clinical trial. The review period is defined as the time from submission to the FDA until approval by the FDA, and is calculated as the time until formal approval, not the time to obtain Emergency Use Authorization (EUA), as was the case with the COVID-19 vaccine. The time period is calculated as the time until official approval, not the time to obtain Emergency Use Authorization (EUA), as was the case with COVID-19 vaccine.

The data related to the development period included in the database are not limited to drugs that have finally been approved, but also include data on drugs that are still under development or have been discontinued, even if they have progressed to the next phase of development. For example, if there is a development product X for which development was decided to be discontinued after implementation of Phase 2, the Phase 1 period for development product X will be included in the database, but not for Phase 2 and beyond.

In analyzing summary statistics such as the median development period, the start date of each phase is limited and tabulated as shown in Table 1 for the purpose of reflecting the relatively recent situation and to ensure a certain sample size to increase the reliability of the data. It should be noted that the information in the database is based on information disclosed by pharmaceutical companies, such as registration information on ClinicalTrial.gov, and does not necessarily cover the development period of all developed products.

In Method 2, after classifying new drug entities (NMEs) approved by the FDA by year of approval, the years and months when these NMEs first started Phase 2 were investigated, and the "time required from the start of Phase 2 to approval (per NME)" was calculated from the difference between the two. We also attempted to calculate the time from the start date of Phase 1 to the approval date, but this analysis was not performed because it was judged that a high percentage of the Phase 1 start dates were not clear when the analysis was limited to approved drugs, and thus the sample size was not sufficient for the analysis.

Development period in each phase

The development time required for each phase was calculated from all data in the database, and the median and interquartile range from 25% to 75%, as well as the number of samples used to calculate these figures, are shown in Table 2. The development time classified by modality was also calculated and is shown in Table 3 as ^well3). The modality ^{classifications4)} in Table 3 include small molecule, recombinant protein (Protein peptide therapeutics), antibody, ^vaccine5), and nucleic acid (DNARNA therapeutics). Other modalities were excluded from the data collection due to small sample size.

As a result, the median duration of Phase 1 was 25 months, Phase 2 was 35 months, Phase 3 was 36 months, and the review period was 10 months, and the total of these periods was 106 months (8 years and 10 months). However, the development period varied greatly from product to product, and rather than converging around the median, the 25th to 75th quartiles ranged from 14 to 44 months for Phase 1, 21 to 55 months for Phase 2, 25 to 50 months for Phase 3, and 6 to 13 months for Filed, with the earlier phases in particular The spread was relatively large. In the case of a product with a new mechanism of action or a new modality, the study protocol is often designed according to the characteristics of the developed product, such as carefully increasing the dosage from a low dosage in the Phase 1 study to maximize safety, and additional studies are conducted to optimize the study protocol for the next phase. The fact that there are cases where additional studies are conducted to optimize the study protocol for the next phase is thought to be the reason for the relatively large spread in the early phases of the development process.

Development time in each phase (by modality)

The analysis results for each modality (Table 3) show that the development period for small molecules, which account for about half of the total, is about the same as the development period for all drugs (Table 2), with a median period of 24 months for Phase 1, 35 months for Phase 2, 36 months for Phase 3, and 10 months for the review period. The combined total was 105 months. The development time for recombinant proteins and antibodies was also roughly the same as the development time calculated for all drugs, with the combined development time being 105 and 102 months, respectively. The development period for vaccines was slightly longer, totaling 115 months, while that for nucleic acid drugs was slightly shorter, totaling 96 months.

The analysis delves deeper into the development time of vaccines. As shown in Table 3, the median development time of vaccines was 30, 37, 36, and 12 months for Phase 1, Phase 2, Phase 3, and the review period, respectively, and the sum of these periods was 115 months. Furthermore, when the data were restricted to pre-2019 data, prior to the COVID-19 pandemic, the median development time was 30, 42.5, 40, and 12 months, respectively, and the sum of these periods was 124.5 months. This means that prior to 2019, the development time for vaccines tended to be particularly long compared to other modalities. Despite this, since the December 2019 outbreak of pneumonia of unknown cause (later COVID-19) in ^China6), various breakthrough vaccines have been created to save people around the world, and this is a particularly noteworthy case in that they have reached commercialization at an unprecedented speed7)8) . ^{7) and 8)}. For example, the FDA granted emergency use ^{authorization9)} for Pfizer-BioNTech's vaccine on December 11, 2020 and official approval on August 23, 2021, ¹⁰⁾ and granted emergency use ^{authorization11)} for Moderna's vaccine on December 18, 2020 and official approval on January 31, 2022 ^.12) One of the factors that enabled the rapid development of vaccines in a short period of time during the COVID-19 pandemic was that various emergency measures, including national policies, were taken based on the threat posed by the novel coronavirus, including its virulence and high infectivity and transmissibility, and that a large number of subjects were quickly recruited. The rapid collection of a large number of test subjects was one of the factors that made it possible to develop the virus in a short period of time. It is also worth noting, however, that innovation has shortened the development period, as in the case of mRNA vaccines, new technologies that have resulted from the accumulation of basic research have made it possible to create vaccines with high efficacy in a short period of time, and the development of new technologies has also contributed to the development of vaccines with high efficacy, Another important factor is the development of digital transformation, which has not only shortened the vaccine design period, but has also enabled real-time data collection and rapid analysis of efficacy in clinical practice, as well as the active use of real-world data. From this perspective, the knowledge and experience gained from the COVID-19 pandemic (and which will continue to be accumulated) may streamline the development of other vaccines, and it is expected that the development period of vaccines will be shortened in the future.

In the case of nucleic acid drugs, the median Phase 3 period tended to be somewhat short (28 months). Although it should be noted that the number of samples used to calculate the time period was 16, which is smaller than that of other modalities, and thus the certainty of the discussion should be taken into account, nine of the 16 products were approved by the FDA through the expedited ^approval13) pathway, which is a unique feature. Rather than the development period being shortened because of nucleic acid drugs, nucleic acid drug discovery is being attempted for diseases that are difficult to treat with conventional modalities such as small molecule drugs, and because it is necessary to deliver new drugs to patients as soon as possible, especially for diseases with high unmet needs. In this context, the adoption of surrogate endpoints in clinical trials may have led to the shortening of the development period.

Development time in each phase (by disease area)

Next, we examined the duration of each phase by disease area. We used the classification criteria on ^{EvaluatePharma14)} for the classification of disease areas. Figure 1 shows the median development time for each phase and the interquartile range (25% to 75%), since there was a large variation in the development time for each product even in the same disease area. In calculating the development time for each disease area, the number of samples was limited to those that could be secured (15 or more samples in each phase), and the number of samples is shown in Table 4.

The median time from Phase 1 to the next phase was 20 to 30 months in most disease areas, and there were no significant differences among the disease areas. However, the development period tended to be slightly longer in the Cancer therapeutic area. This may be due to the fact that Phase 1 trials are often conducted in patients in the Cancer area, where not only safety and pharmacokinetic characteristics but also efficacy are evaluated, resulting in a longer development period.

In terms of the duration of Phase 2, it was confirmed that patients in most disease areas entered the next phase within 30 to 40 months, while patients in the Reproduction area had a slightly longer development period. The Reproduction area includes such diseases as uterine fibroids, endometriosis, infertility, premature birth, and menopausal disorders. A close examination of the actual time required for Phase 2 of the development of products for these diseases reveals that some of them took much longer than 30 to 40 months, which is the median development time for other diseases (individual data is omitted). These diseases include many diseases that still have high unmet needs, and are characterized by the lack of many prior drugs that have been successfully developed. It could be assumed that the long development period was due to the difficulty of following precedents when planning clinical trials, but it was difficult to conduct a more precise analysis. However, the number of samples used to calculate the development period in this therapeutic area was the same as the lower limit of 15 to be evaluated, which is a smaller number than in other therapeutic areas, and it cannot be denied that this may have affected the results.

The Gastrointestinal disease includes various diseases, such as ulcerative colitis, Crohn's disease, constipation, and so on. The Gastrointestinal segment includes a variety of diseases, and among them, the development period tended to be longer for products indicated for ulcerative colitis, Crohn's disease, and constipation, but it was difficult to elaborate (detailed data are omitted).

The review period was generally around 10 months, with no major differences observed, but the only case in the Cancer field was slightly shorter, at around 6 months. Among the cases used in this analysis, about two-thirds (204 out of 332 cases) of the cases in the Cancer field were tagged with Expedited approval, while only about one-fourth (255 out of 1081 cases) of the cases in the non-Cancer field were tagged with Expedited approval. Expedited approval was tagged in about 2/3 (204 out of 332 cases), and only about 1/4 (255 out of 1081 cases) in the non-Cancer field. This difference may be reflected in the difference in review time.

Time from the start of Phase 2 to approval (by NME)

In the aforementioned survey on "development time in each phase," the development time of a drug from Phase 1 to approval was evaluated by comprehensively tabulating all development products, calculating the actual development time required for each phase, and adding up the development time for each phase. This method has the advantage that the average period can be evaluated by breaking it down into phases. However, in the research and development process of a single developed product, each phase is not necessarily carried out in series, and there is a possibility that the actual development period of each developed product cannot be correctly evaluated (≒ estimated too short).

Since the above concerns are assumed, we analyzed the "time taken from the start of Phase 2 to the approval (per NME)" focusing on each development product one by one. In addition, for the purpose of understanding the recent situation, the evaluation was categorized by the year of approval at the FDA.

Figure 2 shows the analysis results for all developed products for which Phase 2 start date and FDA approval date information is available, plus the analysis results for ^only new ^{modalities15)} extracted from those products. The difference in the development period calculation method is illustrated in Figure 3. The median time from the start of Phase 2 to approval (per NME) has been stable around 2,600 to 2,700 days (7 years, 2 months to 7 years, 5 months) in recent years. When restricted to new modalities, the median for this period was around 2,300 to 2,500 days, a somewhat shorter result. When calculated together based on the results in Table 2, the time from Phase 2 to application is 81 months (6 years and 9 months). The difference between the time periods calculated by the two methods was 5 to 8 months, with the result that the "time required from the start of Phase 2 to approval (per NME)" was longer. Although we cannot rule out the possibility that the difference is based on the difference in the population analyzed, the existence of a certain number of cases like the one shown in Figure 3 (cases that underwent twists and turns, such as changes in indications during the development stage) may be one factor in this difference.

Afterword

In this paper, we attempted to evaluate one factor of R&D productivity (the amount of R&D investment assumed to be required to bring a new drug to market) by surveying and analyzing the development period of pharmaceutical products using a database. The main factors that are important in examining R&D productivity are "success probability," "R&D duration," and "R&D cost. In Policy Research Institute News No. 66, we investigated "success probability " ¹⁾. The success probability was calculated in various sizes and showed large differences when compared by modality or disease area, and it was considered important to accurately estimate and grasp the success probability in order to visualize R&D productivity. On the other hand, the results of the analysis of "R&D duration" in this paper showed that, with the exception of a few cases, there were no significant differences by modality or disease area. In other words, it was considered possible to roughly estimate the development period based on past cases.

However, there are some caveats to this conclusion. Limitations of the analysis and future issues are described below. First, although no major differences were observed as far as the median development period was analyzed, large variations were observed when looking at individual developed products, and this is not suitable for analysis from a micro perspective. Second, the sum of the duration of each phase does not necessarily match the development period of each individual product. As shown in Figure 3, there are cases in which the actual total development period is longer than the sum of the periods of each phase, such as when multiple trials are conducted in the same phase for a single development product due to a change in the disease indication. Third, since the period of each phase is defined as "the period from the start date of the phase to the start date of the next phase," if development is terminated in one phase and does not proceed to the next phase, the period of that phase is not included in the total. In other words, the estimation of the development period is not sufficient for cases of development failure. Based on the results of this study, it is difficult to analyze whether there was a difference in the development period between successful and unsuccessful drug discovery cases. Fourth, since this analysis is based on the information available in the database, it does not include the period of basic research and non-clinical studies prior to the start of clinical trials, and thus does not include the development period of the entire drug discovery process.

Although the results of this analysis can provide useful information for understanding the current state of the pharmaceutical industry, as mentioned above, there are various limitations in the data, and it is difficult to say that the results are sufficient. In order to obtain information that cannot be obtained from databases, etc., the National Institute for Policy Studies (NIPR) has conducted a survey of member companies of the Pharmaceutical Manufacturers Association of Japan (PMAJ) in the past to visualize the R&D productivity of the pharmaceutical ^industry17). However, this survey was an analysis covering the period from 2000 to 2008. It can be inferred that the current state of the pharmaceutical industry has changed significantly since the time of the survey, and we would like to consider conducting a new survey study using the same methodology to address the remaining issues in this research study.

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