key: cord-0716037-20s03dtq
authors: Beall, Reed F; Kesselheim, Aaron S; Hollis, Aidan
title: Pre-market development times for innovative vaccines – to what extent are the COVID-19 vaccines outliers?
date: 2021-04-29
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab389
sha: b5f3c4b2fbbdce25867265b89def0ec6c6008c74
doc_id: 716037
cord_uid: 20s03dtq

One reason expressed in surveys of people reporting COVID-19 vaccine hesitancy is how rapidly these vaccines have reached the market. To estimate the length of time the COVID-19 vaccine spent in research and development as compared to other novel vaccines, we apply previously-established methods for estimating medical product development times, using the earliest associated patent filings cited by the manufacturer as the marker of when commercial development activity began. Applying these methods to a cohort of recently approved innovative vaccines and comparing them to the development time of the first-approved COVID-19 vaccine (BioNTech/Pfizer), we found patent filings for the technology in this COVID-19 vaccine occurred 10.0 years prior to regulatory authorization. Furthermore, the development timelines for innovative vaccines have been shortening since the 1980s and the COVID-19 vaccine comfortably fits within this pattern. Vaccine development timelines have now even drawn to parity with many of the most commonly-used drugs.

M a n u s c r i p t A c c e p t e d M a n u s c r i p t 3 A frequently-mentioned reason for hesitancy surrounding the vaccines for COVID-19 is the perceived speed in which they were developed and approved for use. 1 In certain respects, the recent rapid development of COVID-19 vaccines has indeed been an unprecedented marvel in drug research and development. After the disease began receiving global press in January 2020, the genome of the virus was sequenced within the same month. 2 By April, more clinical trials related to COVID-19 had been launched than for other similar public health emergencies combined, 3 including vaccine trials that would lead to regulatory authorizations starting seven months later. 4 Past studies of drug development timelines have often used the date development activity began on the end product as the starting point, rather than the time from the discovery of the disease. [5] [6] [7] One marker of the beginning of this development activity that has been used in the literature is the earliest associated patent filing cited by the manufacturer. Patents protecting pharmaceuticals may pertain to the therapeutic substance itself; the formulation (e.g., oral, injectable); the use in treatment for a specific medical condition; and a method of manufacturing. It is not uncommon for novel biotechnologies to find their ultimate therapeutic purposes at later stages in the development process prior to initiating clinical testing in humans. As such, a drug's earliest patents may not always include a reference to the specific treatment indication eventually listed on the label, either because its therapeutic utility was unknown at the time or it originally While other studies have examined time segments within the clinical testing and regulatory review timelines for cohorts of vaccines as compared to COVID-19 vaccines, 8 we sought to evaluate the time from original patent filing related to a vaccine to marketing authorization. To determine the extent to which this COVID-19 vaccine is an outlier in terms of this measurement of development speed, we calculate key pre-market vaccine development timelines for a cohort of innovative vaccines in wide use, and compared those development timelines to that of the COVID-19 vaccine BNT162b2 (generic name: tozinameran; manufacturer: BioNTech-Pfizer).

We focused on a cohort of innovative vaccines flagged as novel and clinically important in Health Canada's "Register of Innovative Drugs," 9 a list that also includes vaccines and that has been maintained since 2006. Drugs and vaccines are included in the Register if the product contains a new active ingredient never before approved by Health Canada. We separated out vaccines as any products using the WHO's ATC codes for vaccines (i.e., "J07…"). 10 This designation of "innovative" is important because non-innovative products can represent an improvement upon a previouslyapproved product containing the same or a similar active ingredient. Development timelines for new versions of existing products may appear deceptively long (even though they are known to require less development time) when measuring from the earliest patent filing on the original product. For this reason, while some previously-approved vaccine products that have been reformulated such that may qualify as a "innovative" according to Health Canada's definition, we have nevertheless used the originally approved version, rather than retaining both versions in our cohort. For example, we included Gardasil and Prevnar but not Gardasil 9 and Prevnar 13. We otherwise included in our cohort only products actively marketed in the US and Canada to derive a sample of widely-used products by manufacturers that have brought those vaccines to market in multiple countries with strong drug regulation infrastructures. Unfortunate delays in the development and pre-market A c c e p t e d M a n u s c r i p t 5 clinical testing of some vaccines for use in lower income settings have been documented, such as was observed in 2017 with an Ebola vaccine, 11 and may therefore produce more heterogenous results with respect to speed-to-market.

To gather US regulatory approval dates as well as application submission dates, we consulted the FDA's database of approved vaccines 12 and the Database of Licensed Biological Products (Purple Book). 13 To derive the earliest patent filing date internationally for our cohort innovative vaccines, we used the Espacenet database maintained by the European Patent Office to locate the earliest priority filing dates globally for the American and Canadian patents associated with the products in our cohort. 14 This method for deriving the earliest patent filing date has been used in other published studies. 5 7 As of March 25 2021, regulatory bodies in the US and Canada had not yet published patent information on the Pfizer-BioNTech COVID-19 vaccine; however, the inventors have disclosed in the scientific literature that they hold relevant patents, and other published reports identify these patent holdings. 15 16 We calculated the development time for each vaccine by subtracting its regulatory approval date by the earliest priority patent filing date internationally for the product in question. We report descriptive statistics, including the median and interquartile ranges as well as a time series analysis of development speeds based on the year of first patent filing.

We performed three additional analyses for sensitivity testing. First, we recalculated development time estimates based on the Health Canada authorization date to account for the possibility that development times may differ between countries and regulatory bodies. Second, we reran our calculations with the manufacturer's submission date of the application to the FDA, rather than the regulatory authorization date itself, to isolate the development time without the additional time required for regulatory review. Third, to assess whether the development speed for tozinameran is different from other COVID-19 vaccines, we repeated our process for calculating the Table 1) .

The earliest patent reported to be associated with the technology used to develop tozinameran had a filing date of 3 December 2010, 10.0 years prior to gaining FDA authorization.

Using the same methods to calculate development times for other COVID-19 vaccines, we found similar results as compared to tozinameran. The full development time for the NIH-Moderna vaccine was 10.7 years 17 and the AstraZeneca/Oxford University vaccine was 9.8 years, using the date of emergency use authorization in Canada. 18 The full cohort of seven vaccines reflect decreasing vaccine development times, ranging from 18.5 years for Prevnar (first patent filings in 1981), to 12.6 years for Shingrix, and finally to tozinameran (Figure 1) .

When all development times were based on Health Canada (rather than FDA) authorization, the number of years was similar or slightly slower-a median of 15 Our results are consistent with remarks by US NIAID director Anthony Fauci, who estimated the development timelines for mRNA vaccines, based upon his own personal experience and knowledge of these products, to be about 10 years. He added that the basic science undergirding vaccine platform technologies pioneered by Barney Graham and other dates back a decade or more, were well-established prior to the publication of COVID-19's genetic sequencing, and were securely positioned to be effectively leveraged to address This speed is also on par with other innovative vaccines as well as novel drugs. In a previous study, 5 A limitation of our study is that while the inclusion criteria for our cohort of vaccines was highly selective and resulted in a sample of products relevant to the study at hand, it also resulted in a small sample specific to the needs of North American populations. Future study may expand the sample size to include more vaccines used in a wider variety of global settings to determine the extent to which the patterns observed by this investigation can be observed elsewhere. Secondly, our study does not capture the firsthand reports by tozinameran's inventors, who describe their design ideas coming into full formation within a single day. 20 21 The importance of moments of scientific inspiration such as these cannot be understated and must be fully recognized. That said, the impressive patent record of these inventors (Ugur Sahin's name is on 140 patents and Özlem Türeci is on 40 as of March 2021) reflects an accumulation of innovation and capacity over time, which reached maturation at a key moment when these scientists were positioned to mobilize the technology they had been developing for many years to fight the novel coronavirus pandemic.

When considering speed-to-market of new medical products, it is important to consider the fuller picture of when the key underlying technologies were originally developed for clinical use, rather than only considering the time between a disease's discovery and treatment's authorization to treat it. From this view, the COVID-19 vaccines' timelines are reasonably in line with previous experience of vaccine development and actually still required more time to develop than some of the most commonly used types of drugs today, including small-molecule drugs and non-vaccinebased biologics. This message may be reassuring for vaccine-hesitant populations who worry that the basic science undergirding the COVID-19 vaccines had been rushed.

A c c e p t e d M a n u s c r i p t 9

RB, ASK and AH wrote the manuscript; RB, ASK, and AH designed the research; RB and AH performed the research; RB, ASK, and AH analyzed the data. All authors read and approved the final manuscript.

Patient involvement: No patient involvement was relevant for this study.

Study data analyzed in this manuscript is publicly available. 

The authors declare that they have no conflicts of interest.

A c c e p t e d M a n u s c r i p t

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Global clinical trial mobilization for COVID-19: higher, faster, stronger

Study to Describe the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals

Pre-market development times for biologic versus smallmolecule drugs

Development Time and Patent Extension for Prescription Drugs in Canada: A Cohort Study

Major Events in the Life Course of New Drugs

Speed, Evidence, and Safety Characteristics of Vaccine Approvals by the US Food and Drug Administration

Register of Innovative Drugs

WHO Collaborating Centre for Drug Statistics Methology. J07 VACCINES 2021

Is Canada patent deal obstructing Ebola vaccine development?

United States Food and Drug Administration. Vaccines Licensed for Use in the United States

Purple Book Database of Licensed Biological Products

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BioNTech and Pfizer's BNT162 Vaccine Patent Landscape: Public Citizen

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Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single

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The co-founder of BioNTech designed the coronavirus vaccine it made with Pfizer in just a few hours over a single day: Business Insider

The Vaccine Revolution: Time Magazine

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Trumenba To prevent invasive disease caused by Neisseria meningitidis serogroup B

A c c e p t e d M a n u s c r i p t 13 A c c e p t e d M a n u s c r i p t 15 A c c e p t e d M a n u s c r i p t 16 Figure 1