Vaccine R&D Success Rates and Development Times
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© 1996 Nature Publishing Group http://www.nature.com/naturebiotechnology • FEATURE VACCINE DEVELOPMENT TIMES Vaccine R&D success rates and development times The real time saving in vaccine development is not in the preclinical development itself, but in the accelerated clinical development and reduced regulatory process of dossier preparation and review. Mark-M. Struck Two of the most important factors in compa give life-long protection against disease from database1' . Success rate statistics were derived nies' decisions about whether or not to very few administrations. However, because from a total of 266 projects-not all projects, develop vaccines---the time of development vaccines are given to healthy people, adverse just those for which reports could be traced and the success rate in development-are events associated with vaccinations must be in the literature, from company reports, or relatively poorly characterized. This article lower than for drugs. Although vaccines other sources. In addition, I included 14 vac endeavors to remedy that by providing esti comprise a specialized pharmaceutical mar cine projects (7 launched, 3 discontinued, 4 mates of these factors from data on the ket, they can achieve substantial sales (for ongoing) from our company; these are not progress of vaccine projects between 1983 instance, the hepatitis B vaccine). listed in Pharma Projects but have been pub and 1994. Similar data have also been used to lished elsewhere" ". predict more generally the growth rate for The analysis In this survey, vaccine candidates are con the pharmaceutical and biopharmaceutical I have designated seven stages of develop sidered to have failed if a project has been industries'". Combined with other consider ment through which any vaccine project has terminated or suspended. The rare with ations, such as return on investment, price, to progress to reach the market place: pre drawals of vaccines from the market in the potential market volume, achievable vaccine clinical development; clinical phases I,II, and postmarketing surveillance period have been coverage, and acceptance and distribution', III; preregistration; registration; and launch. excluded from the analysis'•. such data can aid rational decision processes There is a limited preclinical phase in which It is difficult to estimate the extent to in development. The data indicate that to evaluate potential toxicological, pharma which failed projects are underreported in although vaccine development-from pre cokinetic, and pharmacodynamic effects'. publicly available databases'". However, there clinical studies to launch-takes an average Then follow clinical studies in phase I and is some reassurance in the fact that the inclu of two years less than biopharmaceutical phase II', in which investigators look at sion of data on 14 extra vaccine projects development, only half as many preclinical immunogenicity, generate limited safety from our company did not significantly alter vaccine candidates make it through the data, and study adjuvant effects, dosage, and the transition probabilities and development process. The disease prevention-driven vaccination schemes. Subsequent clinical times. approach underlying vaccine development, phase III trials evaluate efficacy in field stud and the nature of the data that its clinical tri ies, household contact studies, or challenge Progression through the pipeline als yield, account for much of the differences study settings10• The next phase is preregis The numbers of projects per development in the development pattern. tration, during which data is evaluated, ana stage (Table 1) decreases along the research Alarming reports of waning immunity in lyzed, and compiled for submission to and development pipeline, as expected. adults', the emergence of new diseases, and regulatory agencies for review"·". Once regu The first interesting aspect of the phase the resurgence of old ones'·' have put vacci latory approval has been granted, batches of transition data (Table 2) is the similarity of nation back in the public spotlight. This has vaccines are released by prompted numerous vaccination initiatives the national control Table 1. Breakdown of vaccine projects per development worldwide, including Article 129 of the authority and market stage. European Community treaty of Maastricht. launch is initiated. Change in stage Successful Suspended Discontinued Vaccination is the most elegant and cost Of course, vaccine Preclinical to phase I 27 3 111 effective way to prevent outbreak of a disease development does not Phase I to phase II 17 3 32 and sequelae resulting from it. The Mercer always follow this scheme Phase II to phase Ill 16 0 15 Report commissioned by the US Department exactly (for reasons dis Phase Ill to preregistration 5 0 10 of Health and Human Services (Washington, cussed previously for Preregistration to 2 0 2 registration DC) found that vaccines offer very high eco biopharmaceuticals1). Registration to launch 22 nomic and health returns on investment'. Multicomponent vac 0 They often contain multiple active ingredi cines, especially, may not ents (in contrast to single active ingredients always fit into this Table 2. Transition probabilities of vaccines compared to used in drugs or biopharmaceuticals) and scheme"·". biopharmaceuticals. The analysis here is Transition Vaccine Biopharmaceutical based on 577 vaccine Preclinical to phase I 0.57 0.57 Mark-M. Struck is head of registration and projects between 1983 Phase I to phase II 0.72 0,88 regulatory affairs at Swiss Serum and Vaccine, and 1994 using source Phase II to phase Ill 0.79 0.86 Phase 111 to registration 0.71 0.93 79, CH-3018 Bern, data from the publicly Inc. , Rehhagstrasse Registration to launch 0.96 1.00 Switzerland. available Pharma Projects NATURE BIOTECHNOLOGY VOLUME 14 MAY 1996 591 © 1996 Nature Publishing Group http://www.nature.com/naturebiotechnology FEATURE VACCINE• DEVELOPMENT TIMES the preclinical to phase I transition probabili development, the product has only been test pharmaceutical groups for the phase III to ties for vaccines and biopharmaceuticals and ed in healthy volunteers up to this point. preregistration and preregistration to regis the fact that the probability in both cases is Although surrogate markers of efficacy such trations phase are statistically significant (by much higher than for "non-bio" pharmaceu as serum titers, animal challenge data, or the Student t-test). ticals. For both vaccines and biopharmaceu neutralizing antibodies for vaccines are mon The overall development (preclinical to ticals, species specificity means that there is itored in early development phases, they may launch) time for vaccines is less-by roughly little animal toxicological data that could be misleading as indicators of the real efficacy two years-than biopharmaceuticals and stop a project from developing past preclini of the vaccine. Pharmaceuticals and biophar "non-bio" drugs; ten years compared with cal studies. Equally, pharmacological investi maceuticals will have been given to affected twelve. Two years less in development means gations with vaccines are rarely performed' patient subsets in phase I or II". Therefore, two years earlier into the market, a signifi so projects are unlikely to fail on that count. the decision to put vaccines into phase III is cant advantage in cost-saving, sales genera The other main difference is that "lead struc based on generally less decisive data. tion, and market positioning. tures" for vaccines and biopharmaceuticals are much easier to identify at the beginning The chances of ultimate success Conclusions of the preclinical phase than are drug leads. So what are the chances that a vaccine at a Vaccine development, like the development We can know at the outset that an attenuated given stage of development will make it to the of other pharmaceuticals, is still a complex organism has a chance of being a vaccine or market? Market entrance probabilities (Table process that takes substantial resources and that a protein will correct a protein-deficien 3) can be calculated by multiplying the vari requires serious and enthusiastic commit cy disease in a way that we cannot know it ous phase transition probabilities. The mar ment over a period of roughly ten years. for small molecule drugs. Thus, proportion ket entrance probabilities for preclinical The contexts for vaccine and biopharma ally fewer "hopeless" vaccine and biophar vaccine candidates is about half that for pre ceutical development are very different. The maceutical candidates will enter the clinical biopharmaceuticals1, largely, of general clinical settings and study endpoints preclinical phase. course, because of the lower phase I to phase for vaccines are clearer from the start and In later phases transitions, there are dif II and phase III to registration transition seem to be better controlled than for bio ferences between vaccines and biopharma probabilities. In other words, preclinical bio pharmaceuticals. Researchers already know ceuticals (see Table 2), differences that are pharmaceuticals are nearly twice as likely to about the disease, the responsible pathogens, statistically significant despite the sparseness succeed than preclinical vaccine candidates. and the immune response elicited in humans of some of the data. Vaccine projects have a The strikingly high success rate for bio during infection. Disease staging is not a 72% chance of progressing from phase I to pharmaceuticals is