Review
Clinical Design and Analysis Strategies for the Development of Gene Therapies: Considerations for Quantitative Drug Development in the Age of Genetic Medicine
Avery McIntosh,
Oleksandr Sverdlov,
Li Yu, Petra Kaufmann,
Corresponding Author
Avery McIntosh
Novartis Gene Therapies, Bannockburn, Illinois, USA
Correspondence: Avery McIntosh ([email protected])
Search for more papers by this authorOleksandr Sverdlov
Novartis Pharmaceuticals, Cambridge, Massachusetts, USA
Search for more papers by this authorPetra Kaufmann
Novartis Gene Therapies, Bannockburn, Illinois, USA
Search for more papers by this authorAvery McIntosh,
Oleksandr Sverdlov,
Li Yu, Petra Kaufmann,
Corresponding Author
Avery McIntosh
Novartis Gene Therapies, Bannockburn, Illinois, USA
Correspondence: Avery McIntosh ([email protected])
Search for more papers by this authorOleksandr Sverdlov
Novartis Pharmaceuticals, Cambridge, Massachusetts, USA
Search for more papers by this authorPetra Kaufmann
Novartis Gene Therapies, Bannockburn, Illinois, USA
Search for more papers by this author[Correction added on 10 April 2021, after first online publication: the in-text reference citation numbering has been corrected in this version.]
Abstract
Cell and gene therapies have shown enormous promise across a range of diseases in recent years. Numerous adoptive cell therapy modalities as well as systemic and direct-to-target tissue gene transfer administrations are currently in clinical development. The clinical trial design, development, reporting, and analysis of novel cell and gene therapies can differ significantly from established practices for small molecule drugs and biologics. Here, we discuss important quantitative considerations and key competencies for drug developers in preclinical requirements, trial design, and lifecycle planning for gene therapies. We argue that the unique development path of gene therapies requires practicing quantitative drug developers—statisticians, pharmacometricians, pharmacokineticists, epidemiologists, and medical and translational science leads—to exercise active collaboration and cross-functional learning across development stages.
CONFLICT OF INTEREST
A.M., L.Y., and P.K. are employees of Novartis Gene Therapies. O.S. is an employee of Novartis Pharmaceuticals.
References
- 1Li, C. & Jude Samulski, R. Engineering adeno-associated virus vectors for gene therapy. Nat. Rev. Genet. 24, 255–272 (2020).
- 2Themis, M. et al. Successful expression of β-galactosidase and factor IX transgenes in fetal and neonatal sheep after ultrasound-guided percutaneous adenovirus vector administration into the umbilical vein. Gene Ther. 6, 1239–1248 (1999).
- 3Chen, K.-T., Wei, K.-C. & Liu, H.-L. Theranostic strategy of focused ultrasound induced blood-brain barrier opening for CNS disease treatment. Front. Pharmacol. 10, 86 (2019).
- 4Berns, K.I. The unusual properties of the AAV inverted terminal repeat. Hum. Gene Ther. 31, 518–523 (2020).
- 5Quinn, C. et al. Estimating the clinical pipeline of cell and gene therapies and their potential economic impact on the US healthcare system. Value Health 22, 621–626 (2019).
- 6Cauchon, N.S. et al. Innovation in chemistry, manufacturing, and controls—a regulatory perspective from industry. J. Pharm. Sci. 108, 2207–2237 (2019).
- 7Galli, M.C. & Serabian, M. Regulatory Aspects of Gene Therapy and Cell Therapy Products. A Global Perspective (Springer International, Cham, 2015).
10.1007/978-3-319-18618-4 Google Scholar
- 8Mackenzie, A. & Blandford, L. How health system and payer perception of value may determine the promise of gene therapies. J. Clin. Pathways 3, 35–36 (2017).
- 9Elverum, K. & Whitman, M. Delivering cellular and gene therapies to patients: solutions for realizing the potential of the next generation of medicine. Gene Ther. 27, 537–544 (2020).
- 10Kruger, S.F. et al. Challenges in clinical trial design for T cell-based cancer immunotherapy. Clin. Pharmacol. Ther. 1, 47–49 (2020).
- 11 US Food and Drug Administration. What is gene therapy? <https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy>. Accessed January 5, 2021.
- 12Wilson, R.C. & Gilbert, L.A. The promise and challenge of in vivo delivery for genome therapeutics. ACS Chem. Biol. 13, 376–382 (2018).
- 13Ehrhardt, A., Xu, H. & Kay, M.A. Episomal persistence of recombinant adenoviral vector genomes during the cell cycle in vivo. J. Virol. 77, 7689–7695 (2003).
- 14Kuzmin, D.A. et al. The clinical landscape for AAV gene therapies. Nat. Rev. Drug Discov. 20, 173–174 (2021).
- 15Hudry, E. & Vandenberghe, L.H. Therapeutic AAV gene transfer to the nervous system: a clinical reality. Neuron 101, 839–862 (2019).
- 16Wirth, T., Parker, N. & Ylä-Herttuala, S. History of gene therapy. Gene 525, 162–169 (2013).
- 17 European Medicines Agency. Glybera <https://www.ema.europa.eu/en/medicines/human/EPAR/glybera>. Accessed February 16, 2021.
- 18Maude, S.L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
- 19Mendell, J.R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017).
- 20Foust, K.D. & Kaspar, B.K. Over the barrier and through the blood: To CNS delivery we go. Cell Cycle 8, 4017–4018 (2009).
- 21Sehara, Y. et al. Persistent expression of dopamine-synthesizing enzymes 15 years after gene transfer in a primate model of Parkinson's disease. Hum. Gene Ther. Clin. Devel. 28, 74–79 (2017).
- 22 US Food and Drug Administration. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality <https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease>. Accessed January 5, 2021.
- 23 US Food and Drug Administration. May 24, 2019 Summary Basis for Regulatory Action – ZOLGENSMA <https://www.fda.gov/media/127961/download>. Accessed October 25, 2020.
- 24Finkel, R.S. et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 83, 810–817 (2014).
- 25Maguire, A.M. et al. Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutation–associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology 126, 1273–1285 (2019).
- 26 US Food and Drug Administration. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. 18 December 2017 <https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss>. Accessed January 5, 2021.
- 27Cox, G.F. The art and science of choosing efficacy endpoints for rare disease clinical trials. Am. J. Med. Genet. A 176, 759–772 (2018).
- 28Abrahamyan, L. et al. Alternative designs for clinical trials in rare diseases. Am. J. Med. Genet. Part C Semin. Med. Genet. 172, 313–331 (2016).
- 29 US Department of Health and Human Services. Human gene therapy for rare diseases; guidance for industry. <https://www.fda.gov/media/113807/download> (2020).
- 30 US Food and Drug Administration. Rare diseases: natural history studies for drug development guidance for industry. <https://www.fda.gov/media/122425/download> (2019).
- 31Bryant, L.M. et al. Lessons learned from the clinical development and market authorization of Glybera. Hum. Gene Ther. Clin. Devel. 24, 55–64 (2013).
- 32Kim, J. et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N. Engl. J. Med. 381, 1644–1652 (2019).
- 33Woodcock, J. & Marks, P. Drug regulation in the era of individualized therapies. N. Engl. J. Med. 381, 1678–1680 (2019).
- 34Vassar, M. & Matthew, H. The retrospective chart review: important methodological considerations. J. Educ. Eval. Health Prof. 10, 12 (2013).
- 35Beggs, A.H. et al. A multicenter, retrospective medical record review of X-linked myotubular myopathy: the RECENSUS study. Muscle Nerve 57, 550–560 (2018).
- 36Graham, R.J. et al. Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis. Arch. Dis. Child. 105, 332–338 (2020).
- 37Wald, A. Sequential tests of statistical hypotheses. Ann. Math. Stat. 16, 117–186 (1945).
- 38Lachin, J.M. Applications of the Wei-Lachin multivariate one-sided test for multiple outcomes on possibly different scales. PLoS One 9, e108784 (2014).
- 39Harmatz, P. et al. A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease. Mol. Genet. Metab. 123, 488–494 (2018).
- 40Friede, T. et al. Recent advances in methodology for clinical trials in small populations: the InSPiRe project. Orphanet J. Rare Dis. 13, 186 (2018).
- 41Schuessler-Lenz, M., Enzmann, H. & Vamvakas, S. Regulators' advice can make a difference: European medicines agency approval of zynteglo for beta thalassemia. Clin. Pharmacol. Ther. 107, 492 (2020).
- 42Lin, X., Lee, S., Scott, J. & Lin, M. Graphical analyses in the regulatory evaluation of gene therapy applications. Ther. Innov. Regul. Sci. 55, 346–359 (2021).
- 43Ildstad, S.T. & Evans Jr, C.H. eds. Small Clinical Trials: Issues and Challenges (National Academies Press, Washington, DC, 2001).
- 44Schmidli, H., Häring, D.A., Thomas, M., Cassidy, A., Weber, S. & Bretz, F. Beyond randomized clinical trials: Use of external controls. Clin. Pharmacol. Ther. 107, 806–816 (2020).
- 45 Food and Drug Administration Draft Guidance for Industry: Interacting with the FDA on Complex Innovative Trial Designs for Drugs and Biological Products (Food and Drug Administration, Washington, DC, 2019).
- 46Berry, S. Potential statistical issues between designers and regulators in confirmatory basket, umbrella, and platform trials. Clin. Pharmacol. Ther. 108, 444–446 (2020).
- 47Neuenschwander, B. et al. Robust exchangeability designs for early phase clinical trials with multiple strata. Pharmaceut. Stat. 15, 123–134 (2016).
- 48Chand, D. et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J. Hepatol. 74, 560–566 (2020).
- 49 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials. Proceedings of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Committee for Medicinal Products for Human Use. <https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e9-r1-addendum-estimands-sensitivity-analysis-clinical-trials-guideline-statistical-principles_en.pdf> (2019).
- 50Bernardo, M.E. & Aiuti, A. The role of conditioning in hematopoietic stem-cell gene therapy. Hum. Gene Ther. 27, 741–748 (2016).
- 51Jennison, C. & Turnbull, B.W. Group Sequential Methods with Applications to Clinical Trials (CRC Press, London, 1999).
10.1201/9780367805326 Google Scholar
- 52Hobbs, B.P. et al. Seamless designs: current practice and considerations for early-phase drug development in oncology. J. Natl. Cancer Inst. 111, 118–128 (2019).
- 53Galbraith, S. & Marschner, I.C. Interim analysis of continuous long-term endpoints in clinical trials with longitudinal outcomes. Stat. Med. 22, 1787–1805 (2003).
- 54Hampson, L.V. & Jennison, C. Group sequential tests for delayed responses (with discussion). J. R. Stat. Soc. Series B Stat. Method. 75, 3–54 (2013).
- 55Van Lancker, K., Vandebosch, A. & Vansteelandt, S. Improving interim decisions in randomized trials by exploiting information on short-term endpoints and prognostic baseline covariates. Pharmaceut. Stat. 19, 583–601 (2020).
- 56Woodcock, J. & LaVange, L.M. Master protocols to study multiple therapies, multiple diseases, or both. N. Engl. J. Med. 377, 62–70 (2017).
- 57Brooks, P.J. et al. The platform vector gene therapies project: increasing the efficiency of adeno-associated virus gene therapy clinical trial startup. Hum. Gene Ther. 31, 1034–1042 (2020).
- 58Marks, P. & Witten, C. Toward a new framework for the development of individualized therapies. Gene Ther. https://doi.org/1.1038/s41434-020-043-y. [e-pub ahead of print].
- 59Sverdlov, O. ed. Modern Adaptive Randomized Clinical Trials: Statistical and Practical Aspects. Vol. 81. (CRC Press, Boca Raton, FL, 2015).
10.1201/b18640 Google Scholar
- 60Sverdlov, O. et al. Digital therapeutics: an integral component of digital innovation in drug development. Clin. Pharmacol. Ther. 104, 72–80 (2018).
- 61Mehta, N., Wang, J., Wang, Y., Zhu, H. & Liu, Q. The use of mobile technology in drug development. Clin. Pharmacol. Ther. 108, 706–709 (2020).
- 62Kanzler, C.M. et al. A data-driven framework for selecting and validating digital health metrics: use-case in neurological sensorimotor impairments. NPJ Dig. Med. 3, 1–17 (2020).
- 63Lasiter, L. et al. Use of patient-reported outcomes to understand & measure the patient experience of novel cell and gene therapies. Therapeut. Innov. Regul. Sci. 54, 1566–1575 (2020).
- 64Fajgenbaum, D.C. & June, C.H. Cytokine storm. N. Engl. J. Med. 383, 2255–2273 (2020).
- 65 US Food and Drug Administration. Long term follow-up after administration of human gene therapy products. <https://www.fda.gov/regulatory-information/search-fda-guidance-documents/long-term-follow-after-administration-human-gene-therapy-products> (2020).
- 66Vollmer, S.H. & Howard, G. Statistical power, the Belmont report, and the ethics of clinical trials. Sci. Eng. Ethics 16, 675–691 (2010).
- 67Hacein-Bey-Abina, S. et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Investig. 118, 3132–3142 (2008).
- 68 US Food and Drug Administration. CFR - Code of Federal Regulations Title 21 <https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50&showFR=1&subpartNode=21:1.0.1.1.20.4>. Accessed October 26, 2020.
- 69 US Food and Drug Administration. Considerations for the design of early-phase clinical trials of cellular and gene therapy products. <https://www.fda.gov/media/106369/download> (2015).
- 70Ananthakrishnan, R. et al. Systematic comparison of the statistical operating characteristics of various phase I oncology designs. Contemp. Clin. Trials Commun. 5, 34–48 (2017).
- 71Colella, P., Ronzitti, G. & Mingozzi, F. Emerging issues in AAV-mediated in vivo gene therapy. Mol. Ther. Meth. Clin. Devel. 8, 87–104 (2018).
- 72Colin, L. & Smith, B. Safety in early phase studies. In Statistical Methods in Biomarker and Early Clinical Development. 247–274 (Springer, Cham, 2019).
10.1007/978-3-030-31503-0_12 Google Scholar
- 73Bonate, P.L. The application of extreme value theory to pharmacometrics. J. Pharmacokinet. Pharmacodyn. https://doi.org/10.1007/s10928-020-09721-0. [e-pub ahead of print].
10.1007/s10928?020?09721?0 Google Scholar
- 74Fleming, T.R., Ellenberg, S.S. & DeMets, D.L. Data monitoring committees: current issues. Clin. Trials 15, 321–328 (2018).
- 75Wright, J.F. Manufacturing and characterizing AAV-based vectors for use in clinical studies. Gene Ther. 15, 840–848 (2008).
- 76Persson, T. & Rootzen, H. Simple and highly efficient estimators for a type I censored normal sample. Biometrika 64, 123–128 (1977).
- 77Al-Zaidy, S.A. & Mendell, J.R. From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1. Pediatr. Neurol. 100, 3–11 (2019).
- 78Conlon, T.J. & Mavilio, F. The pharmacology of gene and cell therapy. Molecular Ther. Method. Clin. Devel. 8, 181–182 (2018).
- 79Ylä-Herttuala, S. The pharmacology of gene therapy. Mol. Ther. 25, 1731–1732 (2017).
- 80Obach, M. et al. Regulatory framework of advanced therapies medicinal products in Europe and United States. Front. Pharmacol. 10, 921 (2019).
- 81Havert, M. et al. IPRF reflection paper on biodistribution. Mol. Ther. Method Clin. Devel. 11, 166 (2018).
- 82t'Hart, B.A. et al. Gene therapy in nonhuman primate models of human autoimmune disease. Gene Ther. 10, 890–901 (2003).
- 83Brennan, F.R. et al. Nonclinical safety testing of biopharmaceuticals–addressing current challenges of these novel and emerging therapies. Regul. Toxicol. Pharmacol. 73, 265–275 (2015).
- 84Lima, B.S. & Videira, M.A. Toxicology and biodistribution: the clinical value of animal biodistribution studies. Mol. Ther. Methods Clin. Dev. 8, 183–197 (2018).
- 85Slone, J. & Huang, T. The special considerations of gene therapy for mitochondrial diseases. NPJ Geno. Med. 5, 1–7 (2020).
- 86Cheng, S.H. & Smith, A.E. Gene therapy progress and prospects: gene therapy of lysosomal storage disorders. Gene Ther. 10, 1275–1281 (2003).
- 87Havert, M. et al. Regulation of adenoviral vector-based therapies: an FDA perspective. In Adenoviral Vectors for Gene Therapy. pp. 803–832 (Academic Press, Cambridge, MA, 2016). <https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-and-analysis-shedding-studies-virus-or-bacteria-based-gene-therapy-and-oncolytic-products>
10.1016/B978-0-12-800276-6.00032-2 Google Scholar
- 88 US Food and Drug Administration. Guidance for industry: design and analysis of shedding studies for virus or bacteria-based gene therapy and oncolytic products <https://www.fda.gov/media/89036/download> (2015).
- 89Fedorov, V.V. & Leonov, S.L. Optimal Design for Nonlinear Response Models. (CRC Press, Boca Raton, FL, 2013).
10.1201/b15054 Google Scholar
- 90Atkinson, A., Donev, A. & Tobias, R. Optimum Experimental Designs, With SAS, Vol. 34 (Oxford University Press, Oxford, 2007).
10.1093/oso/9780199296590.001.0001 Google Scholar
- 91Musante, C.J. et al. Quantitative systems pharmacology: a case for disease models. Clin. Pharmacol. Ther. 101, 24–27 (2017).
- 92 US Food and Drug Administration. Impact story: supporting drug development through physiologically based pharmacokinetic modeling. February 22, 2019 <https://www.fda.gov/drugs/regulatory-science-action/impact-story-supporting-drug-development-through-physiologically-based-pharmacokinetic-modeling>. Accessed September 13, 2020
- 93Barrett, J.S. Time to expect more from pharmacometrics. Clin. Pharmacol. Ther. 108, 1129 (2020).
- 94Chowdhury, E.A. et al. Current progress and limitations of AAV mediated delivery of protein therapeutic genes and the importance of developing quantitative pharmacokinetic/pharmacodynamic (PK/PD) models. Adv. Drug Deliv. Rev. 170, 214–237 (2021).
- 95Bornkamp, B. Functional uniform priors for nonlinear modeling. Biometrics 68, 893–901 (2012).
- 96Gibson, E. et al. Key aspects of modern, quantitative drug development. Stat. Biosci. 10, 283–296 (2018).
- 97Grimstein, M. et al. Physiologically based pharmacokinetic modeling in regulatory science: an update from the US Food and Drug Administration’s Office of Clinical Pharmacology. J. Pharm. Sci. 108, 21–25 (2019).
- 98 CBER SBIA Chronicles. FDA modernizes clinical trials with master protocols <https://www.fda.gov/media/125556/download> February 26, 2019. Accessed January 5, 2021.
- 99Lalonde, R.L. et al. Model-based drug development. Clin. Pharmacol. Ther. 82, 21–32 (2007).
