Abstract
The United States (U.S.) has ever been, and still is, a world leader in the field of cell and gene therapies. This is mirrored by the US regulatory framework which fosters research on, as well as development, application and marketing of, cell and gene therapy (CGT) products without compromising their safety, efficacy and quality. The applicable framework is product-based, i.e. its rules apply independent of the processes used to manufacture the products. The legal basis for CGT product regulation is the Federal Food, Drug, and Cosmetic Act (FFDCA) which is complemented by a whole series of regulations and guidances issued by the Food and Drug Administration (FDA). In addition, CGT products may be eligible for certain FDA programs the purpose of which is to facilitate the development of, and access to, highly innovative products. In this regard, the program most applicable to CGT products is the ‘Regenerative Medicine Advanced Therapy Designation’ (RMAT) the purpose of which is to expedite review, and accelerate approval, of regenerative medicine products. FDA reviews and controls “Chemistry, Manufacturing, and Controls” (CMC) information submitted by the applicant for purposes of product approval. As regards biological data, de-identified data is not covered by U.S. data protection law. Data which has not been de-identified may be used for secondary research upon patient consent.
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Notes
- 1.
- 2.
National Research Service Award Act of 1974, Section 214, Pub.L 93-340 (July 12, 1974).
- 3.
Section 509 of NIH Budget for 1996, Pub. L. 104-99, Section 128, 110 Stat. 26, 34 (Jan. 26, 1996).
- 4.
Snead (2005).
- 5.
Expanding Approved Stem Cell Lines in Ethically Responsible Ways, Executive Order 13435 (June 20, 2007).
- 6.
Removing Barriers to Responsible Scientific Research Involving Human Stem Cells, Executive Order 13505 (Mar. 9, 2009).
- 7.
National Institutes of Health, Guidelines for Human Stem Cell Research, July 7, 2009, available at https://stemcells.nih.gov/policy/2009-guidelines.htm.
- 8.
Id.
- 9.
MarketWatch (2019).
- 10.
America Recovery and Reinvestment Act, Pub. L 111-5 (Feb. 17, 2009).
- 11.
Albert (2020).
- 12.
Clinicaltrials.gov (as of August 25, 2019). Many of the studies registered in the NIH database on iPSCs are occurring outside the U.S.
- 13.
See U.S. Food & Drug Administration (2020b).
- 14.
Vatsan (2019).
- 15.
See U.S. Food & Drug Administration (2020a).
- 16.
See Silverman (2020).
- 17.
Id. at 5.
- 18.
Id. at 6.
- 19.
42 U.S.C. § 262(i).
- 20.
42 U.S.C. § 262(j).
- 21.
42 U.S.C. § 262(a)(2)(c).
- 22.
21 C.F.R. Part 600, et seq.
- 23.
For a full list of Cellular and Gene Therapy Guidances, see www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances (as of Jan. 2020).
- 24.
21 C.F.R. § 1271(d)(3).
- 25.
21 C.F.R. § 1271.10.
- 26.
See National Institutes of Health (2020).
- 27.
Food and Drug Administration, Guidance for Industry, Guidance for Human Somatic Cell Therapy and Gene Therapy (Mar. 1998), available at https://www.fda.gov/media/72402/download, pp. 7–8. Food and Drug Administration, Guidance for Industry, Regulation of Human Cells, Tissues, and Cellular and Tissue-based Products (HCT/Ps): Small Entity Compliance Guide 4 (Aug. 2007), available at https://www.fda.gov/media/70689/download.
- 28.
21 C.F.R. § 1271.3(f)(1).
- 29.
21 C.F.R. § 1271(c)(3).
- 30.
United States v. Regenerative Sciences, Inc. No. 1:10-CV-1327, at 7 (D.D.C., July 23, 2012) (memorandum opinion) [hereinafter Memorandum Opinion]; see United States v. Regenerative Sciences, LLC, No. 10-1327 (D.D.C., July 23, 2012) (order).
- 31.
See e.g., U.S. Food & Drug Administration (2019).
- 32.
U.S. Food & Drug Administration (2018).
- 33.
U.S. v. U.S. Stem Cell Clinic, LLC, et al., Case No. 0:18-cv-61047-UU (S.D. FL June 19, 2019) (order granting FDA’s motion for summary judgment).
- 34.
Food and Drug Administration, Guidance for Industry, Same Surgical Procedure Exception Under 21 C.F.R. 1271.15(b): Questions and Answers Regarding the scope of the Exception (Nov. 2017), available at https://www.fda.gov/media/89920/download.
- 35.
U.S. v. U.S. Stem Cell Clinic, LLC, et al., Case No. 0:18-cv-61047-UU (S.D. FL June 19, 2019) (order granting FDA’s motion for summary judgment) at 27, 29.
- 36.
Id. at ftn. 12.
- 37.
The Court dismissed the defendant’s practice of medicine argument in a footnote, and therefore did not provide substantial analysis of the potential conflict between the physician’s right to practice medicine which, for example, extends to prescribing FDA-approved drug products for unapproved uses, and FDA’s jurisdiction. Historically, the enforcement mechanism for improper practice of medicine in the U.S. has been through state licensing enforcement actions and malpractice/negligence lawsuits brought by injured patients. Therefore, there will continue to be legal debate about where the line is between practicing medicine and manufacturing therapeutic stem cell drug products.
- 38.
Stromal Vascular Fraction.
- 39.
U.S. v. CA Stem Cell Treatment Center, Inc., No. EDCV 18-1005 JGB (KKx) (C.D. CA. Jan. 27, 2020).
- 40.
Food and Drug Administration website on Cellular and Gene Therapy Guidances, available at https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances.
- 41.
See Food and Drug Administration, Guidance for Industry, Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (Feb. 2019), available at https://www.fda.gov/media/120267/download.
- 42.
Twenty-first Century Cures Act, § 3033, Pub. L. 114-255 (2016).
- 43.
For a summary of these programs, see Food and Drug Administration, Guidance for Industry, Expedited Programs for Serious Conditions—Drugs and Biologics (May 2014), available at https://www.fda.gov/media/86377/download.
- 44.
See U.S. Food & Drug Administration (2020b).
- 45.
21 C.F.R. § 312.23(a)(8).
- 46.
Magnetic Resonance Imaging.
- 47.
Food and Drug Administration, Guidance for Industry, FDA Preclinical Assessment of Investigational Cellular and Gene Therapy Products (Nov. 2013), available at https://www.fda.gov/media/87564/download.
- 48.
Oncolytic vectors are defined by FDA as oncolytic viruses that have been genetically modified to carry an exogenous therapeutic gene. Oncolytic viruses which are not so modified are not gene therapies, and are not covered by this guidance. Id. at 23.
- 49.
Food and Drug Administration, Guidance for Industry, Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products (June 2015), available at https://www.fda.gov/media/106369/download.
- 50.
Food and Drug Administration, Guidance for Industry, Long Term Follow-Up After Administration of Human Gene Therapy Products (Jan. 2020), available at https://www.fda.gov/media/113768/download.
- 51.
Food and Drug Administration, Guidance for Industry, Potency Tests for Cellular and Gene Therapy Products (Jan. 2011), available at https://www.fda.gov/media/79856/download.
- 52.
Food and Drug Administration, Guidance for Industry, Recommendations for Microbial Vectors used for Gene Therapy (Sept. 2016), available at https://www.fda.gov/media/94200/download.
- 53.
Food and Drug Administration, Guidance for Industry, Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up (Jan. 2020), available at https://www.fda.gov/media/113790/download.
- 54.
Food and Drug Administration, Guidance for Industry, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) (Jan. 2020), available at https://www.fda.gov/media/113760/download.
- 55.
Id.
- 56.
Section 506 of the FFDCA, 21 U. S. C. § 356. The definition of serious disease or condition is a disease or condition associated with morbidity that has a substantial impact on day-to-day functioning.
- 57.
21 U.S.C. § 356(g).
- 58.
See Food and Drug Administration, Guidance for Industry, Expedited Program for Regenerative Medicine Therapies for Serious Condition (Feb. 2019) available at https://www.fda.gov/media/120267/download.
- 59.
Id.
- 60.
Id.
- 61.
Id.
- 62.
See Brennan (2019).
- 63.
For a full discussion of the HIPAA rule, see https://www.hhs.gov/hipaa/index.html.
- 64.
HIPAA, § 1171(5), 45 C.F.R. § 160.103.
- 65.
See 45 C.F.R. § 164.502 (d) and § 514 (a) and (b).
- 66.
78 Fed. Reg. 5566, 5659 (Jan. 25, 2013).
- 67.
45 C.F.R. § 160.103.
- 68.
45 C.F.R. § 164.502(e).
- 69.
Human Subjects are protected in the US under both the Common Rule for federally funded research at 45 C.F.R. Part 46, and FDA’s regulations at 21 C.F.R. Part 50, which applies to research conducted to support a regulatory filing such as an NDA or BLA.
- 70.
82 Fed. Reg. 7149 (Jan. 19, 2017).
- 71.
U.S. Department of Health & Human Services (2018).
- 72.
See U.S. Department of Health & Human Services (2011).
- 73.
See 21 C.F.R. § 812.3(p).
- 74.
In Vitro Diagnostics.
- 75.
Prostate Specific Antigen.
- 76.
See United States Senator for California (2019).
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Sanzo, K.M. (2022). Regulation of Genome Editing in Human iPS Cells: United States. In: Dederer, HG., Frenken, G. (eds) Regulation of Genome Editing in Human iPS Cells. Springer, Cham. https://doi.org/10.1007/978-3-030-93023-3_6
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