opharmaceutical companies could have dramatically lower predictability regarding return on investment from an approved drug and thus decide to invest less in the advancement of medicines.PhRMA Amicus Brief, at 19-20.Although the question before the Supreme Court at the moment is only whether to take these appeals, the merits issues are deeply entwined with the cert-worthiness of cases. From initial approval decisions, through supplemental changes, to risk mitigation decisions, FDA puts manufacturers through the wringer, resulting in an approval of only an average of 38 new drugs annually. SeeCongressional Budget Office, Research and Development in the Pharmaceutical Industry at 1 (Apr. 2021). Thus, the PhRMA amicus explains that while the Fifth Circuit’s ruling was based on its criticisms of the FDA’s regulatory rigor, the FDA’s procedures are far from cavalier:The new drug approval process starts with laboratory studies to test how a proposed medicine works and assess its safety. See 21 C.F.R. § 312.23(a)(8).If the results are promising, the company submits an investigational New Drug Application to FDA, explaining those results and a clinical trial plan. See 21 U.S.C.§ 355(i)(2); 21 C.F.R. § 312.20(a)–(b).After completing multiple rounds of clinical trials, the company can submit a New Drug Application, often 100,000 pages long. See 21 C.F.R. § 312.21. The New Drug Application must include (among other things) “full reports of investigations which have been made to show whether such drug is safe for use and whether such drug is effective in use.” 21 U.S.C. § 355(b)(1)(A).Then, an FDA review team comprised of multidisciplinary experts diligently evaluates the studies submitted. If the FDA concludes the drug is safe and effective for its proposed use and that “none” of the seven specified “grounds for denying approval” apply, then FDA can approve the drug for use. See 21 U.S.C. § 355(c)(1)(A), (d).Post-approval, the company may submit supplemental applications seeking changes that, among o

rs-To-Come.4Notice of availability, Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products; Draft Guidance for Industry; Availability, 88 Fed. Reg. 45,222 (July 14, 2023).5See generally U.S. Food & Drug Admin., Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products (1996), available athttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstration-comparability-human-biological-products-including-therapeutic-biotechnology-derived.6See Draft CGT Changes Guidance at 2 (referring to management of CGT product manufacturing changes as “more challenging”).7Id.8Id.9See id.10See1996 Comparability Guidance § 2.11See Draft CGT Changes Guidance at 2.12See id. at 6.13See id. at 2, 5-6.14See id. at 3.15Id. at 4.16See id. at 6.17See id.18Id. at 2.19See id. at 8-9.20See id. at 6.21See id.22See id. at 7 (For BLA holders, referencing 21 C.F.R. § 601.12(a)(2) and for IND sponsors, referencing 21 C.F.R. § 312.23(a)(7)(i).).23See id. at 9.24See id. at 7 (referencing 21 C.F.R. § 312.20).25Id.26See id. at 8.27See id. at 10.28See id. at 11 (“Please note that relying solely on established release tests and in-process controls is generally insufficient to assess the impact of manufacturing changes.”).29See id. This seems particularly advisable if the method has limitations, and aligns with FDA’s advice elsewhere in the guidance regarding the use of “several analytical methods” to assess potency if the routine assay is imprecise or otherwise lacking in ability to measure all aspects of a product’s MOA that could be affected by the change. See id. at 14-15.30See id. at 10-12.31See id. at 12.32See id. at 12-13.33See id. at 17.34See id. at 13-14.35See id. at 14.36See id. at 14-15.37See id. at 15-16.38See id. at 16.39See id. at 10.40See id. at 16.41See id. at 16-17.42See id. at 17.43See id. at 18-19.v44See id. at 20-21.45See id. at 2 (“We note that while improvement of product quality is always desirable and enc

investigational drug is shown to be an agonist at 5-HT2B receptors, a thorough microscopic evaluation to assess the potential heart valve thickening in both rodent and nonrodent repeat-dose toxicity studies should be conducted.This assessment would include sectioning of all heart valves.What is not clear, and may need to be raised in comments, is whether this assessment is necessary where there is already extensive human exposure.FDA also raises the issue of long-term exposure to 5-HT2B agonists in its clinical pharmacology section. FDA notes that this exposure may induce cardiac valve stiffening, so FDA recommends that sponsors exclude subjects with preexisting valvulopathy or pulmonary hypertension from multiple-dose studies until the risk can be better characterized.In the clinical section, FDA recommends collecting baseline and follow-up echocardiograms to assess valve structure and function and pulmonary artery pressures.Regarding the length of nonclinical studies, FDA notes that 21 CFR 312.23(a)(8) specifies that “[t]he kind, duration, and scope of animal and other tests required [to conduct the proposed clinical investigation] varies with the duration and nature of the proposed clinical investigations”.Therefore, FDA recommends that “[n]onclinical studies to support chronic or chronic-intermittent dosing should be provided if the treatment effect is not durable and repeat dosing is expected.”Clinical PharmacologyFDA highlights several areas where sponsors may need to study the clinical pharmacology of their investigational psychedelic drug.For example, FDA recommends evaluating the effect of a high-fat meal on the pharmacokinetics of oral psychedelic drugs “early in development”.Results of this testing may require changing clinical study design.There are a number of drug-drug and drug-disease interactions that FDA flags in the guidance.These include:cytochrome P450 enzyme- and transporter-mediated drug interactions that may affect the metabolism of LSD or other psychedelics,gas

ience, study sponsors often designate a central IRB to streamline IRB review and prevent consistent outcomes and delays that can occur when several IRBs review the same study. Some institutions, however, may prefer to have their own IRB review a study even when the sponsor is using a central IRB because they believe another IRB does not have sufficient local context for the institution, and may not meet the same standards as the institution’s IRB, or is not subject to adequate institutional oversight. Some institutions’ IRBs also currently perform functions of an institutional human research protection program that are not required to be performed by an IRB.In a departure from what the revised Common Rule requires, the FDA is not proposing that a specific party involved in the research select the IRB when a single IRB process is used, but for practical reasons, this will usually be the study sponsor. The sponsor is already required to identify the reviewing IRB in the IND application (21 C.F.R. § 312.23(a)(6)(iii)(b)) or an IDE application (21 C.F.R. § 812.20(b)(6)) submitted to FDA.Reliance AgreementsThe FDA proposes requiring documentation of an institution’s reliance on an external IRB that would describe the responsibilities each entity will undertake to ensure compliance with FDA regulations. Examples of documentation that would meet this requirement include a written agreement between the institution and the IRB, an institution-wide policy directive providing the allocation of responsibilities between the institution and an external IRB, or a research protocol section that provides that allocation. IRB authorization or reliance agreements are not new; even before they were required by the revised Common Rule, the Office for Human Research Protections (OHRP) expected them to be in place for research subject to an OHRP-approved Federalwide Assurance (FWA) and had developed a basic template for institutions to use as a resource.Many research institutions and some commercial IRBs have signed a M

Further, Vanda alleges that FDA’s regulations do not specify that chronic toxicity studies must be conducted in non-rodent species; that such studies must be conducted in particular non-rodent species; or, that such studies must have a specified duration. Instead, Vanda argues, FDA’s regulations call for appropriate toxicity studies based on the drug and clinical development program at hand under 21 C.F.R. § 312.23(a)(8)(ii) (stating that “[d]epending on the nature of the drug and the phase of the investigation, the description [of toxicological effects of the drug in humans and animals] is to include the results of acute, subacute, and chronic toxicity tests . . . .”). But the only alternative to the 9-month dog studies that FDA offered would still eventually require Vanda to conduct the 9-month study and would therefore require the sacrifice of even more dogs.The Complaint touches on a lot of criticisms commonly lobbed at the agency – blind enforcement of certain requirements, regulating by guidance document, outdated policies.

Certain preclinical testing, as well as the manufacture and testing of drug product must be completed prior to filing an investigational new drug application (IND) to initiate human testing of a drug. See 21 C.F.R. § 312.23(a)(7). Initial U.S. clinical trials, on the other hand, can only occur after an IND is opened and in effect.

FDA’s reasoning is that an IND is authorized under section 505(i) of the FDC Act and defined by regulation as “an investigational new drug application.” 21 C.F.R. § 312.23(a) (emphasis added). With regard to new protocol submissions to existing INDs, the guidance indicates that such a submission is “the investigational stage analog to an efficacy supplement to an NDA or BLA.”