FDA Issues More Guidance on Gene and Cell Therapy Products

February 03, 2021

January was a busy month for the US Food and Drug Administration’s precision medicine efforts, as the agency produced guidance on ASO drugs for patients with debilitating or life-threatening genetic disorders and guidance on manufacturing considerations for certain cellular and gene therapy products during the COVID-19 pandemic.

The agency first issued a draft guidance to facilitate the development of individualized antisense oligonucleotide (ASO) drugs for patients with severely debilitating or life-threatening genetic disorders (ASO Guidance). The Food and Drug Administration (FDA) also issued a guidance, with immediate effect, on manufacturing considerations for licensed and investigational cellular and gene therapy products during the COVID-19 public health emergency (Manufacturing Guidance). Sponsors investigating or marketing these products should pay special attention to the discussion in these documents, as FDA outlines its approach to COVID-19 and development considerations with respect to these personalized therapies.

Manufacturing Guidance

The Manufacturing Guidance supplements FDA’s June 2020 guidance on Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing. However, because cell and gene therapy (CGT) manufacturers may face special challenges, FDA recommends that CGT manufacturers perform risk assessments to identify, evaluate, and mitigate factors that may allow for the transmission of SARS-CoV-2 through CGT products. Any plans should take into account FDA’s view that allogeneic products may be associated with a higher risk of infection compared to autologous products.

FDA specifically recommends the following:

  • Donor Screening: For autologous products, FDA recommends routine screening. For both autologous and allogeneic products, FDA also recommends that manufacturers consider donor COVID-19 risk factors dating back 28 days from the date of collection. At this time, FDA does not recommend using laboratory tests to screen asymptomatic donors. However, if a manufacturer is considering donor testing, molecular or antigen tests that have been approved, cleared, or authorized by FDA should be used. FDA also does not recommend screening for or deferring donors who have received a nonreplicated, inactivated, or RNA-based COVID-19 vaccination.
  • Source Material Assessment: Manufacturers should consider the known viral characteristics, as well as the ability of SARS-CoV-2 to infect and replicate in source cells and tissues. Manufacturers should also consider whether the virus could infect and propagate in source materials during the manufacturing process, as well as the risk of infection of specific donor systems (e.g., respiratory vs. central nervous systems).
  • Manufacturing: FDA recommends that manufacturers consider a product’s starting materials, manufacturing processes used to control viral spread, and manufacturing contamination risk because SARS-CoV-2 has been shown to be capable of infecting and replicating in cells commonly used for vector production. Moreover, as always, manufacturers must ensure that employees practice good sanitation and health habits.
  • Material Testing: FDA does not have specific recommendations for material testing, but it states that manufacturers may include testing as a mitigation strategy based on their assessment of the potential risk.

As always, any adopted risk assessment and mitigation strategies must be documented and approved by the manufacturer’s quality unit, should include scientific justification and literature references, and should be submitted to FDA.

ASO Guidance

Turning away from the current COVID-19 crisis, FDA indicated that it is also looking ahead to the continued advancement of personalized therapies, issuing the ASO Guidance to assist sponsor investigators in the development of individualized ASO products for severely debilitating or life-threatening genetic diseases that are tailored to a patient’s specific genetic variant. As noted by FDA, the ASO Guidance is targeted to academic investigators, who may be less familiar with FDA’s requirements and less experienced in interacting with FDA.

While the specific impetus for this guidance is unclear, assumedly FDA is receiving more inquiries regarding individualized ASO drugs from investigators, patients, or those acting on their behalf. Regardless of the reason, healthcare institutions where ASO products are used should familiarize themselves with FDA’s requirements and processes to ensure that any use of an investigational ASO product accords with FDA’s regulations. It will also be important that manufacturers supporting the use of ASO products or that later intend to work with ASO product investigators ensure that programs comply with FDA’s regulations via contractual agreements and, as appropriate, due diligence.

For these programs, FDA recommends the following:

  • Early FDA Interactions: Because patients will generally require prompt medical intervention, FDA recommends that sponsors request a pre-investigational new drug application (pre-IND) meeting as soon as a patient and at least one potential ASO drug with “convincing proof-of-concept data” are identified. FDA also recommends establishing a communication strategy with the agency so that FDA staff can respond to questions and requests promptly and comprehensively.
  • Confidentiality: If a trial participant, family member, or other advocate attends a meeting between FDA and the sponsor, the sponsor should be sure to first establish a confidentiality agreement with such third parties. In the absence of such an agreement, FDA will consider any information discussed to be disclosed publicly, permitting the agency to release the information under the Freedom of Information Act (FOIA). The sponsor should also provide FDA a certification regarding the existence of the confidentiality agreement. The sponsor should further set up a secure email with FDA to permit email communications.
  • Submissions: Prior to beginning patient treatment, the sponsor will need to submit a research IND to FDA. The IND content will be determined during the pre-IND meeting, as some content and formatting requirements may not be relevant to ASO applications.
  • Ethics: Importantly, because of the nontraditional nature of ASO drug development, “complex ethical issues may arise.” Accordingly, FDA recommends consulting with a medical ethicist when developing ASO study protocols. In addition, as with all clinical studies, an Institutional Review Board (IRB) must review the study protocol and the sponsor must obtain patient informed consent. The informed consent form (ICF) should be clear that the ASO drug is experimental and, if applicable, will be used for the first time in humans; that the benefits and risks are uncertain; and that the patient may incur additional costs from the administration of the ASO drug. ICFs should further include relevant nonclinical study information that may inform participant safety.

The ASO Guidance is likely a first step in the development of individualized therapies. As stated by FDA, the agency is “optimistic that development of [ASO] individualized drug products may spur gene sequencing that leads to the development of additional individualized drug products.” Accordingly, through the ASO Guidance, FDA aims to determine the most effective and efficient way to bring personalized drugs to patients, while ensuring the right risk-benefit balance.


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