FDA rolls out more guidance on 'N of 1' gene therapies

Regulatory NewsRegulatory News | 07 December 2021 |  By 

Developers of individualized investigational antisense oligonucleotide (ASO) therapies for ultra-rare diseases received additional guidance from the US Food and Drug Administration (FDA). In two draft documents, the agency has provided new information for sponsor-investigators and for those overseeing manufacture of these so-called “N of 1” therapies for people with severely debilitating or life-threatening genetic disease.
"Progress in individualized medicines provides hope to patients with severely debilitating or life-threatening genetic diseases,” said acting FDA commissioner Janet Woodcock in a press release accompanying the new draft guidances. “Advances in technology enable targeting a drug to an individual patient's genes. Single-subject clinical trials—also called 'N of 1' trials—focus on evaluating investigational drug products developed for an individual patient.”
Woodcock continued, “This field is rapidly evolving, and antisense oligonucleotide drugs are the most advanced in this space. However, many N of 1 trials are carried out by academic investigators who may not have much experience interacting with the FDA. Earlier this year, the FDA took initial steps to provide draft guidance to investigators carrying out this critical work. Today, we are issuing additional draft guidance in this area. Once finalized, this guidance will detail important clinical and production considerations to support applications for these types of clinical trials and drug development programs.”
The newly released draft guidances complement a January 2021 draft guidance covering administrative and procedural considerations for ASO developers and an April document that focuses on nonclinical testing of the therapies. (RELATED: 'N of 1' therapies addressed in draft FDA guidance, Regulatory Focus 5 January 2021)
Woodcock and Peter Marks, head of FDA’s biologics center, addressed some of the ethical and practical issues that arise in regulating these hyper-specialized therapies in a 2019 New England Journal of Medicine editorial. “On a larger scale, we need to consider how such truncated programs fit into the spectrum of drug development in general: what are the differences between treating one, ten, or thousands of patients?” asked the regulators in the editorial.
Guidance for clinical investigators
The draft guidance for clinical investigators covers a gamut of clinical considerations ranging from ethical and human subject considerations to recommendations for conducting diagnostic and genetic testing and determining dosing. The document also lays out suggested procedures for administration of the drug product and provides guidance on assessing both safety and clinical response to ASO therapy.
In addition to obtaining informed consent for participants, sponsors should conduct genetic testing that ensures that the gene variant or variants intended to be the target of an ASO drug is the cause of the patient’s pathology, and that the variant is unique to that patient.
Dosing considerations should build on experience with related ASO drug products; the starting dose should be expected to have a pharmacologic effect. These dose estimates may have to be calculated based on known interspecies differences; investigators should plan for a dose escalation strategy and monitor patients closely while cautiously increasing the dose. De-escalation in case of toxicity should be planned for.
ASO administration should be conducted in an inpatient setting with special staffing and monitoring precautions taken when doses are administered intrathecally. The guidance specifies what routine safety assessments should be conducted, providing special considerations for ASOs that have phosphorothioate or mixed-phosphorothioate backbones, since these products can cause thrombocytopenia. This portion of the guidance also advises investigators to be on the lookout for such ASO-specific risks as off-target genetic effects, building on experience with other ASO products in the same chemical class and on bioinformatics analyses.
Clinical response can be evaluated through a clearly defined program of clinical assessments that may include performance-based, clinician-reported, and patient- or caregiver-reported assessments. Biomarkers that are “scientifically justified and relevant to the target disease” may also be helpful in assessing response. In weighing whether to continue administering an ASO product, sponsors should weigh toxicity against any observed clinical benefits.
CMC considerations
A second guidance document released on Tuesday lays out general considerations for chemistry, manufacturing and controls (CMC) in ASO drug development. These recommendations “support first-in-human exposure for the individualized ASO drug products covered under this guidance and do not address regulatory considerations for continued, long-term administration of an individualized ASO drug product” or other circumstances that fall outside of the N of 1 investigational sphere, according to the guidance.
Although there are many aspects of the manufacturing process of an investigational ASO drug product that differ from traditional pharmaceutical products, FDA still expects that sponsor will provide enough CMC information in their investigational new drug (IND) application “to ensure the proper identification, quality, purity, and strength of the investigational drug product.” The draft guidance recommends a pre-IND meeting with FDA to talk through CMC plans for the ASO product.
Another key regulatory consideration is that ASO drug products do not ordinarily move from phase 1 to 2 to 3 in their clinical development process. Accordingly, the manufacture of the first batch of an ASO drug product can confirm with the current good manufacturing practices (CGMP) expected at the phase 1 stage, but subsequent batches should comply with CGMP requirements for finished pharmaceuticals as laid out in 21 CFR 211.
Taking these regulatory recommendations into account, the draft guidance on CMC for ASO drug products recommends that, “when possible, the same batch of drug product used for the nonclinical studies be used for initial clinical investigations,” to simplify quality assessments.
It could also be the case that CMC information from other individualized ASO drug products could be incorporated by reference either to another IND or a drug master file, noted FDA in the draft guidance.
As for other drug substances, sponsors of “N of 1” ASO drug products should provide a description of the physical and chemical characteristics of the drug, including such ASO-specific information as the base moieties and backbone of the therapy. The submission should also include information about the general method for preparation, with a flow diagram and “a clear description of process controls that ensure quality of the drug substance.”
In terms of characterization, the sequence determination should be included in the IND or provided as soon as possible in an amendment after providing a justification in the IND. Both ASO-related and nonrelated impurities should also be addressed in the characterization.
The specification section of the IND should include the identity of the ASO drug substance achieved through a combination or two or more methods, such as sequencing and molecular weight determination; a strength assay; quantities of determined and unidentified impurities; microbiological testing; bacterial endotoxins, and other items.
The guidance also reviews how to address other required CMC data for individualized ASO drug products, giving advice about how to assess stability when extended storage conditions might be necessary.
If a sponsor is considering developing a targeted treatment that could treat “more than a few” patients, then the suite of guidances that FDA has issued addressing ASO therapies in “N of 1” trials would not apply. FDA recommends that sponsors of individualized ASO drug product INDs provide a claim for categorical exclusion from environmental analysis requirements.
“The FDA is hopeful these draft guidances, once finalized, will help promising drugs reach patients in a timely manner. We are optimistic that the development of these individualized drug products may continue to change the landscape for treating rare diseases, and the FDA is committed to providing resources and guidance to those advancing these technologies to treat patients in need," said Woodcock.
Clinical guidance for ASO drug products

CMC considerations


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