The U.S. Food and Drug Administration (FDA) took in the new year to introduce draft guidance on investigational new drug (IND) submissions for individualized antisense oligonucleotide (ASO) products, in an effort to bring clarity to what is an emerging area of individualized drug development. The FDA has developed this guidance document to advise drug developers involved with the development of ASO products on an approach to interacting with, and making regulatory submissions to the agency. In the FDA’s recent press release they share the key points that the guidance addresses, including the following: A) the approach to obtaining feedback from the agency, B) associated expectations and process for making regulatory submissions to the FDA, C) recommendations about the requirement for Institutional Review Board (IRB) review of the protocols within, and D) how to obtain informed consent.
TrialSite provides a brief breakdown of the background context and other information associated with the FDA’s most recent guidance document involving the development of ASO products.
Why are antisense oligonucleotides (ASO) the next frontier treatment of diseases such as neurological disorders?
Short, synthetic, single-stranded oligodeoxynucleotides with the power to alter RNA and reduce, restore or modify protein expression via a number of specific mechanisms, ASOs mediated therapies target a specific source of a pathogenesis hence increasing the chances of success as compared to therapies developed for downstream pathways. By 2017, it was recognized that advances in the knowledge of ASO pharmacology offered drug developers momentum for translating such therapies into the clinic.
What is the Purpose of the Guidance?
The most recent FDA guidance focuses on offering guidance to sponsor-investigators developing “individualized investigational ASO investigational drug products for a severely debilitating or life-threatening genetic disease.
Background—The Drug Development Revolution: Toward Personalization
The FDA has generally been quite active in the last several years approving many more drugs for the treatment of rare diseases thanks to advances in scientific knowledge and drug development technology. In the past eight years alone, the FDA has approved more than twice as many drugs for rare diseases and these are often referred to as “orphan drugs.”
Moreover, recent breakthroughs in testing and molecular diagnosis have enabled researchers in some cases to pinpoint the specific reason for a particular patient’s disease. New precision or personalized therapy involves the development of a drug product purpose-designed to address an individual patient’s specific genetic variant is not possible.
With rare genetic diseases, the result for patients is a life of pain and suffering as the disease rapidly progresses, debilitating the patient in many cases and the possibility of premature death if not somehow treated.
Hence the introduction of “n of 1” therapies, that is products designed for a patient population of one person. The FDA shares the “challenges and considerations” involving this kind of personalized drug development, including 1) the genetic disease advances quickly necessitating expedited treatment; and 2) drug development in these scenarios may be carried out by academic investigators instead of industry and these investigators may not be as familiarized with FDA regulations, policies and practices. Moreover, they are less experienced in working with the agency.
Unprecedented Level of Individual and Family Engagement
Novel or unorthodox various ethical and societal issues arise with “N of 1” precision drug development in the case such as with ASO products. For example, individuals and their families “often function more like drug development collaborators than traditional trial participants.” Hence the importance of the drug developer engaging with the family as to efficacy and how to measure effectiveness. The individual and participating family members must also understand “…parameters for continuing administration of the investigational drug product before emotions influence decisions” while they must understand that such products can actually lead to even worse results, unintended side effects, etc.
Drug Developers and FDA Engagement
The FDA will engage with ASO drug developers in order to bring the investigational products safely to the patients they were developed for—the FDA expresses its intent on actual engagement for instance, on developing a clarification on what additional data and relevant information is necessary in an IND in order for clinical testing to commence. The FDA is presently working on policy to address some aspects of this effort.
FDA Addresses Additional Personalized Gene-based Drug Development for Same Person
The FDA notes that they are “optimistic that development of these individualized drug products may spur gene sequencing that leads to the development of additional drug products for the same disease” often caused by differing mutation(s). The agency acknowledges the need for “collectively” a way to “effectively” develop and bring these novel gene-based drugs to those who need them. In the process, an acceptable balance of “risk to benefit” is sought.
Call to Action: Follow the link for the guidance which focuses on the early development and IND process. It’s the FDA’s first step in engaging with the groups developing such individualized products.