FDA Releases Draft Guidance On Clinical Recommendations For "N of 1" Gene Therapies

By Neil DiSpirito, Esq.; Symin J. Charpentier, Esq., Pharm.D.; Adam M. Schoen, Esq.; and Robert B. Ruh, Esq.; Brown Rudnick

Estimates vary, but as many as 1 in 25 patients may not be treated by their medication because of genetic factors that in some cases render existing therapies useless for that patient or prevent the use of those existing therapies due to adverse events.¹ To eliminate ineffectiveness due to genetic differences, clinical trials of individual patients, described as an “N of 1,” or single-subject trial, can provide crucial insight. The goal of a single subject trial is to determine the best treatment for an individual patient using objective, data-driven criteria.² However, this is a difficult goal to achieve, and the regulatory path for conducting such single subject trials has been difficult to ascertain until the recent release of the FDA’s clinical guidance on the matter.³

The FDA on Dec. 7, 2021, provided a new draft guidance, “IND Submissions for Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases: Clinical Recommendations”⁴ and it will have a broad impact on the gene therapy and clinical trials industry. Although the guidance is specifically for individualized antisense oligonucleotide drugs, the clinical considerations contained therein have much broader potential for non-responsive individual patients and individualized therapies overall. The draft guidance is designed to give a basic framework for clinicians and researchers to conduct N of 1 trials. This draft guidance complements a previous draft guidance from April 2021 containing administrative and procedural recommendations and another draft guidance from December 2021 containing chemistry, manufacturing, and controls recommendations.⁵

Antisense oligonucleotides are therapeutic drug products that are designed to be complementary to a subject’s specific genetic sequence. Binding to the subject’s own genetic material, the antisense oligonucleotide is expected to alter the expression of those genes to achieve the desired therapeutic effect, which can differ based on the disease state being treated, e.g., turning transcription on or off, or forcing the cell to treat other parts of the genetic material in a certain way. While a few antisense therapeutics have been approved for rare but not unique disease states, such as Duchenne’s muscular dystrophy, this draft guidance focuses on antisense therapy designed with one or a few patients in mind.

Prior to this draft guidance, individualized therapies were usually considered a treatment of a single patient and did not fit within the definition of a trial. Moving N of 1 from the legal-regulatory definition of a treatment to the FDA defined definition of a clinical trial will cause challenges, but it is crucial in advancing personalized treatment of patients. The draft guidance contains recommendations that help frame future research and therapy in the area of individualized genetic treatments.

Key Takeaways Of The Draft Guidance

Critical takeaways from the FDA’s draft guidance include provision for trials that include more than one but not more than a few patients.⁶ Despite the nomenclature of single-subject trials, these trials may be conducted on a very small subset of patients with similar but still very rare genetic predispositions or mutations. The sponsor of such a trial is requested to provide evidence of that rarity in its submissions. Of course, the language of the draft guidance questions how “a few” patients is defined, and even the former acting FDA commissioner, Dr. Janet Woodcock, raised the question of how many patients can be treated in a trial designed like those covered by this draft guidance.⁷ Medical ethics and the practicalities of having a vanishingly small patient population may prevent the use of control groups or may result in there being no therapeutic standard against the antisense oligonucleotide therapy can be measured.

The FDA counsels that these trials be conducted using therapeutics that are closely related to existing chemical classes; thus, while the draft guidance is titled and targeted toward antisense oligonucleotide therapeutics, the draft guidance also seems to contemplate its application to other categories of therapeutics that may have applicability on a very small scale to one or only a few patients.⁸ The FDA counsels the use of dosing based on known factors from in vitro studies and comparable therapies. To help practitioners maintain the highest degree of safety possible, the FDA further recommends that these antisense oligonucleotides be administered in an inpatient setting where the patient can be closely monitored.

The FDA’s mission states that it must protect the public health, and aspects of this draft guidance are aligned with that part of its mission. The FDA encourages N of 1 trials be conducted only on patients who have severely debilitating or life-threatening genetic diseases or variants of diseases; this helps to advance the public health because of the time and cost that it takes to invest in these therapeutics, as well as the limited applicability to other patients that even a successful trial can provide.

The FDA’s mission to protect public health is also evident in its recommendations for the applicability of these studies to other patients. Here, the FDA and the research sponsor must tread a very narrow line between assessing and reporting success or failure of the trial and acknowledging that the unique genetic factors that require a patient to be treated with this therapy also prevents wider applicability for other patients. Patient-specific factors need to be considered when assessing whether a therapy has halted or retarded disease progression, as compared to the expected course of that patient’s prognosis. For example, a disease that has relapsing remitting characteristics might be in an extended period of remission, and it is difficult for the clinician to assign the fact of that remission to administration of the therapeutic or to the natural course of the disease. On the other hand, there remains the potential for almost unlimited confounders; if the therapeutic is administered and the patient worsens, the progression of the disease might be inevitable, it may be due to concomitant diseases or drugs, or the therapeutic may in fact have worsened the patient’s disease state. Further consideration must be given to other factors that may include the administration of combinations of medications, which may include traditional small molecule therapeutics, biologics, and the antisense oligonucleotide that is being studied.⁹ There may also be more than one genetic abnormality that lies at the etiology of the patient’s disease state.

With N of 1 studies, there is no opportunity for the traditional gold standard of placebo-controlled randomized trials, conducted on hundreds or thousands of patients, in a well-known three-phase model, that are used to provide evidence-based guidance for the management of the vast majority of patients and disease states. Patient-specific factors may affect the endpoint of these trials. Time of enrollment in a study or administration of a therapeutic compared to the timeline of the progression of the disease state is critical in assessing the external applicability of these trials. The FDA contemplates in the draft guidance some of the non-clinical implications of this type of therapy. The FDA expects that patients and families are going to be collaborators in these very small studies and may in some instances attend meetings between the research sponsor and the FDA.¹⁰ The draft guidance emphasizes the importance of approach and methodology of N of 1 trials and deemphasizes the importance of the mechanism of action of the therapeutic in reporting that study to the public. This contrasts with the clinical utility of larger-scale studies wherein understanding the mechanism of action of the therapeutic is critical to determining whether or not that therapy can be administered to future subjects.

Analysis

Future questions left unanswered by the draft guidance abound. While evidence-based medicine seeks to assign levels of evidence that form the basis for recommendations, especially in clinical guidelines for management of larger-scale disease states, there is as yet not any agreement on the level of evidence that can be assigned to the results of an N of 1 treatment.¹¹ The FDA and thought leaders must thereby provide clinicians, researchers, and patients with more clarity on the ability of a patient suffering from a grave genetic disorder to hope that they might be treated with a therapy like one researched within N of 1 trials.

Beyond the United States, researchers and clinicians in other countries will remain critical to the advancement of therapies in this N of 1 area. Collaboration, comparison, and conversation will be important to identifying potential genetic abnormalities that are suitable for this type of therapy, designing therapeutic agents as well as the dosing regimens for them, and evaluating whether a therapy or therapeutic can be deemed a success. The International Collaborative Network for N-of-1 Trials and Single-Case Designs (ICN) is an organization that was created to help clinicians and researchers in the use of personalized clinical studies and as a way to share information and build collaboration around the globe.¹² While not specifically focused on antisense oligonucleotide therapeutics, this international network provides a framework for sharing the critical data about the patients and therapeutics used in trials conducted pursuant to this draft guidance. Established in 2017, the ICN provides an opportunity for researchers and clinicians to answer some of the questions that cannot be answered solely within the United States, especially because of the rarity of these genetic mutations or abnormalities.

The FDA also has an opportunity to leverage the immense resources of the United States and its healthcare system in order to help the rest of the world stay up to date with N of 1 therapies. Significant access to care issues will restrict patients in the United States and around the world from obtaining these treatments. Clinicians and researchers that conduct antisense oligonucleotide trials are few and far between; they are most likely located at tertiary care and academic research institutions. Even the FDA’s recommendation that these trials be conducted in an inpatient setting has enormous implications for the ability of many patients to access this type of care. With some of the consequences of the global pandemic including bed shortages around the world, the cost of treating one or a few patients both in financial expense as well as time must be considered.

Issuing the draft guidance for individualized antisense oligonucleotide drug products, the FDA begins sailing into new waters. The draft guidance will help clinicians and researchers chart a course when designing critical new therapies for severely ill patients with rare genetic conditions. Nevertheless, more work is needed to ensure that resources are used wisely to benefit these and all patients and that the right lessons are drawn from these initial forays into individualized treatments. Future versions of this draft guidance will hopefully define more clearly how medical and academic communities in the United States around the world can work together and what lessons they can appropriately draw from N of 1 studies.