Long-term Follow-up Studies: Gene Therapy Products, Protocols and Potential Issues

What is a long-term follow-up study?

A “long-term” study is one that gathers data on research subjects for 5 years or more. Long-term follow‑up observations are extended assessments that continue some of the scheduled observations of a clinical trial past the active follow-up period.¹

There are several arguments for conducting studies to assessing the long-term risk of drugs. The information gained from this research can play an important role in health promotion and disease prevention. Regulatory authorities can use data from long-term drug studies to require changes in labeling or medication guidance, or even withdraw a drug. Physicians and patients can use the data from long-term studies to make decisions related to treatment or prevention. In addition, long-term studies are needed for monitoring effectiveness and long-term safety, particularly for studies in patients who require chronic treatment for their disease.² Information provided by long-term clinical studies complements the results of short-term, randomized, controlled trials, which often form the basis of regulatory approval for a new drug application.³

Long-term follow-up: Gene Therapy

Gene therapy (GT) products are often designed to achieve therapeutic effect through permanent or long-acting changes in the human body.² As a result of long-term exposure to an investigational GT product, study subjects may be at increased risk of undesirable and unpredictable outcomes that may present as delayed adverse event(s). In addition, novel GT products developed as a result of emerging technologies (e.g., transposon-based gene insertion and genome editing) raise concern for delayed AEs due to unique genome modifying activity of such products. To understand and mitigate the risk of a delayed adverse event, subjects in GT trials may be monitored for an extended period, (i.e., LTFU period of a clinical study).

Characteristics unique to human GT products that may be associated with delayed adverse events include:

• The integration activity of the GT product
• Genome editing activity
• Prolonged expression
• Latency
• Establishment of persistent infections

In addition to product-related factors, the long-term risk profile of a GT product should also take into consideration the target cell/tissues/organ, and the patient population (age, immune status, risk of mortality etc.), and the relevant disease characteristic.

To assess the risk of delayed AEs for a GT product, available preclinical and clinical evidence should be used, and current information about the product and similar products based on studies that the sponsor and others have performed should be considered. The assessment of risk should be a continuous process; as more data accumulates, it is recommended that the risk to subjects is reassessed and, if appropriate, the existing LTFU observations study protocol should be revised or an LTFU observations study protocol should be initiated, if previously allowed to proceed without an LTFU observations study protocol.

In general, when the risk of delayed adverse events is low following exposure to a GT product based on the answers to the following questions, a plan for LTFU observations may not be necessary to mitigate risks to subjects.

• Does your GT product utilize genome-editing technology?
• Is your vector used for only ex vivo modification of cells?
• Do preclinical study results show persistence of the GT product?
• Are your vector sequences integrated or is the human genome otherwise genetically altered?
• Does the GT product have the potential for latency and reactivation?

A full risk assessment should be performed by the sponsor based on the factors outlined in the Long‑term Follow-up After Administration of Human Gene Therapy Products Guidance for Industry.²

Long-term follow-up: Goals of the Long-Term Follow-up Observations

Typically, LTFU observations are conducted under a protocol (LTFU protocol) that is separate from the main study protocol or as an extension of the main protocol study and may begin immediately after the first subject completes their last visit in the main study and enrolls in the LTFU study. ²

The objective of LTFU observations in clinical development of a GT product is to identify and mitigate the long-term risks to the patients receiving the GT product. The LTFU protocol for gene therapy trials should be primarily designed to capture delayed adverse events in study subjects as well as to understand the persistence of the GT product. As a sponsor, you may also consider designing the LTFU protocol to assess the long-term clinical efficacy, and durability of your product. The LTFU observations for novel GT products should be designed to consider product-specific characteristics, the basic and translational knowledge generated in the field, and the product specific preclinical data generated to enable investigational new drug application (IND) studies.

The following general elements should be included as part of the LTFU protocol and therefore, summarized in the CSR:

• A detailed record of exposures to mutagenic agents and other medicinal products and corresponding AEs
• Emergence of new clinical conditions, including but not limited to:
  • New malignancies
  • New incidence or exacerbation of pre-existing neurologic disorder
  • New incidence or exacerbation of prior rheumatologic or other autoimmune disorder
  • New incidence of hematologic disorder
  • New incidence of infection (potentially product-related)
• New findings for study subjects including history, physical examination, or laboratory testing as applicable to the study population as well as delayed AEs including unexpected illness and hospitalization by study subjects

This is not an all-inclusive list. For additional information regarding the content of the LTFU protocol, refer to the Guidance for Industry Long term Follow-up After Administration of Human Gene Therapy Products. ²

Potential issues with long-term follow-up studies

Long-term studies of drugs can be difficult to design and implement. For ethical and practical reasons, experimental methods, such as randomized controlled trials, are usually not a legitimate option for long‑term medication studies.¹ Subjects randomly assigned to a particular treatment regimen for 5 or more years or to a control placebo group (if allowed by the medical condition, drug, and study design) may decide to opt out of the study when a better treatment becomes available, or when they want to switch medications for some other reason. Furthermore, with increasing study duration, the use of placebo becomes less ethical, forcing an open label study design where a reference estimate for comparison, a placebo-treated cohort, is no longer available.

In addition, following subjects for a long time can be logistically difficult because the subjects might change phone numbers, addresses, pass away, or simply lose interest in the study. Any of these situations would lead to a high attrition rate, which could compromise the validity of the study. Additionally, experimental studies can be prohibitively expensive, because the sponsor would need to pay for the medication for 5 or more years.

Moreover, as the duration of a study increases and the number of patients continuing in the study declines, missing data becomes more of a problem due to the potential to bias the results. ³ Missing data can bias estimates of treatment effects when a proportion of patients is lost to follow up, which is often the case in long-term clinical studies. Incomplete data can have a considerable effect on study results as the amount, distribution, and reasons for missing data may all introduce bias. Therefore, before completion of a clinical study, consideration must be given to which patients should be included in the final analyses, and how missing data should be handled. The choice of a statistical approach will depend on the therapeutic area, the objective, the endpoint, and the design of each study.

Conclusions

Overall, despite the potential challenges, long‑term clinical studies are essential for monitoring the effectiveness and safety of a drug. Information provided by long-term clinical studies complements the results of short-term, randomized, controlled trials, which often form the basis of regulatory approval for a new drug application. The information gained from long-term drug studies can be useful to regulators, healthcare professionals, and patients. In particular, LTFU observations are an integral portion of the study and are important to monitor long‑term safety of some investigational GT products.

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References:

1. Resnik DB. Beyond post-marketing research and MedWatch: Long-term studies of drug risks. Drug Des Devel Ther. 2007;1:1-5.

2. FDA Guidance for Industry Long Term Follow-Up After Administration of Human Gene Therapy Products (2020).

3. Papp K, Fonjallaz P, Casset-Semanaz F, Krueger JG, Wittkowski KM. Approaches to reporting long-term data. Curr Med Res Opin. 2008;24(7):2001–2008.