Natural History Study Best Practices for Engaging Regulatory Authorities

When seeking guidance from the FDA, EMA, or other regulatory agencies regarding the inclusion of a Natural History study in your clinical development program, it is crucial to initiate early and frequent discussions with the regulatory authority to establish a mutually agreed-upon plan for conducting the study.

While the use of each study can vary depending on the indication and therapeutic area, Veristat regulatory experts have shared best practices for effectively engaging with agencies about Natural History studies:

1. Start Early

Natural History studies are generally expected to start early within the development program. While this creates a challenge in ensuring that the sampled population aligns with the interventional study, it is considered a best practice. Having upfront discussions and milestone meetings with regulatory authorities is key to determining an acceptable approach.

2. Pre-specify Parameters

Sponsors should clearly outline the data points to be collected, including the planned endpoints and how these are captured, as well as the timing of assessments – all of which must be presented and documented in a form that is acceptable to regulatory reviewers.

In addition to the pre-specification of data to be collected, the temporal classification of data collection should be specified as retrospective (i.e., collection of past assessments), prospective (i.e., collection of current or future assessments), or a combination of the two classifications. There are advantages to both retrospective and prospective data collection. The critical component for the most appropriate implementation within a natural history study is to establish how to best measure well-defined, easily identifiable endpoints that can be used to assess change over a reasonable time period of study.

3. Use as External Control: Endpoint Selection

Data from a natural history study may be most directly used as an external control for an interventional study if:

1. The disease is predictable.

2. The outcome is well-defined and easily identifiable.

3. The outcome occurs within a short period of time after diagnosis

In this paradigm, the impact of treatment can be easily measured and the opportunity for bias can be controlled if there are no alternative treatments available. The use of such a natural history study as an external control should be pre-specified and discussed with regulatory agencies early in the clinical development planning.

Particularly for rare diseases, meeting the identifiability criteria can be difficult and may not be met. This requires a creative approach to the proper use of natural history data as an external control and within the overall clinical development program. The identification of and planning for endpoint selection should be discussed with regulatory authorities to ensure agreement with the planned approach.

4. Use as External Control: Reducing Bias

When considering natural history data as an external control to an interventional trial, measures should be taken to control sources of bias, and discussion of the potential sources of bias should be had with regulatory authorities. Some sources of bias and methods for bias control include:

• Selection Bias: Ensuring similarity between the natural history sampling population and the intervention sampling population to reduce differences in the underlying population between studies.
  
  
• Unmeasured Confounding: Collecting possible confounding variables or effect modifiers that may affect disease progression – such measures should be captured in as similar a manner as possible among both the natural history and intervention sample.
  
  
• Time Bias: Reducing time lags between natural history and intervention study sampling by enrolling a prospective cohort within the natural history study.
  
  
• Plan for Operational Biases, including (but not limited to): Missing data, reporting opportunity bias (prospective samples may have more opportunity to report change in disease than retrospective samples), etc.

Implementing methods to reduce bias safeguards the reliability and validity of the study outcomes, ensuring that the natural history study findings can be accurately compared to the interventional treatment, reflect the characteristics and progression of the disease, and are appropriate and valuable for your development program.

The identification and planned bias mitigation strategies should be presented to regulatory authorities to address any outstanding sources of bias.

Additional Considerations to Keep in Mind

It should also be noted that in general, both the FDA and EMA prefer randomized controlled trials and, while exceptions do occur, there is not a clear precedence for when and why external controls may be acceptable.

Sponsors should be prepared that some regulatory reviewers may be uncomfortable accepting Natural History studies or may lack experience in the area. Therefore, there is learning that would be required on both sides of the discussion. While direct feedback may not always be provided, a sponsor will have the best opportunity for alignment with the regulatory authority if they have proposed to the regulatory agency a clear plan for the Natural History study and its eventual use within the clinical development program.

Since rare and ultra-rare diseases demand more complex clinical program planning and involve a complicated regulatory approval process, developing a strong relationship with the governing Health Authority early on is essential to moving your program forward. Veristat Regulatory experts ensure that your clinical trial or program design supports your regulatory strategy in this specialized area.

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