Historical Control vs. External Control in Clinical Trials

Last week, I had an opportunity to attend the annual ICSA Applied Statistics Symposium in Raleigh, North Carolina. The symposium had a lot of good sessions to discuss contemporary statistical issues. Representing the DIA NEED group, we presented a session about “historical control in clinical trials”.

What is the historical control?

21 CRF Part 314 section 126 (Adequate and well-controlled studies) defined the history control in this way:

(v) Historical Control. The results of treatment with the test drug are compared with experience historically derived from the adequately documented natural history of the disease or condition, or from the results of active treatment, in comparable patients or population. Because historical control populations usually cannot be as well assessed with respect to pertinent variables as can concurrently control populations, historical control designs are usually reserved for special circumstances. Examples include studies of diseases with high and predictable mortality (for example, certain malignancies) and studies in which the effect of the drug is self-evident (general anesthetics, drug metabolism).

ICH E10 (Choices of Control Group and Related Issues In Clinical Trials) defined the historical control in this way :

“The external control can be a group of patients treated at an earlier time (historical control),…”

In a recent FDA guidance (2019) “Rare Diseases: Common Issues in Drug Development”, the historical control and external control was used interchangeably.

1. Historical (external) controlsFor serious rare diseases with unmet medical need, interest is frequently expressed in using an external, historical, control in which all enrolled patients receive the investigational drug, and there is no randomization to a concurrent comparator group (e.g., placebo/standard of care). The inability to eliminate systematic differences between nonconcurrent treatment groups, however, is a major problem with that design. This situation generally restricts use of historical control designs to assessment of serious disease when (1) there is an unmet medical need; (2) there is a well-documented, highly predictable disease course that can be objectively measured and verified, such as high and temporally predictable mortality; and (3) there is an expected drug effect that is large, self-evident, and temporally closely associated with the intervention. However, even diseases with a highly predictable clinical course and an objectively verifiable outcome measure may have important prognostic covariates that are either unknown or unrecorded in the historical data.

What is the difference between historical control and external control?

The historical control was used to be one type of external controls that had a time (early time) component. In more recent guidelines, the historical control and external control are used interchangeably. The concept of historical control has a broader meaning now. In terms of the clinical trial design and statistical analyses, the same issues will apply no matter it is a study using historical control or external control.

Examples of Clinical Trials with Successful use of Historical or External Control

The randomized, controlled trials (RCTs) are still the golden standard, the study with historical control or external control can be used when concurrent controls are impractical or unethical. Many drugs, biological products or medical devices have successfully been approved or cleared by regulatory agencies for marketing authorization using the evidence generated from the clinical trials with historical or external control.

Here are some examples:

Brineura for Battten Disease	Brineura for Batten disease was approved by FDA based on a non-randomized, single-arm study in 22 subjects and a comparison with 42 subjects from a natural history cohort (a historical control group) •       FDA NDA Statistical Review for Brineura •       Shultz 2018 Study of Intraventricular Cerliponase Alfa for CLN2 Disease
Venetoclax for Relapsed/Refractory Chronic Lymphocytic Leukemia	Venetoclas for R/R CLL was approved by FDA based on a single-arm study in 106 subjects with a comparison of the overall response rate to a 40% response rate that was considered as clinically meaningful. •       FDA BLA Medical / Statistical Review •       Stilgenbauer et al 2016 Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study
IGIV as Replacement Therapy for Primary Humoral Immunodeficiency	Multiple IGIV products were approved based on FDA guidance. The guidance suggested to measure the rate of serious bacterial infections during regularly repeated administration of the investigational IGIV product in adult and pediatric subjects for 12 months (to avoid seasonal biases) and compare the observed infection rate to a relevant historical standard - a statistical demonstration of a serious infection rate per person-year less than 1.0. IGIV as Replacement Therapy for Primary Humoral Immunodeficiency Guideline on the clinical investigation of human normal immunoglobulin for intravenous administration (IVIg)
XVIVO XPS EVLP (ex-vivo lung perfusion) Lung Transplantation	FDA recently approved XVIVI XPS EVLP device to help increase access to more lungs for transplant. According to Summary of Safety and Effectiveness, the PMA approval was based on a single-arm study with a matched control to demonstrate the lung transplants with EVLP lungs were not inferior to the matched control group (all other lungs transplanted at that transplant center during the same time period). The one-year survival rate was compared to the matched control group and also the large database from UNOS (United Network for Organ Sharing). This is a good example of a study using ‘external control’.    https://www.accessdata.fda.gov/cdrh_docs/pdf18/P180014b.pdf