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

Six-Minute Walk Test (6MWT), 2-Minute Walk Test (2MWT), 12-Minute Walk Test (12MWT), and Timed Walk (T25FW, T10MW)

Six-Minute Walk Test (6MWT) is to measure the distance in a fixed duration (6 minutes). It has been used as a clinical trial endpoint to measure the functional capacity in many therapeutical areas especially in pulmonary diseases (such as COPD, Pulmonary Hypertension) and neurology diseases (such as Duchenne Muscular Dystrophy) and others (such as the treatment of Mucopolysaccharidosis type VII (MPS VII, Sly syndrome)). The distances measured through 6MWT is 'Six-Minute Walk Distance' (6MWD).

Guidelines for Performing Standardized 6MWT

There are several guidelines for performing standardized 6MWT. The guidelines by the  American Thoracic Society is the one we usually follow:

• American Thoracic Society. ATS Statement: Guidelines for the Six-Minute Walk Test. American Journal of Respiratory Care and Critical Medicine 2002;166:111-117
• Holland AE, Spruit MA, et al. Official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014;44:1428-46
• Singh SJ, Puhan MA, Andrianopoulos V, et al. An official systematic review of the ERS/ATS: measurement properties of field walking tests in chronic respiratory disease. Eur Respir J. 2014;44: 1447–78

6MWT is one of the approaches to measure 'exercise capacity' and is considered as a simulated test for measuring the function. FDA has a long-standing position that the clinical trial endpoint needs to measure patients' feel, function, and survival. 6MWT is measuring patients' function.

In FDA's guidance "Chronic Obstructive Pulmonary Disease: Developing Drugs for Treatment", 6MWT along with other exercise capacity measures were described as the following:

"Exercise capacity. Reduced capacity for exercise is a typical consequence of airflow obstruction in COPD patients, particularly because of dynamic hyperinflation occurring during exercise. Assessment of exercise capacity by treadmill or cycle ergometry combined with lung volume assessment potentially can be a tool to assess efficacy of a drug. Alternate assessments of exercise capacity, such as the Six Minute Walk or Shuttle Walk, also can be used. However, all these assessments have limitations. For instance, the Six Minute Walk test reflects not only physiological capacity for exercise, but also psychological motivation. Some of these assessments are not rigorously precise and may prove difficult in standardizing and garnering consistent results over time. These factors may limit the sensitivity of these measures and, therefore, limit their utility as efficacy endpoints, since true, but small, clinical benefits may be obscured by measurement noise."

History of the Six-Minute Walk Test: 

On "ATS Statement: Guidelines for the Six-Minute Walk Test" contained the following descriptions about the history of 6MWT.

Assessment of functional capacity has traditionally been done by merely asking patients the following: “How many flights of stairs can you climb or how many blocks can you walk?” However, patients vary in their recollection and may report overestimations or underestimations of their true functional capacity. Objective measurements are usually better than self-reports. In the early 1960s, Balke developed a simple test to evaluate the functional capacity by measuring the distance walked during a defined period of time. A 12-minute field performance test was then developed to evaluate the level of physical fitness of healthy individuals. The walking test was also adapted to assess disability in patients with chronic bronchitis. In an attempt to accommodate patients with respiratory disease for whom walking 12 minutes was too exhausting, a 6-minute walk was found to perform as well as the 12-minute walk. A recent review of functional walkingtests concluded that “the 6MWT is easy to administer, better tolerated, and more reflective of activities of daily living than the other walk tests”.

History of the Six-Minute Walk Test in Pulmonary Arterial Hypertension:

6MWD has been accepted by the FDA as the primary efficacy endpoint in the drug development in pulmonary arterial hypertension (PAH). According to a presentation by Dr. Barbara LeVarge "Exercise physiology and noninvasive assessment in PAH', the use of 6MWT in PAH started with the clinical development program of Epoprostenol.

6MWT versus Timed Walk
I am curious why 6MWT is a popular measure, but not the timed walk. To assess the functional capacity, we can either fix the time, then measure the distance (such as 6MWT), or fix the distance, then measure the time (such as Timed 25 Foot Walk [T25FW] and Timed 10-Meter Walk [T10MW or 10-MWT]). In sports, for all events in track and field and swimming, we always fix the distance and then measure the time.

In terms of the measurement accuracy, timed walk (such as T25FW and T6MW or 10-MWT) seems to be more accurate than 6MWT. For the timed walk, we need to make sure the recording of the time is accurate because the distance is fixed. For 6MWT, we need to make sure the recordings of both time and distance are accurate - while time is fixed, it usually needs to be measured as well.

The timed walk is actually used in clinical trials in neurology area and is accepted by the FDA as a clinical trial endpoint, for example, the timed walk is used to measure the improvement of walking ability in multiple sclerosis patients

• Fampridine Sustained Release (4- aminopyridine) FDA Medical Review
• AMPYRA® (dalfampridine)  label 
• OnpattroTM (patisiran) for Treatment of adults with hereditary transthyretinmediated amyloidosis (hATTR) FDA NDA review (Timed 10-meter walk test (10-MWT, gait speed was used as secondary efficacy endpoint)

2MWT, 6MWT, and 12MWT 

While 6MWT is the most commonly used, the 12-minute Walk Test (12MWT) was initially used to measure the functional capacity by Balke and 2-Minute Walk Test (2MWT) has also used in some clinical trials.

Leung et al (2006) did a study to validate the 6MWT in severe COPD "Reliability, Validity, and Responsiveness of a 2-Min Walk Test To Assess Exercise Capacity of COPD Patients" and they concluded:

The 2MWT was shown to be a reliable and valid test for the assessment of exercise capacity and responsive following rehabilitation in patients with moderate-to-severe COPD. It is practical, simple, and well-tolerated by patients with severe COPD symptoms.

Grifols is currently conducting a pivotal FORCE study "Study of the Efficacy and Safety of Immune Globulin Intravenous (Human) Flebogamma 5% DIF in Patients with Post-Polio Syndrome" where 2MWD is the primary efficacy endpoint.