Inter-center 6MWT performance variation and data variability were observed in children with PAH in the real-world clinical setting at pediatric PAH programs. Our findings suggests that procedural variations seem to associate with 6MWD data variability.

The ATS has documented several sources of 6MWD variability in adults (7, 8). These sources of 6MWD variability have also been seen in studies of children with and without disease (12). When performing and interpreting the 6MWT in healthy children/adolescents, it has been documented that age, sex, height, and weight influence the measurement (20, 21). A literature review of the reference values and equations for the 6MWT in healthy children/adolescents has shown to range substantially from studies in different countries (22). Therefore, sources of variability caused by the test procedure itself should be controlled as much as possible.

As with any procedure that requires effort in children, the 6MWT has its limitations. Lack of motivation has been considered a factor that affects performance more in children than in adults. This has led some to modify the ATS guidelines, such as implementing a method to give “a task” to help the children focus and to serve as an intrinsic motivational factor (23). Others have given participants small objects to drop at the end of each minute as a marker of distance walked in that minute (24). Some have used a “safety chaser” (an assistant who walks behind the participant during the test, provides extra encouragement, and assists in the case of a fall) (12, 16, 25). Still others have given small monetary incentives (16, 26).

Lack of understanding has also been considered a factor that affects performance, which has led some to develop an orientation video to assist children in their understanding of the nature and expectations of the test (27, 28). Review of the literature for the 6MWT in children has shown that some clinical trials go so far as to not allow any encouragement (21, 29).

The significant effect of observed differential encouragement on distance achieved during a 6MWT in adults with chronic cardiopulmonary disorders was originally reported by Guyatt et al. in 1984 (10). This helped lead to the recommendation of its standardization by the ATS. Encouragement of the patient during the test is recommended if it is given in standard phrases in an even tone, as noted in Table II (7).

Table II Phrases of Encouragement (7)6

Data from our study suggests that parental/caregiver involvement may have contributed to 6MWT data variation in children with PAH across medical centers in different geographic areas. It should be noted that we did not analyze intra-subject and intra-center data variations. Our findings also suggest that the location of the 6MWT track may play a role in 6MWD data variation; thus, an indoor, quiet, secluded straight corridor or walkway area is recommended. There should also be a standardized measured distance, which some have recommended for children to be 15–20 m between turning points (23, 30), in contrast to the 30 m recommended for adults. We hypothesize that a shorter distance that keeps a child’s caretaker in close sight may decrease their anxiety; we recommend that this be investigated and confirmed before any final recommendations are generated for a pediatric guideline.

Limitations of Results and Adjustments Made

Although interpretation of our results is limited by the small sample size, our findings suggest that equivalent parental/caregiver involvement customized to the pediatric population among centers with removal of parental/caregiver cheering, and standardizing 6MWT procedures in children would be necessary in the future when considering real world clinical data to systemically assess drug efficacy during regulatory review.

Disease severity can impact on the distance that patients with PAH can walk. We do not have suitable hemodynamic data or NT-proBNP or BNP data to match patients’ disease severity in the comparison groups. To achieve disease severity matched analyses, patients with Panama FC II were selected for comparison. Change in disease severity and motivation to walk over time can potentially result in intra-subject 6MWD variability with multiple tests, and subsequently impact on intra- and inter-center data variability. Therefore, we used the first qualified walks of the study of all eligible subjects so correlation between observations taken from the same patient would not be an issue. Additionally, variability based only on first observations (Fig. 3) does not appear very different from what was seen when adding in subsequent visits. Future study/studies with adequate sample size and well-defined study design would be helpful to validate this hypothesis.

As noted earlier, it has been reported that altitude and the age, sex, height, and weight of children can have an impact on 6MWD. To address this concern, our comparison groups were similarly matched for altitude, age, height, and weight, although sex was slightly unbalanced.

It has been reported that 6MWTs can only be performed in children older than 5 years of age as those under 5 years of age cannot reliably perform 6MWTs (31), although some studies have successfully evaluated children as young as 3–4 years old (23, 32). No child younger than 7 years of age was enrolled into the study. In addition, those children with a significant physical or cognitive impairment that would prevent a reliable 6MWT were also excluded.

Our analysis has explained, at least in part, 6MWT data variability and that parental encouragement, testing procedures, and the setting of the 6MWT track could contribute to the variability of 6MWD in children with PAH.

As real-world data (RWD) are being incorporated into evidence for understanding the effectiveness and safety of treatments (33, 34), focus on the use of these types of data to support regulatory decision-making will intensify with the encouraging boost from the passage of the 21 st Century Cures Act in 2016 (35). FDA has acknowledged that data collected during clinical care may not be as accurate or complete or have the same quality controls as data collected within a clinical trial setting, yet this RWD may be of acceptable quality to monitor post-market safety or support expedited access to medical products for unmet medical needs (36). However, FDA relies only upon valid scientific evidence from scientifically robust methods and approaches to determine whether there is a statutory standard of assurance that a pre-approval product is safe and effective for marketing (36). Real world evidence (RWE) can meet this threshold under conditions where the underlying RWD were accurately and reliably captured. In this context, our analysis has shown that testing variability can potentially impact on the utility of the RWE. We hope investigators will take into consideration such potential testing variability that may need to be controlled. Furthermore, there have been growing interests to develop novel endpoints for children with PAH that can be used in real world setting (37, 38). In this context, testing variability reduction or procedural standardization could improve the use of 6MWD data to compare against these potential novel endpoints with less data variability (38).

Suggestions for Consideration

Time has come to have a pediatric guideline for the 6MWT. This guideline could easily reflect similar recommendations from the ATS adult guideline for 6MWT with age-appropriate differences. From our experience and from the experiences of others found in the literature search, we would like to offer some suggestions and considerations that can be included a pediatric guideline as the following:

1.

Testing should be done in a single, straight hallway.

2.

A child should never be out of the sight of the tester.

3.

Testing should be done in a quiet hallway, preferably with no other pedestrian traffic.

4.

The testing track should have a measured distance. For older children, this could be the same distance as in adults (30 m/100 feet). For younger children, this distance may appear to be too far from the tester and/or parent, leading to anxiety, and the pediatric guideline could recommend age-appropriate changes to the distance walked (such as 10/15/20 m) (12, 24). One can use a smaller track length as long as it is the same length for every child and age in the center.

5.

Comfortable shoes are recommended; children should not walk in stocking feet, heavy boots, or awkward footwear.

6.

Walking should be done in a straight line, not allowing the child to alter the course. If need be, chairs or other safe barriers should be set up to prevent the child from weaving excessively.

7.

There should be no holding of the child’s hand (17, 31). Occasionally, if assistance is needed (due to a physical or mental challenge), children should use their usual walking aids during the test (cane, walker, etc.) (7) and it should be documented what was used. They should also be allowed to use their supplemental oxygen with documentation. However, as was done in our study to limit variability, generally such children should be excluded from enrollment in a clinical study that is using 6MWD as an endpoint (39).

8.

There should be no parental/caregiver’s cheering or enthusiastic encouragement. A steady, consistent voice could be allowed for encouragement and giving information on the child’s progress but would preferably be from the tester with standard phrases recommended in Table II.

If a study intends to include results of 6MWTs in a real world setting from multiple clinical centers, the sponsor of the study should be aware of how the test is performed at each center. Then, as much as possible, the sponsor should try to standardize any significant variabilities. A suggested sample questionnaire is presented in Appendix 1.

During our study, we also became aware of the fact that not all centers collect the same information during the 6MWT. Some centers collect heart rate and oxygen saturation every minute; some centers only collect the information at the start and at the completion of the study. Some centers collect a Modified Borg Rating of Perceived Exertion (RPE) Dyspnea Scale (40), while other centers do not. A suggested Borg Dyspnea Scale worksheet is presented in Appendix 2. If a study intends to include results of 6MWTs from multiple clinical centers, it is recommended that there is uniform data collection. A suggested 6MWT worksheet is presented in Appendix 3.