I went back to watch
the FDA CRDAC (Cardiovascular and Renal Drugs Advisory Committee) meeting to discuss Alnylam's drug Patisiran for the treatment of ATTR-CM (Transthyretin Amyloidosis) - a rare form of heart disease. The meeting discussion was centered on the clinical meaningfulness of the efficacy measures in the primary efficacy endpoint of 6MWD (how many meters patients can walk in 6 minutes) and the secondary endpoint of KCCQ - a patient-reported quality of life measure.
To judge if the treatment difference is clinically meaningful, people will compare the magnitude of the treatment differences from the study with the MCID (minimal clinically important difference). MCID. MCID is the smallest change in a treatment outcome that individual patients would identify as important and which would indicate a change in the patients' management. The MCID is a patient-centered concept that captures both the magnitude of the improvement and the value patients place on the change. In other words, the MCID is the smallest amount of change in the score of a scale recognized by the patient without considering the side effects and cost.
The 6MWT, a performance outcome (PerfO), is a practical simple test that measures the distance that a
patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD). It evaluates the
global and integrated responses of all the systems involved during exercise. The results of the APOLLO-B
trial showed a statistically significant but small treatment effect for the primary efficacy endpoint.
Subjects treated with patisiran experienced an average decrease in their 6MWD of 13 m at Month 12
from an average 6MWD of 361 m at baseline, while subjects in the placebo arm experienced an average
decrease in their 6MWD of 31 m at Month 12 from an average 6MWD of 375 m at baseline. The change
from baseline at Month 12 in 6MWT (Hodges-Lehmann [HL] estimate of median difference) for patisiran
vs. placebo was 14.7 m (95% confidence interval [CI] 0.7, 28.7; p-value 0.04). Literature has reported a
range of meaningful differences (22 to 90 m) reflective of the heterogeneity in cardiomyopathy patients
(Mathai et al. 2012; Shoemaker et al. 2012).
The KCCQ, a patient-reported outcome (PRO) and a disease-specific measure for HF, is a 23-item self-administered questionnaire developed to measure the patient’s perception of their health status, which
includes heart failure symptoms, impact on physical and social function, and how heart failure impacts
their quality of life (QOL) within a 2-week recall period. The KCCQ-OSS has a 0-100 transformed score
range where higher scores reflect better health status (based on the Physical Limitation, Symptom
Frequency, Symptom Burden, Quality of Life and Social Limitations Domain Scores). In the APOLLO-B
trial,the treatment effect for the first secondary efficacy endpoint, change from baseline at Month 12 in
KCCQ-OSS was small (3.7 points on a 0 to 100 transformed score range; 95% CI 0.2, 7.2; p-value 0.04).
On average, subjects treated with patisiran had an increase in KCCQ-OSS of 0.3 points at Month 12 from
the average baseline score of 69.8 points, while subjects in the placebo arm had a decrease in KCCQ-OSS
of 3.4 points at Month 12 from the average baseline score of 70.3 points.
Sponsor, Alnyam's
briefing book and
presentation spent a lot of effort to defend that the small, but statistically significant treatment differences are clinically meaningful.
Sponsor attempted to derive an MCID using KCCQ category as an anchor based on the data from the study itself (APOLLO-B study).
Not surprisingly, the MCID they generated were much smaller (MCID in the range of 7 - 8 meters) than the MCIDs reported in the literature. If the MCID is indeed in the range of 7 - 8 meters, the 14.7 meters (treatment difference observed in Apollo-B study) would be clinically meaningful.
During the FDA advisory committee meeting, most of the members were not convinced by sponsor's presentation to defend the clinical meaningfulness of small treatment difference in 6MWD (about 14 meter). However, majority of them (9-3) still voted in favor of the Patisiran's efficacy and the benefit-risk profile.
Pfizer's tafamidis is the only approved drug for the treatment of ATTR-CM. According to the product label, the treatment difference in 6MWD was much larger - 76 meters with 95% confidence interval 58, 94 meters at month 30.
For the same 6MWD, the MCID may be different depending on the treating diseases, different patient population, whether patients receiving the background therapies,... However, a treatment difference of 14 meters is still not a convincing number to be clinical meaningful. Putting on the relative scale, the 14 meters in patients with baseline 6MWD 361 meter is less than 5%. It is difficult to convince people a treatment difference less than 5% is clinically meaningful.
I am particularlly interested in the MCID of 6MWD in lung diseases (especially the pulmonary arterial hypertension).
Anne E. Holland (2014) "
An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease" stated
“Available evidence suggests a minimal important difference (MID) of 30 m for the 6MWD in adults with chronic respiratory disease.”
Jude Moutchia (2023) "
Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension" found:
The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27–38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29–43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class.
Here is a table containing some literatures with estimated MCID. The MCID was found to be in the range of 20 - 54 meters depending on the indication/disease.
Latest update:
In the end, the FDA did not approve Patisiran for the treatment of ATTR-CM because the treatment difference in 6MWD was too small (way below the MCID) and not clinically meaningful even though the FDA advisory committee voted in favor of the Patisiran's benefit and there was no issue with the safety and the manufacturing.
Alnylam Announces Receipt of Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Patisiran for the Treatment of the Cardiomyopathy of ATTR Amyloidosis
"In its Complete Response Letter (CRL), the regulator said that Alnylam had not provided enough evidence of the therapy’s benefit in the proposed indication. At the same time, the FDA did not flag any problems with patisiran’s clinical safety, drug quality, manufacturing processes or study conduct.
“The CRL indicated that the clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis had not been established,” according to the company’s announcement. In light of the rejection, Alnylam will no long work toward an expanded label for Onpattro in the U.S."
