Terry, I think you could have spent a little more time with the literature and dug up more material to help your readers understand better what might be
going on in the FDA's mind.
Here's what the FDA had concluded in their briefing materials prior to the last (actually, the first) AdCom:
"Immunogenicity data supporting lot consistency was shown, and HEPLISAV was non-inferior to Engerix B with respect to seroprotection rates in
this second pivotal study. The overall rates of solicited and unsolicited AEs, SAEs and AESIs were similar among the consistency lots,
the older manufacturing lot TDG006, and Engerix-B. No significant differences in [anti-nuclear antibody] ANA titers or [Anti-Double Stranded DNA]
anti-dsDNA levels were seen among the different treatment arms. While the incidence of autoimmune events was low, all autoimmune AEs occurred in
HEPLISAV recipients. Given the randomization ratio employed in this study and the low background incidence of many autoimmune diseases,
the clinical significance of the 0.5% difference in the incidence of potential autoimmune disease between groups is unclear.
Due to the reports of thyroid disorders, an independent CBER analysis revealed that thyroid related AEs were reported by HEPLISAV recipients
with a frequency similar to that of Engerix-B recipients and the background incidence rate across all studies. As the numerical differences in
the incidence of these AIAEs in this study did not persist upon integrated analysis of all studies, CBER determined that study DV2-HBV-16 did not
reveal clinically significant safety concerns. However, it is acknowledged that the ability to reliably evaluate uncommon specific autoimmune events is limited
due to the size of the study."
That said, you are correct in that the CRL was issued because the agency felt there were insufficient data in some
areas (e.g., minorities, certain age groups) that prevented assessments of safety-related issues. For this reason, a third Phase 3 study was conducted.
An overview of the results for this study can be found here:
HBV-23 was a randomized, observer-blinded, active-controlled, multi-center study. Participants were randomized to HEPLISAV-B or Engerix-B in a
two to one ratio. They were stratified into two age groups, 18 to 39 years and 40 to 70 years.
Two doses of HEPLISAV-B were given one month apart compared to the conventional Engerix-B regimen of three doses given over six months.
HEPLISAV-B participants were followed for 52 weeks after the last dose, and Engerix-B participants were followed for 28 weeks after the last dose.
HEPLISAV-B demonstrated statistically significant higher protection rates than Engerix-B in both age groups.
The seroprotection rate in all participants who received HEPLISAV-B was 95 percent compared to 81 percent for Engerix-B.
Of participants 18 to 39 years of age, 99 percent who received HEPLISAV-B and 93 percent who received Engerix-B were seroprotected.
In participants 40 to 70 years of age, a larger difference in seroprotection rates was seen with the HEPLISAV-B rate of 95 percent compared to 79 percent for
Engerix-B.
The rates of local and systemic reactions, adverse events, serious adverse events, and deaths were similar between the HEPLISAV-B and
Engerix-B groups. All adverse events considered to represent potential immune-mediated disorders were reviewed by an independent,
blinded Safety Evaluation and Adjudication Committee and classified as not related to vaccination. Of the new onset immune-mediated adverse events,
Bell's palsy occurred in 0.09% of HEPLISAV-B and 0.04% of Engerix-B participants. Additionally, in the HEPLISAV-B group, there was a single case
each of alopecia areata, polymyalgia rheumatica, and ulcerative colitis.
With the HBV-23 trial, the total safety database now comprises 14,238 participants: 10,038 of whom received HEPLISAV-B and 4200 of whom received Engerix-B.
So, the bottom line is this: the combined, three-trial database now comprises over 14,000 patients, more than sufficient (I believe) for the agency's purposes.
There is no question that HEPLISAV is superior to the GSK product. On safety, it appears the two products have similar profiles.
So, what's going on?
I think that because DVAX's product uses an adjuvant, the FDA is being extra careful with its review and taking whatever time it wants and needs to ensure
that the data are scrubbed to a fare thee well before the next AdCom is held.
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Dynavax Sinks 32% As FDA Cancels Its AdComm Meeting
Terry, I think you could have spent a little more time with the literature and dug up more material to help your readers understand better what might be going on in the FDA's mind.
Here's what the FDA had concluded in their briefing materials prior to the last (actually, the first) AdCom:
"Immunogenicity data supporting lot consistency was shown, and HEPLISAV was non-inferior to Engerix B with respect to seroprotection rates in this second pivotal study. The overall rates of solicited and unsolicited AEs, SAEs and AESIs were similar among the consistency lots, the older manufacturing lot TDG006, and Engerix-B. No significant differences in [anti-nuclear antibody] ANA titers or [Anti-Double Stranded DNA] anti-dsDNA levels were seen among the different treatment arms. While the incidence of autoimmune events was low, all autoimmune AEs occurred in HEPLISAV recipients. Given the randomization ratio employed in this study and the low background incidence of many autoimmune diseases, the clinical significance of the 0.5% difference in the incidence of potential autoimmune disease between groups is unclear. Due to the reports of thyroid disorders, an independent CBER analysis revealed that thyroid related AEs were reported by HEPLISAV recipients with a frequency similar to that of Engerix-B recipients and the background incidence rate across all studies. As the numerical differences in the incidence of these AIAEs in this study did not persist upon integrated analysis of all studies, CBER determined that study DV2-HBV-16 did not reveal clinically significant safety concerns. However, it is acknowledged that the ability to reliably evaluate uncommon specific autoimmune events is limited due to the size of the study."
That said, you are correct in that the CRL was issued because the agency felt there were insufficient data in some areas (e.g., minorities, certain age groups) that prevented assessments of safety-related issues. For this reason, a third Phase 3 study was conducted. An overview of the results for this study can be found here:
investors.dynavax.com/releasedetail.cfm
From this URL, importantly:
HBV-23 was a randomized, observer-blinded, active-controlled, multi-center study. Participants were randomized to HEPLISAV-B or Engerix-B in a two to one ratio. They were stratified into two age groups, 18 to 39 years and 40 to 70 years. Two doses of HEPLISAV-B were given one month apart compared to the conventional Engerix-B regimen of three doses given over six months. HEPLISAV-B participants were followed for 52 weeks after the last dose, and Engerix-B participants were followed for 28 weeks after the last dose.
HEPLISAV-B demonstrated statistically significant higher protection rates than Engerix-B in both age groups. The seroprotection rate in all participants who received HEPLISAV-B was 95 percent compared to 81 percent for Engerix-B. Of participants 18 to 39 years of age, 99 percent who received HEPLISAV-B and 93 percent who received Engerix-B were seroprotected. In participants 40 to 70 years of age, a larger difference in seroprotection rates was seen with the HEPLISAV-B rate of 95 percent compared to 79 percent for Engerix-B.
The rates of local and systemic reactions, adverse events, serious adverse events, and deaths were similar between the HEPLISAV-B and Engerix-B groups. All adverse events considered to represent potential immune-mediated disorders were reviewed by an independent, blinded Safety Evaluation and Adjudication Committee and classified as not related to vaccination. Of the new onset immune-mediated adverse events, Bell's palsy occurred in 0.09% of HEPLISAV-B and 0.04% of Engerix-B participants. Additionally, in the HEPLISAV-B group, there was a single case each of alopecia areata, polymyalgia rheumatica, and ulcerative colitis. With the HBV-23 trial, the total safety database now comprises 14,238 participants: 10,038 of whom received HEPLISAV-B and 4200 of whom received Engerix-B.
So, the bottom line is this: the combined, three-trial database now comprises over 14,000 patients, more than sufficient (I believe) for the agency's purposes. There is no question that HEPLISAV is superior to the GSK product. On safety, it appears the two products have similar profiles.
So, what's going on? I think that because DVAX's product uses an adjuvant, the FDA is being extra careful with its review and taking whatever time it wants and needs to ensure that the data are scrubbed to a fare thee well before the next AdCom is held.