ClosetInvestor,
Thanks for your response. You bring up an interesting point about whether or not CYDY has access to labs before unblinding. Several posters on YMB brought that question up and I am pasting Science + Compliance's answers below (plus some other questions he responded to). He/she claims to have experience managing clinical trials. There are now 81 replies to the original message. It is an interesting read.
Q: Why would you think Cytodyn has access to lab data? I believe the only insights they have during the blinded trial are SAE's. They go through so much trouble to blind and eliminate bias and you think they would leave an obvious back door open to compromise the integrity of the trial?
A (by S + C): Amarex is their CRO and Amarex uses a 3rd party CTL (they don’t have this capability). CYDY is the Sponsor and has access to any data they want through the eTMF. The blinding prevents bias at the dosing level and is independent of the lab test data. Again, this is all part of building a robust trial and it’s easy to identify a well constructed study. (Note: eTMF is electronic trial master file - I had to look it up)
Q: I see what you're saying, but do we know who's doing the labs?
I think with masking it would be impossible for Cydy to know anything.
The CRO is Amarex. I think it would be a massive issue if Amarex shared data, (if they even have it), with Cydy the sponsor.
A: The Sponsor has access to all data in a trial to meet the required regulatory oversight. What I’m saying is the lab data with the secondary endpoints chosen would clearly indicate to the expert eye who received LL and who didn’t.
Q: Are you saying Cytodyn has access on going to the Secondary Endpoint data, but not the Primary Endpoint data?
Dr Nader P. has quite emphatic in stating that data is blinded to them....
A: The primary endpoint is mortality and any death is a reportable SAE. These patients still had initial baseline data (T0) collected to confirm they meet the inclusion and exclusion criteria, and if they made it to Day 14 a second set of data comparable to T0. The comparison of T0 secondary endpoints data to the Day 14 secondary endpoint data is what is telling the story now.
Just to add the data is still blinded. Looking at lab data that is aligned to the disease state is a “back door” approach to look at efficacy. Again, the study has to be structured (if possible) to use this approach. Ph 1 or 1/2 trials often aren’t able to use this type of alignment to the endpoints as they are often exploratory in nature.
Q: CRO and sponsor can see the data, but are still blinded.
When CYDY says 87, they know that first hand, with no third party filter, correct?
So, I will ask this. If they can already see the blinded data, does it make sense that they are analyzing it as it comes in, or do they really have to wait until day 28 of last patient dosed?
It just seems like they would want to have analyses done as they go, with mortality as the endpoint.
A: To your first question the answer is yes CYDY knows this first hand. Again, they are the Sponsor and the sponsor is privy to the eTMF.
To your second question, if you look at the secondary endpoint there is a Day 14 evaluation and blood draw, so with this criteria and time point they don’t need to wait until day 28. The day 14 visit is used to also determine if inclusion and exclusion criteria are still being met, so it’s important.
They are likely having data analyzed as they go. This has been the case with 95% of the trials I’ve managed.
Q: When should we reasonably expect readout by CytoDyn or FDA.
A: The "official" review can only take place after the last timepoint listed in either the primary or secondary endpoints - Day-28. After Day-28 there are steps followed described below. Keep in mind these are only my best assumptions as I'm not privy to the level of specific detail on these steps are how they are worked through with CYDY and Amarex as Sponsor and CRO.
The high-level steps to data readout are:
1) Database lock; this step can be completed within a day after the last timepoint [AMAREX]
2) Data QA(QC); if this part of the eTMF has been validated during the UAT, QA effort is minimal (e.g. 1-day). If manual review is required this can take slightly longer. In my experience this is part of the UAT and should require minimal efforts (1-2 days and can be done immediately after DB lock).[AMAREX + CYDY]
3) Unblinding and discussions with the biostatisticians (1-2 days depending upon the depth).[AMAREX + CYDY]
4) Data QA after unblinding; very quick just to confirm unblinding followed the protocol. [AMAREX]
4) Data analysis; this step is "assembling" the data in a manner FDA wants to see it based upon internal discussions with CYDY. This can/will involve the DSMC and is the most time consuming ( 3-6 days depending on number of people on it). [AMAREX + CYDY + 3rd PARTY TESTING LAB (if questions)]
5) Review and approval (internally) of the arranged data (1-2 Days). [AMAREX + CYDY]
6) Submission of data (1 day). [AMAREX + CYDY]
7) FDA approval; I would guess this response should very quick from an FDA timelines perspective, however, I wouldn't be able to provide an accurate estimate.
Release of data
Please keep in mind some of these steps can be performed concurrently and the timelines could be compressed. I will add that in my experience FDA can/will provide a response to submitted data within a few days of data submission if the study is important.
I would also guess that if the FDA has been working intimately with CYDY as we've been informed, they have likely had dialogue and eyes on the SAE data as it's come in. This will ultimately decrease wait times.
Hopefully I added some useful information in a previous post. As far as a time estimate, I can only use my experience in studies that were < 50 and >1000 patients (I support rare diseases now). I've seen release times of 1-8 weeks. I know this isn't much help, but the detail of data processed in endpoints and the number of patients are rate limiting factors. Unfortunately, the CRO can also have an impact...the nice part is Amarex is a solid CR.
Q: Dr BP has on several occasions referred to leronlimab in trials containing a fluorescent tag (at least early on). Do we know if tagged leronlimab has been used ongoing?
A: I really don't know without seeing the lab analysis protocol. This level of detail would only be visible in lab data, however, the analysis would need to be setup in the instrumentation to see the fluorescent tag.
Thanks for your response. You bring up an interesting point about whether or not CYDY has access to labs before unblinding. Several posters on YMB brought that question up and I am pasting Science + Compliance's answers below (plus some other questions he responded to). He/she claims to have experience managing clinical trials. There are now 81 replies to the original message. It is an interesting read.
Q: Why would you think Cytodyn has access to lab data? I believe the only insights they have during the blinded trial are SAE's. They go through so much trouble to blind and eliminate bias and you think they would leave an obvious back door open to compromise the integrity of the trial?
A (by S + C): Amarex is their CRO and Amarex uses a 3rd party CTL (they don’t have this capability). CYDY is the Sponsor and has access to any data they want through the eTMF. The blinding prevents bias at the dosing level and is independent of the lab test data. Again, this is all part of building a robust trial and it’s easy to identify a well constructed study. (Note: eTMF is electronic trial master file - I had to look it up)
Q: I see what you're saying, but do we know who's doing the labs?
I think with masking it would be impossible for Cydy to know anything.
The CRO is Amarex. I think it would be a massive issue if Amarex shared data, (if they even have it), with Cydy the sponsor.
A: The Sponsor has access to all data in a trial to meet the required regulatory oversight. What I’m saying is the lab data with the secondary endpoints chosen would clearly indicate to the expert eye who received LL and who didn’t.
Q: Are you saying Cytodyn has access on going to the Secondary Endpoint data, but not the Primary Endpoint data?
Dr Nader P. has quite emphatic in stating that data is blinded to them....
A: The primary endpoint is mortality and any death is a reportable SAE. These patients still had initial baseline data (T0) collected to confirm they meet the inclusion and exclusion criteria, and if they made it to Day 14 a second set of data comparable to T0. The comparison of T0 secondary endpoints data to the Day 14 secondary endpoint data is what is telling the story now.
Just to add the data is still blinded. Looking at lab data that is aligned to the disease state is a “back door” approach to look at efficacy. Again, the study has to be structured (if possible) to use this approach. Ph 1 or 1/2 trials often aren’t able to use this type of alignment to the endpoints as they are often exploratory in nature.
Q: CRO and sponsor can see the data, but are still blinded.
When CYDY says 87, they know that first hand, with no third party filter, correct?
So, I will ask this. If they can already see the blinded data, does it make sense that they are analyzing it as it comes in, or do they really have to wait until day 28 of last patient dosed?
It just seems like they would want to have analyses done as they go, with mortality as the endpoint.
A: To your first question the answer is yes CYDY knows this first hand. Again, they are the Sponsor and the sponsor is privy to the eTMF.
To your second question, if you look at the secondary endpoint there is a Day 14 evaluation and blood draw, so with this criteria and time point they don’t need to wait until day 28. The day 14 visit is used to also determine if inclusion and exclusion criteria are still being met, so it’s important.
They are likely having data analyzed as they go. This has been the case with 95% of the trials I’ve managed.
Q: When should we reasonably expect readout by CytoDyn or FDA.
A: The "official" review can only take place after the last timepoint listed in either the primary or secondary endpoints - Day-28. After Day-28 there are steps followed described below. Keep in mind these are only my best assumptions as I'm not privy to the level of specific detail on these steps are how they are worked through with CYDY and Amarex as Sponsor and CRO.
The high-level steps to data readout are:
1) Database lock; this step can be completed within a day after the last timepoint [AMAREX]
2) Data QA(QC); if this part of the eTMF has been validated during the UAT, QA effort is minimal (e.g. 1-day). If manual review is required this can take slightly longer. In my experience this is part of the UAT and should require minimal efforts (1-2 days and can be done immediately after DB lock).[AMAREX + CYDY]
3) Unblinding and discussions with the biostatisticians (1-2 days depending upon the depth).[AMAREX + CYDY]
4) Data QA after unblinding; very quick just to confirm unblinding followed the protocol. [AMAREX]
4) Data analysis; this step is "assembling" the data in a manner FDA wants to see it based upon internal discussions with CYDY. This can/will involve the DSMC and is the most time consuming ( 3-6 days depending on number of people on it). [AMAREX + CYDY + 3rd PARTY TESTING LAB (if questions)]
5) Review and approval (internally) of the arranged data (1-2 Days). [AMAREX + CYDY]
6) Submission of data (1 day). [AMAREX + CYDY]
7) FDA approval; I would guess this response should very quick from an FDA timelines perspective, however, I wouldn't be able to provide an accurate estimate.
Release of data Please keep in mind some of these steps can be performed concurrently and the timelines could be compressed. I will add that in my experience FDA can/will provide a response to submitted data within a few days of data submission if the study is important.
I would also guess that if the FDA has been working intimately with CYDY as we've been informed, they have likely had dialogue and eyes on the SAE data as it's come in. This will ultimately decrease wait times.
Hopefully I added some useful information in a previous post. As far as a time estimate, I can only use my experience in studies that were < 50 and >1000 patients (I support rare diseases now). I've seen release times of 1-8 weeks. I know this isn't much help, but the detail of data processed in endpoints and the number of patients are rate limiting factors. Unfortunately, the CRO can also have an impact...the nice part is Amarex is a solid CR.
Q: Dr BP has on several occasions referred to leronlimab in trials containing a fluorescent tag (at least early on). Do we know if tagged leronlimab has been used ongoing?
A: I really don't know without seeing the lab analysis protocol. This level of detail would only be visible in lab data, however, the analysis would need to be setup in the instrumentation to see the fluorescent tag.
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