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Considerations for Progressive Multifocal Leukoencephalopathy Clinical Trial Designs FDA Workshop - Shared screen with speaker view - Recording 1/2
Candyce Jones
44:00
Hi Jennifer --I'll let our tech know you are here so we can get you moved up to a panelists. You'll need to accept the promotion to panelists on your end in order for it to work.
Candyce Jones
44:20
Hi Avi I'll let our tech know you are here so we can get you moved up to a panelists. You'll need to accept the promotion to panelists on your end in order for it to work.
Candyce Jones
01:04:33
@Gene 2minute warning
Candyce Jones
01:06:06
1 minute @Gene
Elizabeth Clearfield
01:16:20
That last slide was lower viral burden of HIV viral load or JC viral load?
Gloria von Geldern
01:16:57
JC viral load
Elizabeth Clearfield
01:17:05
Thank you
Candyce Jones
01:21:27
@David 5 minute warning
Candyce Jones
01:25:35
@David 1 minute warning
Candyce Jones
01:27:47
@David your designated time has expired
Candyce Jones
01:30:22
Reminder: Meeting participants are encouraged to submit questions via the “Q&A” feature. Questions will be submitted to the panelists for discussion during the designated panel discussions.
Candyce Jones
01:30:47
Also, following the workshop, meeting materials including, speaker slides, recordings, and transcripts, will be available on the workshop webpage: https://www.fda.gov/drugs/news-events-human-drugs/considerations-progressive-multifocal-leukoencephalopathy-clinical-trial-designs-09212021-09212021
Christina Marra
01:31:47
How does the JCV antibody test that is commercially available differ from what was reported before natalizumab, when more than 80% of people were said to be antibody positive?
Christina Marra
01:38:47
How do you take into account withdrawal of life sustaining care when you look at survival data?
Devante.Stephenson@fda.hhs.gov
01:38:48
"If you need Closed Captions, please follow this link: https://captionedtext.com/Client/Event.aspx?EventID=4748278"
Elizabeth Clearfield
01:39:57
Are these scales patient-reported or clinician-reported?
Candyce Jones
01:40:29
@Bryan 5min warning
Nicholas.Guerin@fda.hhs.gov
01:41:47
Your question has been submitted to be addressed by the panelists. We will do our best to address questions if time permits. The FDA also invites all interested parties to submit comments to the public docket: Docket No. FDA-2021-N-0512 (https://www.regulations.gov/document/FDA-2021-N-0512-0001).
Gloria von Geldern
01:42:17
EDSS is based on neurologic exam (though patient reported version exists).
Candyce Jones
01:42:53
We are currently on break. The meeting will resume at 11:15am
Gloria von Geldern
01:42:59
Karnofsky and Modified Rankin are assigned by clinicians but based in part on information reported by patient
Elizabeth Clearfield
01:43:25
Thank you - my father has PML but what he reports to us about how he is feeling and what he is experiencing seems to differ from what his nurses and doctors report (but the doctor seems him infrequently for a quick visit and doesn't hear about the day-to-day problems)
Elizabeth Clearfield
01:43:53
So, I see I need for more PROs if possible
Candyce Jones
01:57:23
@Virginia 5min warning
Christina Marra
02:03:30
I think that the cidofovir trial assessment did not include cognitive assessment.
Candyce Jones
02:06:32
@Laura 5 min warning
Christina Marra
02:10:46
If we skip the T1 in HIV, might we misdiagnose HIV related white matter changes as PML?
Candyce Jones
02:16:31
@Mike 5min warning
Candyce Jones
02:30:19
You will be promoted to panelist shortly
Christina Marra
02:32:58
But very wide confidence intervals should be noted.
Joe Berger
02:35:23
30 and 60 day survival is likely too short to be meaningful and the reduction of sensitivity and specificity at day 90 is unfortunate
Gina Norato
02:36:28
To clarify- it's not survival at 30 and 60 days- its a decline in jcv dna at 30 or 60 days, which is predictive of 1 year survival
Candyce Jones
02:36:40
@Paola 5min warning
Christina Marra
02:38:14
Would taking into account baseline copy number improve predictive value/
Christina Marra
02:38:16
?
Sabrina Tan
02:38:18
Specificity is really good. But sensitivity could certainly be improved.
Lori Dodd
02:39:12
How much do the estimates of sensitivity depend on the underlying disease (e.g., HIV vs MS vs oncology vs etc)?
Sabrina Tan
02:39:12
What is the sensitivity and specificity in the HIV+ group alone?
Gina Norato
02:40:49
Dr Marra- across all three cohorts we did not find that baseline JCV DNA was strongly predictive of 1 year survival but this may still be an important measure to consider for trial design
Candyce Jones
02:41:09
@Paola 1 minute warning
Patrick.Harrington@fda.hhs.gov
02:42:32
I think the baseline question will be worth discussing during the panel discussion, so be ready!
Clemens Warnke
02:42:56
Did you also look at CSF JCV DNA clearance as Surrogate of 1 Y Survival?
Candyce Jones
02:45:00
Speaker and panelist affiliations, disclosures, and bios are available on the meeting’s webpage under “Meeting Materials”: https://www.fda.gov/drugs/news-events-human-drugs/considerations-progressive-multifocal-leukoencephalopathy-clinical-trial-designs-09212021-09212021
Irene Cortese
02:46:03
In response to Clemens - we did look at CSF JCV DNA clearance in the NIH cohort: 32% of survivors achieved clearance by last sampling; 100% of those that died did not
Candyce Jones
02:46:41
Reminder: Meeting participants are encouraged to submit questions via the “Q&A” feature. Questions will be submitted to the panelists for discussion during the designated panel discussions.
Christina Marra
02:52:53
Has anyone looked at longitudinal myelin water fraction in PML?
Christina Marra
02:59:37
What about a composite endpoint or score? Sort of like CHADSvasc? A combination of underlying disease, imaging, clinical findings, PCR?
Roland Martin
03:00:16
I like the idea and think it would capture the issue best.
Paola Cinque
03:00:49
To Clemens. Clearance was achieved in <10% in our cohort of those who were positive at BL. 15% was positive at both BL and FU. Another 15% was negative at BL but detectable at FU
Serena Spudich
03:01:57
I think that a composite endpoint would be most likely to be valuable - agree. Longitudinally obtained.
Christina Marra
03:02:15
Could the cohort data be merged, linear regressions run and scores based on the odds ratios? Then it could be applied to a validation cohort?
Serena Spudich
03:03:21
Can there be a central lab that runs the CSF biomarkers for all PML patients (at least in the US)? Sort of like the Dalmau panel for autoimmunity or the labs that run diagnostic tests for CJD?
Christina Marra
03:03:48
Yes! And maybe for serology too.
Roland Martin
03:04:20
We have had both MS-PML and PML patients with a complicated prior history (cancer, stem cell transplantation), who have presented with low level CSF viral load (30-100 copies), who have clearly been free of PML for a long time after onset of disease. So, in my view, complete elimination of the virus is not a requirement). In these low level patients, we do not have sequencing information, i.e. whether PML variants remain present in the CSF.
Christina Marra
03:12:08
I think that trials for drug-related PML should be separate from trials for PML related to other causes of immunosuppression?
Candyce Jones
03:22:03
@Patrick 5 min warning
Serena Spudich
03:22:05
Christina I think that makes sense and is consistent with Dr. Martin’s comments too.
Serena Spudich
03:22:46
Another benefit of surrogate endpoints and even composite endpoints is that they also can teach us about the biology/mechanisms of disease.
Candyce Jones
03:25:39
@Patrick 1 minute warning
Gloria von Geldern
03:27:31
The nature of clinical course in PML recovery where IRIS can lead to temporary clinical and MRI worsening, makes some measurements as stop-points challenging.
Serena Spudich
04:00:19
Dr Clearfield, we have enrolled small numbers of people with HIV and PML into research studies (observational studies, not clinical trials where therapies were offered) and LPs every few months have been acceptable in this context. Perhaps this study population is unique but LPs at an interval of every 2-3 months have not been a major barrier in these studies. Agree that very frequent LPs are a deterrent.
Candyce Jones
04:03:08
I"ll get you promoted...standby
Candyce Jones
04:06:32
@Joan 5 minute warning
Candyce Jones
04:16:26
@Joan 5min warning
Serena Spudich
04:20:22
Ms. Tobin, thank you for everything that you taught us.
Elizabeth Clearfield
04:25:45
Thanks - I'd agree that an LP every 3 months might be acceptable, but more frequently would not be. The additional question is: what type of change in JC virus in the CSF would translate to functional improvements or prevention of further disability. Has this been quantified? Simply saying that JC viral load is reduced doesn't mean much to a patient who is continuing to lose function, and having spasms and pain.
Candyce Jones
04:26:34
@Luca 5 minute warning
Gloria von Geldern
04:30:27
Thank you to Ms. Tobin and Mr. Isabella for sharing their experiences.
Serena Spudich
04:32:16
Agree thank you both so much. We learned so much and I am so glad to know if the social media groups. Are there links or sites that you are willing to share? Are people living with PML welcome to join?
Clemens Warnke
04:35:32
Just to get back on JCV clearance from CSF and MRI stabilisation as possible surrogate endpoints 1) I understood that the “historic” cohorts suggest that JCV clearance may not occur in a larger proportion of survivors, and I acknowledge that we see JCV DNA CSF “persistency” in a proportion of survivors. However, this may be different if a compound was tested with strong direct anti-JCV effects? How is the frequency of CSF viral clearance in PML patients treated with e.g. JCV or BKV specific T cells? 2) With regards to MRI: what about e.g. “new or enlarging T2/FLAIR” lesion on MRI e.g. at month 6 or 9 as compared to month 3 or 6, complementing a CSF measure? In my view MRI would definitely require a “re-baseline” after 3 or 6 months of therapy due to e.g. IRIS-related initial lesion growth
Candyce Jones
04:47:26
Reminder: Meeting participants are encouraged to submit questions via the “Q&A” feature. Questions will be submitted to the panelists for discussion during the designated panel discussions.
Christina Marra
04:53:28
Pembrolizumab isn’t covered by insurance because it has not been proven effective. If you are going to say it is standard of care, we will never know.
Serena Spudich
04:54:45
Can we refer patients to the NIH or elsewhere for treatment with IL7 or pembrolizumab? Not available in our hospital.
Gloria von Geldern
04:56:24
@Dr. Spudich, yes, there is an IL7 trial actively enrolling at NIG
Serena Spudich
04:58:00
Maybe one of the speakers or panelists can mention this as a resource or other options for referral for therapeutic studies.
Paola Cinque
04:58:07
To Serena. IL7 can be requested to RevImmune (Paris) for compassionate use. Very easy to get. That is an option for cases outside US - where no clinical trial is ongoing
Serena Spudich
05:04:30
Paola - thank you!
Christina Marra
05:05:27
Which is why we need trails!
David Clifford
05:07:02
I agree with Christina. We should give optimal underlying disease control, then placebo trials to new interventions. Mirtazepine/mefloquine could be given for quite safe active care rather than naked placebo...
David Clifford
05:12:01
Just a cautionary note: management of natalizumab use means there are not huge numbers of patients in this class, and the same is true in HIV.... Earlier use of cART is continuing to decrease numbers of PML available with AIDS.
Paola Cinque
05:14:13
Placebo may not always be feasible. Take placebo for infusion of specific T-cells…
Christina Marra
05:15:33
How about newly HIV+ with PML, cART vs. cART plus IL-7 or pemb?
Sabrina Tan
05:15:35
Paola, would the placebo in that case be infusion of allo T cells not specifically selected for JCV?
Gloria von Geldern
05:15:59
@Dr. Marra, I very much like this!
Derrell Porter
05:19:24
Placebo would be a sham infusion, no T cells.
Paola Cinque
05:19:26
Sabrina, that would be something active.. not sure can call it placebo
Derrell Porter
05:19:47
Agree with Sabrina’s comments
Serena Spudich
05:20:05
We are still seeing a lot of people who have HIV as new diagnosis and new diagnosis of PML, meeting criteria that Christina mentions.
Sabrina Tan
05:20:27
Right, but thinking around the placebo question, perhaps it's more palatable if we could find a comparable control that would also be a specific control for the study product.
Paola Cinque
05:21:35
HIV patients starting cART are still the largest group of PML patients I believe. Not sure one wants to set up a clinical trial with those drugs based on retrospective data surveys
Kiran Thakur
05:21:39
I agree, I see too much unfortunately, and a good idea.
David Clifford
05:21:47
It is true that the HIV patients "falling through the cracks" of therapeutics are still being seen -- many of them have significant drug or psychiatric conditions that makes them somewhat problematic as a research population. Further, now these HIV patients I think are under half of total PML patients, so it has declined significantly.
Kerry Jo Lee - FDA
05:23:44
For pooling data as a community, consider the Rare Disease Cures Accelerator https://c-path.org/programs/rdca-dap/
Serena Spudich
05:23:55
Irene the field (providers, investigators, patients) is lucky to have you as an investigator at NIH focused on this condition.
Derrell Porter
05:24:45
Agree - Irene you are doing fantastic work. Thank you
Walter Royal, III
05:24:51
It sounds like we also need to be sure about the current epidemiology of PML to understand what patients will be available to comprise the control group.
Luca Isabella
05:25:10
If someone is interested the facebook page of the page is https://www.facebook.com/PMLSurvivorsSupportersand the private group ishttps://www.facebook.com/groups/1757934231158674We always need content or links for the page, so if anyone has something to add I can be reached at luca.isabella@gmail.com
Christina Marra
05:26:37
We could pitch education at stroke providers. There is a weekly national stroke webinar that might welcome some teaching.
Candyce Jones
05:26:43
@Virginia 5 min warning
Serena Spudich
05:27:36
Other barriers that many of the patients that I see experience include language barriers or concerns about being undocumented immigrants in the US who are worried about intersection with the healthcare system. Are these individuals eligible for compassionate use protocols or NIH research protocols?
suzanne.tobin@gmail.com
05:29:20
Education aimed at stroke providers would be wonderful! The head of my local hospital's stroke team had the humility to admit he didn't know what was wrong with me, and arranged for my inpatient stay at Johns Hopkins that saved my life.
Candyce Jones
05:30:38
@virginia 1 min warning
Elizabeth Clearfield
05:32:56
Suzanne, I agree. My father was diagnosed with a stroke and despite continuing to decline, they kept bringing in the stroke rapid response team. Finally after a month, the neurology team said hmm maybe it is something else. But he declined so much in that month. He walked into the ER on his own the day he was told it was a "stroke." By the time he left, he was unable to walk, hold his head up, or feed himself and needs 24/7 care. If the stroke provider had known about PML it may have been caught earlier and he wouldn't have had such a decline.