The Double Blind Placebo Controlled Trial: The Fool's Gold Standard

[huntingonthebluffs]

https://www.sskrplaw.com/the-double-bli ... tanda.html

Someone posted this on the YMB a few days ago. When went back to see who posted it, it apparently had been erased. This document was on a law firms website publications tab. I found it very interesting and I would have to concur for the most part with the view presented regarding the ethics on the use of placebo. It has also undoubtedly contributed to the length of time to complete enrollments in the Geron P3 CTs.

[biopearl123]

Hi Hunt, in Geron’s case the “placebo” is BAT for the MF study. For the MDS study I suppose BAT could be argued to be Luspatercept or other as yet unproven agents but the design was approved by the FDA before Lus was approved so hard to argue against current “placebo” arms. Especially since RWD dissed by FDA. Your contributions have been stellar by the way, thanks. bp

[Ryan]

No, It is the Gold Standard.

[huntingonthebluffs]

Okay, so I may be standing out in the wilderness mostly alone on this but the gold standard could be interpreted more than one way, for example to mean the majority of phase 3 trials using a placebo which could benefit study quality and/or not be significantly detrimental to the patients is one way to think. However, I don’t think using a double-blind placebo P3 CT is ethically appropriate across the board, gold standard or not. Especially where the study benefit from use of a placebo can be described as marginal, the patients are clearly gambling with their lives or taking on risks of reducing their time of survival vs potential extension of their lives.

If one can live with the ethics associated with not attempting to at least therapeutically treat terminal diseases using the so called placebo gold standard, then describe the true cost vs benefit? The 55+ in the MDS P3 and 105+ in the MF P3 studies that are being given a placebo versus Imetelstat basically have much to lose while gaining little if anything and essentially contributing their lives to science just as if they weren’t in a trial at all. In addition, the placebo patients do not have a switchover option in these CTs after disease progression, etc. and in the case of the MF patients, will very likely not live long enough to receive Imetelstat after approval / commercialization. How does that play out ethically?

As with most things, any standard, regulation, policy, rule, law, etc. should have an “exception” clause(s), especially if substantial ethical considerations are at play. In this day and age, the FDA seems to be living in an alternate reality by using a non-negotiable placebo standard for studies in terminal and late-stage terminal cancer. Especially true for the Imetelstat CTs which have clear separation between degree of illness required to be accepted into the CTs and very likely no level of recovery possible without significant effect of the drug’s efficacy.

Your point biopearl123 is spot on regarding the “FDA dissing RWD” as a placebo alternative. Why in this digital age did they revert to pencil and paper? I believe it is truly misguided, maybe even sinister, in regards to studies like the Geron P3 CTs. In the MF study, we know that once R/R to a JAK inhibitor, the patient has possibly a “median” year and change to live period, spending valuable time in a CT hoping for Imetelstat’s benefits while taking a placebo is clearly unethical and unjustified. How would you feel if you or your loved one were one of those taking the placebo? How would most doctors feel given their oath to do no harm if they knew they recommended a patient for Geron P3 CT who was given a placebo? How can playing Russian roulette be termed the gold standard in this context?

And as long as I’m on a rant, IMHO if the FDA was really interested in doing what was optimally right and ethical, Imetelstat would already be approved, extending lives, reducing blood transfusions, improving QOL, reducing medical costs & patient financial burdens, helping to address the blood bank crisis, etc. Certainly not in a painfully long late stage CT asking patients to risk being given a blank load. Rather if anything short of full MA, assuming the regulators still can’t see the light, they could require Geron to provide a P4 version of data validation while allowing patients at large to receive Imetelstat.

[biopearl123]

Hunt, if it’s any consolation, CKTC made the astute observation and pointed it out to me, that there IS a crossover option afforded the placebo MF patients in the IMpact protocol. Would have to go back and review the criterion.

[biopearl123]

But how having mortality as the primary end point and still allowing cross over is not clear to me!

[ashah]

I wish there was some biostats person/expert to comment on this....but here is a question or a thought.

Imagine yourself on the Independent Data Monitoring Committee (IDMC) ... and your job is to ensure that patients are NOT harmed.
You see that the non-Imetelstat patients progress... and time after time ... after they move to the Imetelstat arm, they do better.

What would you do? In theory, could the TTP (Time to Progression) or other end points be relevant in addition to the OS...at least from a regulatory standpoint?
If you are the company, would you not want the OS barrier (which presumably would be high for Imetelstat) to be the barrier that other drugs have to overcome to gain traction?

Very complex issues...and some which certainly compel us to sacrifice the short term pawn for the long run queen (as in chess).

[huntingonthebluffs]

Thanks biopearl123 for keeping this on track and to be fair, the MF P3 study has a comparator of best available therapy (BAT) which is investigator-selected non-JAK-inhibitor treatment and not a placebo. However, for the most part it seems to me it is a blank load for the R/R patients, just not technically a placebo.

ashah, good points as well but the value of competitive OS barrier brings us back to the “not using RWD” for terminal cancer comparisons. Seems to me the accepted longevity for MF Refractory to Janus Kinase (JAK)-Inhibitor is 12-18 months, what is there to compare to here or are they just trying to put the next data point on the current OS graph using BAT. What ever is going on they seem to think it is ethical so just what could I be missing? BAT, by the way, may include but is not limited to hydroxyurea, thalidomide or an analog of thalidomide, interferon, danazol, hypomethylating agents, and chemotherapy, which seems to me would provide a hodge-podge of data results based on what BAT is used.

Maybe CKTC will refresh us on where documentation is for the BAT MF patient to crossover to Imetelstat which would help bring this back into alinement for me on an ethical basis. To your point biopearl123 and ashah, this would stir the questions on just what would the Imetelstat OS data be compared to with the BAT arm.

[ashah]

Participants who meet progressive disease criteria and discontinue BAT, may crossover to receive imetelstat treatment after sponsor's approval.
I revisited the clinicaltrails.org to refresh the study design and have bolded the relevant section.

Some interesting points:

• Cross over is not automatic

• The reduction of duration for primary analysis, from 15 months to 12 months treatment - wonder if the IDMC is seeming something. Certainly there is a longer enrollment tail,but to reduce the duration from 15 to 12 months? What if there is also an efficacy related tail wind?
  From my days in biopharma, greater the potential drug efficacy - shorter the trial duration or fewer the number of patients needed - since the drug can clearly differentiate from its peers

• Investments in to commercialization... worst case timeline, Primary Analysis 1Q23, filing 3/4Q 23, Approval 2Q 24. We are nearly 3 years early...and commercialization efforts seems to be a little early.

For me, some things are not adding up...

[huntingonthebluffs]

Thanks ashah for the info on the crossover. It was right there in front of me but I stopped reading just before and concluded incorrectly. The other thing from the CC yesterday was the MF study is not double blinded per Dr. Rizo, it is only randomized. Of course that is also stated in the CT info but I overlooked that as well. So there is benefit of being randomized to the BAT arm as it includes the special care and attention given as part of the study as well as the possible crossover option. So I will tone down this rant at least regarding the Geron CTs.