Eyes wide open regarding the FDA

[huntingonthebluffs]

Geron, Dr. John Scarlett and company et al deserve significant credit for having weathered the JNJ / Janssen debacle and all the sinister activities of the shorts and to some degree the hedge funds and BP influencing the FDA anti-Geron actions.

IMHO the FDA has blatantly mistreated and maligned Geron and obviously slowed the progress of a needed, powerful FIC drug through the sieve they have used regulations to create, in part for times that are legitimate, but in Geron’s case where money, influence and politics all come heavily into play and used to the competitions benefit. If anyone has doubts about government agencies including the FDA being weaponized by paid cronies, etc. I doubt we are following the same processes, things and events. Yes, I have personally lost all trust in the FDA and associated as if not obvious.

Now that Geron has bludgeoned its way through one P3 CT and has registration quality results in hand, the biotech hedge funds, brokerages, banks, etc. are beginning to believe they can see their way clear to quantify the financial value of Geron / Imetelstat and possibly add positive influence to push Imetelstat through to NDA approval in order to protect and increase their investments. Again IMHO, since Geron’s majority ownership has shifted from residential streets to Wall Street and their skin in the game is reflected via the regulatory agencies thaw in blocking Imetelstat with actual investments in stock and probably influence applied in a way to exact profits in a coordinated way of sorts.

I personally credit Dr. John Scarlett and likely some of his executive team for understanding how this disgusting process could be played externally to actually push Imetelstat across the finish line. While most of us on the sidelines have been immensely frustrated along the way, I believe JS had/has the experience, knowledge and personality to weather this storm and I think both current and future patients and retail investors like ourselves have a debt of gratitude. However, in my cynical and jaded perspective, with all the optimism being expressed these day I still currently expect the road ahead will continue to be very bumpy and fairness unfortunately will come at a steep price if at all.

[biopearl123]

Hunt, I honestly don’t share your pessimism. There is momentum here and good data both in safety and efficacy. It is easy to be a cynic especially with so many second agenda’s, industry lobbyists, and some government agencies that have lost credibility (read Supreme Court and past presidents), but others led by luminaries and honest leaders like Dr. Fauci still can inspire hope. It’s been a long time coming but a lot is going to happen in the next year. Hang in. bp

[KTArsenal]

Well-written post, Bluffs.

And I agree with BP in that the future sure seems to look bright if we only look at PIII data in MDS and doctors from around the world speaking highly of its potential.

Looking forward to Dr. Santini's presentation this Sunday at EHA.

To Bluff:

I agree that where there's money there's probably corruption, because there's tons of evidence to support that claim (including SCOTUS), but I do wonder how many contacts at the FDA Dr. Gottlieb still has, if any, and if he could have a positive affect on the outcome of Geron's NDA; even though that could potentially create a conflict of interest (cough, hack, cough), and presumably be illegal.

Presumably.

[huntingonthebluffs]

biopearl123 / KTArsenal, let there never be any question that I am very bullish (i.e. positive) about Geron and Imetelstat and the forward trajectory (momentum) of the approval process for treating MDS. But here I go on a bit of a rant continuation as we all know MDS treatment is the tip of the iceberg, there can / should be so much more to this story. So, I will continue to be frustratingly outraged by the treatment received from the FDA to date, preventing all efforts to avoid acceleration of the obvious, as treating MDS is only the beginning and it has been a slog. While the acceleration mechanisms supposedly included in the FDA tool bag, for example include the use of RWD, that has never found footing in regards to Imetelstat, especially regarding treatment of MF.

“The 21st Century Cures Act passed by the United States (US) Congress in December 2016 requires the US Food and Drug Administration (FDA) shall establish a program to evaluate the potential use of real-world evidence (RWE) which is generated from real-world data (RWD) to (i) support approval of new indication for a drug approved under section 505 (c) and (ii) satisfy post-approval study requirements.“

And given the incredible catalytic results of using Imetelstat in combination with venetoclax being delayed for unknown and what appears to be illegitimate rationale. And what about frontline, the blood supply constraints, etc. etc. Imetelstat has been, is and will continue to be a prime candidate for FDA acceleration while at the same time the poster child for the FDA’s dishonest inaction regarding acceleration. IMO the delays are strategic actions forced by the FDA powers to be and not based on science, and I don’t think anyone can prove me wrong as the arrogance and stonewall of the FDA is unchallengeable if one knows what is good for them. Maybe, hopefully, that paradigm begins to change now that the institutional investors have finally arrived but I will remain skeptical until proven otherwise.

Of course, all this misbehavior is explained away (or not) using statistics, raising or lowering standards “as needed”, “moving the bar”, so-called mistakes of oversight made intentionally, arrogance, overlooking conflicts of interest, massive lack of transparency and forcing the “tow the line or else” mentality of medical, scientific, media etc. professionals. And of course, intimidation of whistleblowers helps keep the lid on as well. However, most of us have been around a long time and know when “something is too good/bad to be true” or “something/someone is being judged through double (or more) standards” used to manage results based on changing financial, political, legal, landscape, power, etc. outcomes.

IMO, It doesn’t take one very long to research and find material to support ones perspective. However, in the case of the FDA, it is fundamentally slanted to the negative from a process and appearance perspective. It’s not hard to find the smoke of an unmanageable government agency making and enforcing many unjustifiable decisions and not answering to anyone under the cover of sayings like: “It is critical that the decision be made from a place of certainty”. Yes it is quite easy to cherry pick a few downbeat articles on the FDA that can enlighten us about the flagrant goings on because the sample size is surprisingly large to pick from. Here are 5:

Arrogance and lack of transparency is used by the FDA to force compliance of all parties trying to understand and provide a level of external accountability of the FDA leading to lack of public trust:
Forbes: https://www.forbes.com/sites/davidgortl ... 8ce78c13ba

And then there is the case of risky drugs being approved with unexplained reasoning: Why The FDA Cannot Be Trusted:
Harvard: https://ethics.harvard.edu/blog/risky-d ... be-trusted

And here is what might be explained as the anatomy of a failure to honestly, fairly and safely regulate by the FDA:
NY Times: How an Unproven Alzheimer’s Drug Got Approved: https://www.nytimes.com/2021/07/19/heal ... m-fda.html

How FDA Failures Contributed to the Opioid Crisis:
AMA Journal of Ethics: https://journalofethics.ama-assn.org/ar ... is/2020-08

And lastly, a somewhat dated example, but of course some things never change “Dishonesty, Misconduct and Fraud in Clinical Research: an International Problem”:
Journal of International Medical Research: https://journals.sagepub.com/doi/pdf/10 ... 0203000401


Unfortunately, everything these days has gotten incredibly complex because of so many competing narratives. I guess it comes down to whose Kool-Aid and how much of it one drinks that allows us to classify and speak confidently about who has made the greatest positive or negative impact on the various we debate and care intensely about. For me, I will continue to distrust until I believe honesty and true cooperation reappears in the interest of everyone. And given that I am very old, I remember a time when it wasn’t like it is today and hope and pray for the parts I believe were rational and balanced to return while I am still above the grass.

[biopearl123]

Hunt, great post and well researched and supported (thankfully not with conspiracy references recently posted that came from someone on YMB!) I would add a reference you might find interesting: “Empire of Pain” a recent book that looks at the Sackler family and the history of the OxyContin debacle. Unholy historic ties to the FDA as well as unethical pharma/media control is examined there too. I do think the FDA is keen to clean up their act. In the case of Imetelstat we will almost certainly see “accelerated” (read glacial), approval starting soon. I think to your point, “accelerated” approval shaves a few months off the approval process, but at this point in the game, that’s something. Also it’s very unlikely we will see anything like the Alzheimer’s drug controversy and I don’t think it’s too optimistic to expect an advisory panel to come to a unanimous recommendation for Imetelstat approval. That in and of itself will garner a lot of attention. Thanks for your post. Best Regards, bp

[kmall]

Hunt - as always, excellent post. I definitely share you're sentiment to a certain degree. It seems as if Imetelstat has been sidelined through the FDA process on several occasions in the past. Perhaps Dr. Scarlett's experience has been the catalyst to the dotting of "I"'s and crossing of "T"'s which from an investor standpoint, and more importantly, patient, feels like a neverending slog. Within days to the next two weeks, this is slated to end, with the highly anticipated formal NDA submission of Imetelstat.

Almost as frustrating has been a series of FDA guideline revisions focused on Clinical Trials in "speeding up" the process for unmet needs and rare disease in the Oncology space. Here's one from December 2018, three short months after the JNJ/Geron discontinuation......reading through it, Imetelstat should have been propelled to the top of the list meeting their revisions for Clinical Trials into accelerated approval. - "Demonstrating an improvement over available therapy and Overall Survival"......to my recollection, P2 did both. Hard to believe that this is almost 5yrs ago........

https://www.google.com/url?sa=t&source= ... 6-g0havN6y


"The accelerated approval regulations (21 CFR part 314, subpart H and 21 CFR part 601,
subpart E), promulgated in 1992, allow use of additional endpoints for approval of drugs or
biological products that are intended to treat serious or life-threatening diseases and that
generally demonstrate an improvement over available therapy or provide therapy where none
exists. In this setting, the FDA may grant approval based on an effect on a surrogate endpoint
that is reasonably likely to predict clinical benefit.5 Such surrogate endpoints are less well-
established than those surrogate endpoints for traditional approvals, such as blood pressure for
cardiovascular disease. FDA may also grant accelerated approval based on an effect on a
clinical endpoint that can be measured earlier than irreversible morbidity or mortality that is
reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical
benefit (i.e., an intermediate clinical endpoint).6 A drug is approved under the accelerated
approval regulations on condition that the manufacturer conducts clinical studies to verify and describe the actual clinical benefit.7"


"Overall Survival
Overall survival is defined as the time from randomization until death from any cause and is
measured in the intent-to-treat population. Survival is considered the most reliable cancer
endpoint, and when studies can be conducted to adequately assess survival, it is usually the
preferred endpoint. This endpoint is precise and easy to measure, documented by the date of
death. Bias is not a factor in endpoint measurement. Survival improvement should be analyzed as a risk-benefit analysis to assess clinical benefit.
Overall survival should be evaluated in randomized controlled studies. Data derived from externally controlled trials are seldom reliable for time-to-event endpoints, including overall survival. Apparent differences in outcome between external controls and current treatment groups can arise from differences other than drug treatment, including patient selection, improved imaging techniques, or improved supportive care. Randomized studies minimize the effect of these known and unknown differences by providing a direct outcome comparison.

Demonstration of a statistically significant improvement in overall survival can be considered
to be clinically significant if the toxicity profile is acceptable and has often supported new drug
approval.

Difficulties in performing and analyzing survival studies include long follow-up periods in
large trials and subsequent cancer therapy potentially confounding survival analysis."


I wish the cynic in me didn't feel this way, but let's see how "fast" Fast Track Designation is once Geron officially submits the NDA...... something tells me not so fast. -Kmall