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This guidance provides recommendations to applicants on endpoints for cancer clinical trials submitted to the Food and Drug Administration (FDA) to support effectiveness claims in new drug applications (NDAs), biologics license applications (BLAs), or supplemental applications. It also provides background information and discusses general regulatory principles. The endpoints discussed in this guidance are for drugs to treat patients with an existing cancer. This guidance does not address endpoints for drugs to prevent or decrease the incidence of cancer.
This guidance is a revision of the final guidance of the same title that published in May 2007. This guidance replaces the May 2007 guidance of the same title.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
Please state those statutory requirements again for me
Sure. I asked Ex this already and since you seem to be of the same mindset. Can you please send me the link where they/NWBO are required by law to update the US clinical trial site for accepted endpoint changes?
TIA
You do realize NWBO did not update the EU site and had no idea that was going to happen.
They certainly have no plans to update the US site as well.
Blinded Data vs Unblinded Data...duh
Exactly Flip!!
Here's another example
https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-announces-agreement-fda-special-protocol
Regarding SPA:
Next, refining the questions in the SPA request so they provide clarity and concision is important. With few opportunities to interact with FDA, it is important to craft high-level questions very thoughtfully. Ideally, protocols will be fully vetted with solid statistical analysis plans that can be presented to the FDA with just one question, “Does the agency agree that the protocol design will potentially result in data required for FDA review for approval of the proposed indication.” If FDA does not agree, they will provide input needed to address existing issues
An example of FDA approval with modified primary endpoint based on Special Protocol Assessment (SPA)
In connection with the SPA, the FDA recommended, and the Company accepted, modifying the primary efficacy endpoint for the GATHER2 trial
“We are excited to receive this SPA agreement from the FDA,” stated Pravin U. Dugel, MD, President of Iveric Bio. “We thank the FDA for their collaborative interactions and valuable input on the primary efficacy endpoint for the GATHER2 trial, which we believe reflects the FDA’s current thinking. The modification of the primary efficacy endpoint does not require collecting any new data but instead reflects a change in how the data are analyzed. We look forward to continuing to work with the FDA and following their guidance as we work toward preparing the eventual NDA submission for Zimura.”
https://investors.ivericbio.com/news-releases/news-release-details/iveric-bio-receives-fda-agreement-under-special-protocol
Again...you are simply wrong
Multiple studies have shown that adherence to the former FDA regulation regarding ClinicalTrials.gov registration is poor, and despite previous guidelines and requirements trial registration has remained suboptimal [14, 15]. One study points out that although the FDA requires results reporting within 1?year of trial completion, only 13% of trials adhered to this and the average time of reports reporting was 17?months [16]. Though the impact of the most recent recommendations of ClinicalTrials.gov is not known at this time, there remains concern in regard to the completeness of adherence to these guidelines.
The selective reporting of clinical trial endpoints has been well demonstrated between published reports and clinical trial registration and between published reports and protocols [17–21]. For example, one study found discrepancies in endpoint reporting, cohort, intervention, or results between high impact journal publications and ClinicalTrials.gov were in as high as 97% of trials [17]. In addition, evidence of primary outcome discrepancies between publication and registry exist [21]. The focus of this report differs from prior publications as we sought to explore discrepancies between two so called gold standards for endpoints, the registry and the protocol. This is of particular interest as efforts increasing relying upon clinical trial registration need to ensure an accurate and complete representation exists in such registries. Our data suggest that the translation of clinical trial protocol endpoints into clinical trial registries is suboptimal and efforts to ensure alignment of endpoints between protocols and publications at the time of reporting are needed.
Thus, the following types of changes should be appropriate for implementation without prior FDA approval:
Increasing the frequency at which data or information is gathered or lengthening the subject follow-up period. For example, modifying the follow-up schedule such that subjects return every month for evaluation rather than every 2 months or extending the follow-up period from 6 months to one year.
Modifying the protocol to include additional patient observations or measurements. For example, adding a quality of life assessment or performing additional tests on previously collected subject specimens.
Modifying the inclusion/exclusion criteria to better define the target patient population. For example, modifying the criteria to exclude subjects who had been exposed to another investigational device within a certain time period prior to participation in the current study.
Modifying the secondary endpoint(s). For example, eliminating the assessment of post-void residuals in a benign prostatic hyperplasia (BPH) study if this secondary endpoint does not represent a clinically significant outcome measure.
Alternatively, the following types of protocol modifications can have a significant effect on the validity of the data resulting from the trial and/or on the scientific soundness of the trial design and thus would not generally be eligible for implementation without prior approval.
Change in indication. For example, narrowing the indication to a subgroup upon which the device appears to be working better than in the overall population. Such a change could lead to a Type I error in the subgroup and a lack of power to evaluate the subgroups in general.
Change in type of study control. For example, a change from an active control (legally marketed device) to the use of historical (literature) control.
Change in the primary endpoint variable. For example, deciding mid-study to identify a new primary endpoint when the endpoint had not been included in the original protocol and thus data was not being collected to evaluate it. As a second example, exchanging the primary and secondary endpoints because it does not appear that the primary endpoint will meet the success criteria. Such changes would most likely require statistical adjustments, e.g., the original sample size estimate may no longer be valid. Alternatively, adding a new endpoint to the original study endpoints may not require prior approval if no new risks to the patient are introduced when collecting the data to evaluate the endpoint.
Reduction in sample size. Such a change would normally lead to a loss in statistical power.
Change in the method of estimation. For example, changing from an exact method (e.g., hypergeometric model) to an approximate method (e.g., Chi Square).
Early termination of the study (except for reasons related to patient safety). Early termination may invalidate the data as early results may not be typical. For example, deciding that a 6-month rate of ventricular tachycardia recurrence rather than the planned 1-year rate will suffice because few recurrences have occurred at 3 months may later turn out to be an invalid assumption.
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/changes-or-modifications-during-conduct-clinical-investigation-final-guidance-industry-and-cdrh#3_(i)
Lol...God Bless you Doc!!
When this is all said and done, let me know if you need someone to help untangle those lines
WTBS...Whitewater, TOSS THAT SOCK!!
And this is uncommon with other Companies?
What would you like the PR to say? Hey shareholder, doubter and market at large, we continue to execute the plan we have discussed in prior PR's.
For those of you that need us to hold your hand tighter and coddle you through this process, please refer to the Handbook "Feelings of Security for Snowflakes."
Like all of 3 and 6 (but all points have positive aspects for our trial)
DD
Not sure if you have seen this document from 12/13/21
https://www.fda.gov/about-fda/oncology-center-excellence/oce-scientific-collaborative
You sell, I'll buy
We'll discuss a new tractor later
Sir P~
Go outside, get some fresh air and drop the emotional charge around this stock. Realize what you are holding and as you damn well know, this is a new path being paved.
Have the best of things in your life come easy and w/out significant sacrifice? Well, this is the mothership of testing patience and sacrifice.
Decisions made out of pure emotion never end well my friend!! Go get your game on outside and know this will pay back in spades!!
MI~
I am of the opinion this is what's happening with NWBO but certainly don't have all the details.
-The UK decided to join the project as the Medicines and Healthcare products Regulatory Agency (MHRA) will lose the ability to collaborate with EU countries on drug assessments next year. MHRA’s participation will potentially accelerate access to some cancer drugs in the UK by allowing companies to gain approval while targeting the far larger US market.
-Project Orbis is a programme coordinated by the US Food and Drug Administration
(FDA) to review and approve promising cancer treatments. It provides a framework for
concurrent submission and review of oncology products among international partners.
It aims to deliver faster patient access to innovative cancer treatments with potential
benefits over existing therapies across the globe.
The MHRA participate fully in the scheme since 1 January 2021. While the FDA serves
as the primary coordinator for application selection and review, Project Orbis Partners
(POPs) may propose products for inclusion in the scheme.
It involves the regulatory authorities of the following countries:
• Australia (TGA)
• Canada (Health Canada)
• United Kingdom (MHRA)
• Singapore (HSA)
• Switzerland (Swissmedic)
• Brazil (ANVISA)
Each country remains fully independent on their final regulatory decision. Applications
submitted to the MHRA within a Project Orbis procedure are national (GB only)
marketing authorisation applications and variations.
The objective of Project Orbis is to eliminate this delay and allow earlier access to products in countries where regulatory submissions usually lag behind those made in the US. Essentially, one regulatory submission can now yield approvals in multiple different countries.
Look at this Document by FDA for questions on SAP and Orbis Timelines.
https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review
8.The protocol and amendments (a list of major changes for each amendment), SAP, and DMC charter and DMC minutes
The FDA Oncology Center of Excellence commenced the Real-Time Oncology Review (RTOR) pilot project in February 2018 to facilitate earlier submission of topline results and datasets to support an earlier start to the FDA application review. RTOR was initially begun to support supplemental drug applications to add new indications, dosing regimens, or other clinical information to the prescribing information, but was later expanded to include original new drug applications and biological license applications for new molecular entities (NME). From February 2018 to April 2020, RTOR was used to support the submission and review of drug approvals for 20 oncology applications (11 for solid tumor and nine for hematologic malignancy indications). Two were NME drug approvals and 18 were supplemental approvals. All of the applications received priority review and nine (45%) applications had received breakthrough therapy designation status. FDA received the RTOR submissions a median of 5.7 weeks (range 1.7-16.2 weeks) prior to the full application submission. The median time from application submission to FDA approval was 3.3 months (range 0.4-5.9 months). RTOR was also integrated with other review programs including the Assessment Aid and Project Orbis programs. Innovative regulatory processes are critical to expedite the rigorous review of impactful products across the FDA.
https://www.gov.uk/guidance/guidance-on-project-orbis
Products eligible for Project Orbis
New marketing authorisation applications (MAAs) and new indication applications (variations) for oncology products are eligible for Project Orbis.
Selection of products to be included in Project Orbis is coordinated by the FDA, and initial queries received by participating regulatory health authorities are referred to the FDA.
Clinical criteria for FDA selection of applications for Project Orbis include high-impact and clinically significant applications. Project Orbis applications are generally expected to meet the criteria for FDA priority review. Qualifying criteria for FDA priority review include:
-the drug is intended to treat a serious condition
-and if approved, would provide a significant improvement in safety or effectiveness.
Type A
Applications should be submitted concurrently or near-concurrently (within 30 days) to FDA and the POPs. These are termed Type A Orbis (Regular Orbis) and allow for maximal collaboration during the review phase and the possibility of concurrent action with FDA.
Type A Orbis allows for maximal collaboration during the review phase, including:
-sharing of reviews
-exchanging requests for clarification
-participating in multi-country discussions
Can't figure out why we are in a quiet period
Understood and valid concerns given the sheer length this trial has been going on. Times have changed and the FDA along with other RA's recongnize this.
I feel the changes and buyin to the SAP by all 4 RA's was and is crucial.
Also take a look at FDA RTOR program:
https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review
It is my opinion that NWBO has long been in constant communication with the FDA and to how to best approach the success of DCVax in spite of an archaic chemo/rad cancer trial designs.
https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.33205
We will know soon enough if in fact NWBO is paving a new pathway for immunotherapy clinical trials designs/outcomes...hence the quiet period. Change never happens quickly, especially necessary change.
Best to you and the success of this long awaited trial and it's outcome.
Ou...I know you've been in this one for a long time but I want to understand your prediction of the sp. You are long but you think a year from now the sp will be at .35 which essentially means a failed trial?
TIA
In the words of Carlo Rago
Don’t be afraid to use the “C word.”
— Carlo Rago, PhD (@rago_carlo) June 13, 2021
15%+
DCVax-L vs GBM$NWBO
The only action tomorrow will be libations
2022 will be the year you eat crow brah!!
Very interesting article full of relevant info
https://jitc.bmj.com/content/8/1/e000475
Couldn't have said it any better Nick!!
Bravo and GLTU
We just got back from Cambria on Wed night...love that area especially Paso Robles.
Merry Christmas!!
Blessings to you Doc!! Keep up the good fight and all my gratitude for your service
And yet we still have people like Cramer giving his blowhard market assessments everyday on the tube. Obviously enough find him credible to keep him on the air
Meathead!!
It means they're on NWBO time. They actually may not realize that Advent got certified yet...seriously!
I remember leading into the blinded release of data in the Journal of Translational Medicine we were suppose to have a PR all T'D up only to find out that the paper was initially not PR'd by NWBO b/c they (LG acutally) couldn't figure out how some process of getting the PR out. Seriously!! This is actually what happened. LG thought he had it all set up to go out in the morning but I'm sure this doesn's suprise you.
I thought to myself at the time, why don't they have a marketing company handling all of this for them? That was just another moment I realized how understaffed and bootstrapped NWBO was, to a fault.
With all that being said, we have arrived. The finish line is right in front of us and I'm so glad/thankful (in spite of my family thinking I'm crazy) that I have stuck with this investment on a gut feeling that started back in 2013.
It's been my longest investment holding and the one I've been most confident about in spite of enormous frustrations with management.
GLTA...we are very close
HS...I had looked at buying into this back in 2014 but it spiked too quick and I didn't have the $ hop on that rocket ship (had alot of $ in NWBO and EXEL). Hadn't looked at the sp in about 3yrs, shocked to see it at $8 given where it use to be. If I remember correctly this was one of AF's favs!!