Actinium's "Cross-over" Decision, FDA AML Policy Change, and an Ethical Debate

June 2016. NIH reports Actinium's trial design.

Primary Outcome Measures
Durable Complete Remission (dCR)
[Time Frame: 6 months from hematopoietic stem cell transplant (HCT)]
This is 1 of 5 pretransplantation variables that significantly influence survival:
https://pubmed.ncbi.nlm.nih.gov/20625136/

Overall Survival (OS)
[Time Frame: 1-year period following treatment with study drug]

The primary objective of this study is to demonstrate the efficacy of Iomab-B, in conjunction with a protocol-specified allogeneic hematopoietic stem cell transplant (HCT), versus Conventional Care.

Interventional Study Model: Parallel Assignment (not a cross-over design) 
A type of intervention model describing a clinical trial in which two or more groups of participants receive different interventions. For example, a two-arm parallel assignment involves two groups of participants. One group receives drug A, and the other group receives drug B. So during the trial, participants in one group receive drug A "in parallel" to participants in the other group, who receive drug B.
https://clinicaltrials.gov/study/NCT02665065?term=iomab&rank=1

December 2017. "Actinium announced that it will amend the protocol of the SIERRA trial to expand the salvage chemotherapy regimens available in the control arm of the study, following the feedback from investigators at trial sites and the advice of its Scientific Advisory Board that was convened during the recent ASH meeting." "Actinium... reported...doses...to all patients that have crossed over to the Iomab-B arm from the control arm thus far."
https://ir.actiniumpharma.com/press-releases/detail/258/actinium-pharmaceuticals-provides-update-on-pivotal-phase-3 

August 2018. "We'll also be making it easier for patients on the Conventional Care arm who have disease progression to access Iomab-B treatment."
https://ir.actiniumpharma.com/press-releases/detail/291/actinium-to-provide-update-on-pivotal-phase-3-sierra-trial

August 2020.  FDA publishes Acute Myeloid Leukemia:  Developing Drugs and Biological Products for Treatment Guidance for Industry DRAFT GUIDANCE. The FDA states the following efficacy endpoints: Overall Survival, Event-Free Survival, Relapse-Free Survival.
https://www.fda.gov/media/140821/download

Under Treatment without curative intent - Treatments with no expectation of a survival plateau, but where the goal is to extend survival or greatly improve durable CR relative to a control, are considered treatment without curative intent for AML. 
" FDA has accepted OS and EFS as clinical endpoints that represent clinical benefit for traditional approval for treatments without curative intent."
"Durable CR may also support traditional approval depending on the disease setting and benefit-risk ratio."

 Under Treatment of AML with Palliative Intent - "FDA has accepted durable CR and durable CR/CRh with TI as clinical endpoints that represent clinical benefit for traditional approval for treatments with palliative intent."

October 2022. Top-line Results are released for the SIERRA trial and meet the primary endpoint of durable complete remission (dCR) with statistical significance.
https://ir.actiniumpharma.com/press-releases/detail/428/actinium-announces-positive-top-line-results-from-pivotal

October 2022. FDA publishes Acute Myeloid Leukemia: Developing Drugs and Biological Products for Treatment Guidance for Industry FINAL GUIDANCE. 
https://www.fda.gov/media/162362/download

November 2023. Actinium presents Overall Survival data comparing a subpopulation of TP-53 mutated patients, Iomab-B vs. Control. 
https://ir.actiniumpharma.com/press-releases/detail/461/actinium-announces-oral-presentation-at-ash-annual-meeting

August 2024. Actinium press release states "FDA determined that the Phase 3 SIERRA trial is not adequate to support a BLA filing for Iomab-B despite its statistically significant primary endpoint" "Additional head-to-head randomized clinical trial demonstrating overall survival benefit with Iomab-B is required by FDA to support a BLA filing" and "the proposed new study will not allow patients to crossover from the control arm"

Actinium's "Cross-over" Decision. At the recommendation of investigators at trial sites and the advice of its Scientific Advisory Board that met at ASH 2017, Actinium decided to alter the protocol and offer Iomab-B to those in the control arm. While this could be considered an ethically good reason supported by treated/enrolling patients and medical treatment professionals, the study design remained a Parallel Assignment (not a cross-over design) according to clinicaltrials.gov.

FDA AML Guidance to Industry Policy Change. In 2020 and 2022, draft and final guidance respectively was published by the FDA that excluded durable complete remission as an efficacy endpoint. However, it was included as an acceptable endpoint under palliative intent. The FDA already approved Actinium's trial design in 2016 based on durable complete remission and overall survival.

Ethical Questions.
Was Actinium's decision ethical to offer "cross-over" Iomab-B to control arm patients according to the investigators and Scientific Advisory Board advice, thus "confounding" the secondary endpoint of overall survival? 

Was the FDA decision ethical in excluding durable complete remission as an efficacy endpoint, except under the premise of treatment of AML with palliative intent, after knowingly approving it in the SIERRA trial design in 2016? Is the pre-conditioning treatment considered curative, non-curative, or palliative based on FDA AML guidance in 2016 vs. 2022?

Was the FDA recommendation for another trial to be conducted without a cross-over "Iomab-B" an ethical recommendation? Is another trial necessary to come to the same conclusion? Is overall survival the right endpoint when the outcome is based in conjunction with all other factors that affect the overall survival curve of bone marrow transplants?   

Was Actinium's decision ethical to continue to promote plans to submit a BLA/offer expanded access "compassionate use" after failing to meet the overall survival secondary endpoint based on the intent to treat the control arm population?

Debate.
In light of the ethical questions, we need to reiterate that the primary objective of this study was to demonstrate the efficacy of Iomab-B. Simply, was that accomplished? 

Overall Survival. Given the ethical questions about overall survival between Actinium and the FDA, what was made clear in terms of overall survival outcomes: 110 of 153 patients treated with Iomab-B had a median overall survival that lasted longer than those that were not treated with Iomab-B. This was made apparent in the "exploratory endpoint" when survival subgroups were divided and efficacy with the use of Iomab-B was determined. 

Durable Complete Remission. Given the ethical question on FDA AML policy change, after the SIERRA trial was complete, Iomab-B demonstrated that it met the primary endpoint of the original trial design with statistical significance. The efficacy of Iomab-B was demonstrated because patients who achieved the primary endpoint lived longer than the control. Since the 2010 study by Michel Duval and use of the "Duval Score", durable complete remission is a factor that influences the survival outcome of r/r AML bone marrow transplant. 

Elevated to a Congressional Issue.
On April 14, 2024, Dr. Robert Califf updated the Committee on Oversight and Accountability on the "Oversight of the US FDA"
https://www.fda.gov/media/177681/download

(1) "FDA’s workforce is dedicated to helping Americans face extraordinary challenges and navigate extraordinary opportunities. We are responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs"

(2) "The Agency is charged with advancing the public health by helping to expedite innovations that make medical products more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medical products and foods to maintain and improve their health."

(3) "The dramatic improvement in cancer and rare disease therapies and the COVID-19 response shows that if we are strategic in pursuit of the science, we can move disease outcomes in a positive direction, particularly if we combine improved screening, diagnosis, and therapy with access and affordability.

Did Iomab-B improve safety and demonstrate efficacy? 
Yes. Iomab-B proved to be a safer treatment with less incidence of GVHD, Sepsis and Mucositis. The FDA-approved primary endpoint of durable complete remission was achieved and the secondary endpoint of overall survival, following additional exploratory analysis, was met with double overall survival at 1 year.

Does the data justify acceptance of a BLA submission? What do we do with the known data of the 110 of 153 patients treated with Iomab-B in terms of their efficacy OS, EFS, and safety outcomes? 
Yes since the primary endpoint of dCR was met. Additional exploratory analysis with the SIERRA trial data can be conducted to understand why 110 patients treated with Iomab-B + HCT and Iomab-B + Conventional Treatment outcomes showed better OS, EFS, and safety than those not treated with Iomab-B.

Do FDA AML Guidelines need to be updated to account for dCR as an efficacy endpoint since it is 1 of 5 pre-transplant factors that influence survival outcomes in bone marrow transplants?
Yes. Current guidance states "It is common for multiple efficacy endpoints (i.e., OS, EFS, CR) to be assessed in a clinical trial for AML. The statistical analysis plan should prespecify a multiple testing strategy for important secondary endpoints that adjusts for multiplicity conditioned on demonstrating a positive outcome for the primary endpoint. However, current guidance does not consider durable Complete Remission (>6 months) as an efficacy endpoint. dCR is a significant factor according to the Duval Score research because it is a predictor of overall survival in AML patients with relapsed/refractory AML undergoing bone marrow transplant. The SIERRA trial showed between a 60-90% overall survival probability for patients treated with Iomab-B that had a dCR >180 days.
Additional factors such as MRD+/- should also be added as efficacy endpoints since it is also a prognostic predictor of survival outcomes as well.
https://pubmed.ncbi.nlm.nih.gov/20625136/ 
https://ashpublications.org/blood/article/144/3/245/516962/Transplant-MRD-and-predicting-relapse-in-AML

Is conducting another trial to determine overall survival data expediting Iomab-B to patients and helping the public get the information they need to use Iomab-B? 
No, another trial does not expedite Iomab-B to patients, and the SIERRA trial in the exploratory overall survival analysis demonstrated there was an efficacious, safe clinical benefit to using Iomab-B. The decision by Actinium to add a "cross-over" and the decision of 40 patients/doctors to accept the "cross-over" and their improved outcomes demonstrate that patients benefit from the use of Iomab-B now.    

Is delaying further access to Iomab-B by conducting another trial improving acute myeloid leukemia patient outcomes in a positive direction?
No. The new trial design does not permit "crossover" which was the reason, at the recommendation of investigators at trial sites and the advice of its Scientific Advisory Board that met at ASH 2017, Actinium decided to alter the protocol of SIERRA and offer Iomab-B to those in the control arm. It is inhumane to not give a control arm patient a chance to survive when Iomab-B proved to be efficacious, safe, and offer a survival benefit with its use.