Background: Our family, like many others, experienced the devastating effects of blood cancer, Acute Myeloid Leukemia (AML). After watching our loved one suffer, we understand the urgency needed to ADD more effective treatment options for people with AML; especially for the elderly who have no other treatment options. 

Since 2016, Actinium Pharmaceuticals Inc. conducted a Phase III clinical trial to determine the efficacy and safety of Iomab-B. "Iomab-B is a first-in-class targeted radiotherapy intended to improve patient access to potentially curative bone marrow transplant (BMT). Multiple studies demonstrated increased survival in patients receiving BMT, however, an overwhelming majority of patients with blood cancers do not receive BMT as current approaches do not produce a remission, which is needed to advance to BMT, or are too toxic. Studied in over 400 patients, prior studies with Iomab-B demonstrated nearly universal access to BMT, increased survival and tolerability in multiple clinical trials including the completed Phase 3 SIERRA trial in patients with active (leukemic blasts >5%), relapsed or refractory acute myeloid leukemia (r/r AML) age 55 and above."

Durable Complete Remission (dCR) >6-months was the primary endpoint of the trial and was met with a high degree of statistical significance (p<0.0001). 75% of patients (44/59) receiving Iomab-B achieved an initial remission 30 days after their BMT compared to 6.3% of patients (4/64) in the control arm. 22% of the patients receiving Iomab-B maintained dCR lasting >180 days while none on the control arm achieved dCR. According to a 2010, this endpoint is significant because it is one of the five pretransplantation variables that can predict long-term survival in selected patients with acute leukemia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917308/

Overall survival (OS) at 1 year was the secondary endpoint. This endpoint was not met based on the total intent-to-treat (ITT) population in the control arm. This was due to the decision by Actinium Pharmaceuticals Inc. to allow patients in the control arm to "crossover" and be "rescued" with Iomab-B when they failed to get a remission. As a result, median OS in the Iomab-B group was similar to that in the control group. However, in an exploratory analysis that excluded "crossover" subjects from the ITT Analysis Set, the median OS was 6.4 months for the Iomab-B group and double that of 3.2 months for the control group.
https://www.actiniumpharma.com/product-pipeline/iomab-b 

Basis for Petition:
On August 5, 2024, Actinium Pharmaceuticals Inc. said the "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." https://ir.actiniumpharma.com/press-releases/detail/486/actinium-provides-regulatory-update-on-planned-bla-filing 

According to FDA AML Guidance to Industry 2022, there are three AML treatment paths: Curative, Non-Curative, and Palliative. Curative/Non-Curative includes OS, EFS, and RFS endpoints while palliative includes dCR as an acceptable endpoint. However, dCR is the only endpoint variable in these treatment paths that is predictive of long-term survival in selected patients with acute leukemia. In 2024, additional studies suggested that Minimal residual disease (MRD) is an essential tool for disease monitoring, relapse prognosis, and guiding treatment decisions. However, there is a lack of clarity and understanding in the FDA guidance on how these variables significantly impact the survival outcomes of AML patients who receive a bone marrow transplant. The guidance also disregards the fact that SIERRA met the primary endpoint of dCR.
https://www.fda.gov/media/162362/download

The FDA recommended another "additional head-to-head randomized clinical trial demonstrating overall survival benefit with Iomab-B." "The proposed new study will not allow patients to crossover from the control arm." However, the FDA recommendation puts providers at risk and doesn't allow them to humanely treat a patient if they fail the control arm. This is why investigators and a Scientific Advisory Board recommended a "crossover" in the original trial in 2017.

Since the SIERRA Phase 3 Trial lasted for 6 years, numerous AML patients have died waiting to access to Iomab-B. It is clear this was due to a lapse in FDA AML Guidance to Industry and a lack of understanding the variables that affect AML patient bone marrow transplant survival outcomes.

Citizen Petition - 21CFR10.30

A. Action Requested.
(1) Request 1. The FDA accept Actinium Pharmaceuticals BLA submission so that it can be considered for approval based on the achievement of the primary endpoint of durable complete remission, event-free survival secondary endpoint, and overall improved safety. Use the exploratory endpoint of Crossover vs Control OS data to further support the primary endpoint in lieu of another trial. Allow the medical professionals on the Oncology Advisory Board to conduct a vote. Give the ability to initiate the Early Access Program so patients can be treated NOW with Iomab-B. 
(2) Request 2. Update the 2022 FDA AML Guidelines to Industry to account for durable complete remission as an acceptable and adequate efficacy endpoint for a BLA submission. 

B. Statement of Grounds.
(1) Overall Survival Analysis. As the SIERRA study demonstrated, those patients who achieved the primary endpoint of durable complete remission with Iomab-B in both Iomab-B and Crossover Arms survived longer than those not treated with Iomab-B. Targeted precision radiotherapy against a malignant cell is better than radiating both healthy and malignant cells. 
OS Exploratory Endpoint Data:  
Iomab-B Arm: 29 days to HCT, 6.4 months median OS (n=76)
Iomab-B Crossover Arm: 61.6 days to HCT, 7.1 months median OS (n=44)
Conventional Care: 66.5 days to HCT, 3.2 months median OS (n=33)
Over the last 6 years, too many elderly patients with AML have lost their lives waiting to access Iomab-B.

(2) FDA AML Guidance to Industry lacks pretransplantation efficacy endpoints and guidance. 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, the guidance does not include durable Complete Remission (>6 months) as its own efficacy endpoint even though the SIERRA trial design was approved by the FDA with the dCR primary endpoint in 2016. According to Duval, dCR is 1 of 5 predictive factors of overall survival in AML patients with relapsed/refractory AML with subsequent 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.  
https://www.fda.gov/media/162362/download
https://pubmed.ncbi.nlm.nih.gov/20625136/ 
https://ashpublications.org/blood/article/144/3/245/516962/Transplant-MRD-and-predicting-relapse-in-AML

(3) Another Trial FDA Recommendation. The FDA-recommendation to conduct another overall survival trial is inhumane and delays expanded access to care. 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 has already proved to be efficacious, safe, and offer a survival benefit with its use. 

Another trial based on overall survival further delays Expanded Access for patients currently waiting to use Iomab-B supported by the medical community. For example, on July 7, 2023, change.org "Give Patients with Refractory Illness Early Access to drugs waiting FDA Approval" was posted for a NY man 9/11 first responder with AML. "His team of Oncologists at Memorial Sloan Kettering all said the drug Iomab-B would be his best option for treatment." Unfortunately, he passed away in October 2023. The SIERRA showed patients lived longer with Iomab-B than without. 

C. Environmental Impact. Claim of categorical exclusion under § 25.31 Human drugs and biologics.

D. Economic Impact. By accepting the Iomab-B BLA for approval consideration instead of conducting another overall survival trial, AML patients can be treated now with expanded access to Iomab-B. It allows Iomab-B to be considered by the Oncologic Drugs Advisory Committee to validate that Iomab-B is efficacious, safe, and offers a survival benefit with its use.

According to CIBMTR.org, there were 3,000 AML related bone marrow transplants conducted in the United States in 2022. According to SEER Cancer.gov, in 2021, an estimated 75,266 people were living with acute myeloid leukemia in the United States. It is estimated 11,220 deaths in 2024. Between 1992 to 2022, the observed death rate is between 2.3 to 2.6 per 100,000. In a claims-based study conducted presented at ASH 2023, 39% of 5135 newly diagnosed patients and 31% of 934 patients received no treatment for AML. 
https://ash.confex.com/ash/2023/webprogram/Paper178755.html

Join us in pressing the FDA for prompt action. Sign our petition today.