The trial was not stopped over a futile IA. Instead, it was stopped over something to do with "screening". I think I can prove it. :)
The Company provided insight that the process for screening the additional patients required an IRB renewal. Clinical sites, as we know were not closed. And so the only reason to require a renewal -- which incidentally the FDA has not agreed to even on the date of the press release -- is if the Company was going to need to update the consent form to cover a protocol risk. And so, I truly believe that when the Company changes the WBC inclusion criteria, it potentially subjected patients to increase risk to obtain their WBC precursors.
Off the press release, suggesting it was "screening" IRB approvals were needed that caused the halt -- which is in line with what the company told us.
"To date, the regulators have not agreed to remove the partial hold, but have allowed all of the patients in the Trial to continue being treated in accordance with the Protocol. The Company is pursuing ongoing dialog with regulators. However, at this point the Company believes that the potential benefits that could be obtained from enrolling the final 17 patients would not be worth the time it would take, as the process of re-starting and re-training the sites (including through Institutional Review Board renewals) for further enrollment would take months, followed by further months for the recruitment itself.
Accordingly, the Company is no longer seeking to enroll the last 17 of the 348 patients. Rather, the Company is focused on accumulation of the “events” necessary for the Trial endpoints." -- December 8, 2016 PR
According to the protocol, such consent forms are needed with new protocols, including the inclusion WBC change in August 2014. When the company initiated the WBC change, they update regulatory approvals. But we have no record of them changing the US consent form to cover possible risk of obtaining leukaphersis with lower blood counts. The consent copies I have date further back, none from 2014. And yet, we learned recently from the company that recruitment did not stall to a halt in 2014 period.
"If an amendment to the protocol changes the patient participation schedule in scope or activity, or increases the potential risk to the patient, the informed consent document must be amended. Any amended informed consent must be reviewed by the sponsor or designee and approved by the IRB/EC prior to use. The revised informed consent document must be used to obtain re-consent from any patients currently enrolled in the study if the patient is affected by the amendment, and must be used to document consent from any new patients enrolled after the approval date of the amendment." -- protocol
The new protocol was approved in early August 2014. And so, they did not obtain their annual renewal when August 2015 came around.
"The PI or designee is responsible for informing the CA/IRB/IEC of the progress of the study and for obtaining annual CA/IRB/IEC renewal." -- protocol
And so when the following year to obtain IRB approval came along, a practice that they had gone through several times already with no issues, yet this time they were denied due to possible SAE seen on screening eCRF.
Something related to screening, from the prior year's initiated new protocol on WBC inclusion criteria caused a screening "red flag". While we know the study main arm does not have significant SAE, that does not mean screening (before enrollment) didn't encounter any of its own. In light of the December 8, 2016 press release statement of needing new IRB, I'm under the impression screening eCRF revealed consent for newly added Leukaphersis risk (lower WBC) was necessary to continue screening patients, but permission to subject patients to additional screening risk, to date, had not been obtained.
Additional sections of the protocol:
"Follow-up information, such as laboratory reports, discharge summaries, autopsy reports, and information concerning outcome of the event should be submitted only for SAEs deemed at least possibly related to study drug or study procedures such as blood draws, leukapheresis, or study drug injections, with a revised Serious Adverse Event Report Form as soon as the information becomes available." -- protocol
And
"investigators are required by US regulations as described in 21 CFR §312.66 (Assurance of IRB Review) and EU safety reporting guidelines, to notify their Competent Authorities (CA) and Institutional Review Board (IRB)/Independent Ethics Committee (IEC) promptly of all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that the investigator will not make any changes in the research without CA/IRB/EC approval, except where necessary to eliminate apparent immediate hazards to human subjects. This means that the investigator will report to the CA/IRB/EC all SAE occurring at the investigator’s study site(s). In addition, investigators are also required to report to their CA/IRB/EC all SAE that are immediately reportable to this study (i.e., Expedited Safety Reports/SUSARs), regardless of when the SAE occurred. In these situations, the sponsor or its designee will provide the necessary information to the investigator to report to their CA/IRB/EC in the form of an Expedited Safety Report Letter." --protocol
And
"All subjects are informed of the nature of the program, its possible hazards, and their right to withdraw at any time, and each patient signs a form indicating their consent to participate prior to receiving any study-related procedures (see Appendices D and E)." -- protocol
And
"16.1. COMPETENT AUTHORITIES/INSTITUTIONAL REVIEW BOARD/ETHICS BOARD
This protocol and relevant substantive data must be submitted to the appropriate
CA/IRB/IEC for review and approval before the study can be initiated. Amendments to the protocol are also submitted to the CA/IRB/IEC prior to implementation of any
change. The Sponsor must receive a letter that documents CA/IRB/IEC approval prior to initiation of study. The PI or designee is responsible for informing the CA/IRB/IEC of the progress of the study and for obtaining annual CA/IRB/IEC renewal. When the study is completed the CA/IRB/IEC must be informed; the PI or designee should provide the CA/IRB/IEC with a summary of the results of the study. The PI or designee must notify the CA/IRB/IEC, in writing, of any SAE (see Section 11.2)." -- protocol
And
"17.10. INFORMED CONSENT
The PI assumes the responsibility of obtaining written informed consent for each patient or the patient’s legally authorized representative before any study-specific procedures are performed. Patients meeting the criteria set forth in the protocol will be offered the opportunity to participate in the study. To avoid introduction of bias, the investigator must exercise no selectivity with regard to offering eligible patients the opportunity to participate in the study. Patients or parents/legal guardians of all candidate patients will receive a comprehensive explanation of the proposed treatment, including the nature of the therapy, alternative therapies available, any known previously experienced adverse reactions, the investigational status of the study drug, and other factors that are part of obtaining a proper informed consent. Patients will be given the opportunity to ask questions concerning the study, and adequate time to consider their decision to or not to participate. Informed consent will be documented by the use of a written consent form that includes all the elements required by FDA regulations and ICH guidelines. The sponsor or designee will review the informed consent prior to submission to the IRB/EC. The form is to be signed and dated by the patient or patient's legally authorized representative and by the person who administers the consent process. A copy of the signed form will be given to the person who signed it, the original signed consent form will be filed with the patient’s medical records, and copy maintained with the patient’s study records. The date and time of time of the informed consent must be recorded in the source documents.
If an amendment to the protocol changes the patient participation schedule in scope or activity, or increases the potential risk to the patient, the informed consent document must be amended. Any amended informed consent must be reviewed by the sponsor or designee and approved by the IRB/EC prior to use. The revised informed consent document must be used to obtain re-consent from any patients currently enrolled in the study if the patient is affected by the amendment, and must be used to document consent from any new patients enrolled after the approval date of the amendment." -- protocol
