Several recent amendments to clinical trials have been made in order to speed up the process and make it more efficient. One notable amendment is for trials that have received approval from the Institutional Review Board (IRB) to proceed with testing, but require changes to the approved protocol.
Previously, any changes to an approved protocol required prior approval from the IRB which could cause further delays. However, as of September 19th, 2018, this requirement has been removed.
Amendments that do not involve changes to an approved protocol do not need prior IRB approval if the amendment does not alter any of the following: risk/benefit assessment; recruitment procedures; informed consent procedures; supervision of research conduct; and avoidance or mitigation of co-research interactions.
This article will go into further detail about these amendments and when they do not require prior IRB approval.
The amendment does not make any changes that would compromise the validity of results from the original trial
Amendments that do not change the protocol do not need prior approval. However, amendments that make changes to the protocol do require prior approval if they make changes that would compromise the validity of results from the original trial.
For example, if a research team is running a trial using a new drug and finds an effective dose, they can amend their protocol to add a control group. This would not require prior Irb approval because it does not change how the new drug works.
Amendments can also change when participants are assessed or what outcomes are measured, as long as the new assessment or outcome is valid. For example, if participants in a trial have been followed up for five years but the amendment only changes follow-up to three years, this does not require prior Irb approval.
The sponsor consults with the irb prior to submission
As mentioned above, amendments that involve changes to an irb-approved protocol do not need prior irb approval if the sponsor consults with the irb prior to submission.
According to the FCA website, this consultation should take place at an early stage, preferably before starting the trial. The sponsor can then discuss changes to the trial protocol with the investigator team and come to an agreement.
The sponsor can also do this after starting the trial if there is widespread consensus that a change should be made. In either case, if there is disagreement between the investigator team and the sponsor about making a change, then the investigation will be stopped.
The only time an amendment requiring changes to the trial protocol requires prior approval from the IRB is if there is new harm or exposure of individuals taking part in the study.
The sponsor provides a detailed description of all changes in the revised protocol
The sponsor must provide a detailed description of all changes in the revised protocol. This includes changes to procedures, interventions, assessments, and circumstances under which the study is stopped for efficacy or safety.
Amendments that do not require prior IRB approval if the sponsor provides a detailed description of all changes in the revised protocol. This includes changes to procedures, interventions, assessments, and circumstances under which the study is stopped for efficacy or safety.
The updated protocol must be submitted to the IRB within five business days of submission to FDA. The IRB then has five business days to review and approve or disapprove the updated protocol. If there are unresolved concerns on the part of the IRB at this point, they have two business days to convene a review board meeting to address these concerns.
The sponsor provides evidence of public posting of the revised protocol before submission to the irb
A sponsor may submit an amendment to a clinical trial protocol that includes changes to the approved drug, drug dosage, or other elements of the trial without prior IRB approval if:
The sponsor submits evidence of public posting of the revised protocol before submission to the IRB; and The sponsor submits a revised protocol to the IRB no more than 30 days after public posting.
This exception applies only to amendments involving changes to an approved investigational drug protocol—not amendments involving changes in administration of investigational products, additional investigational products, or non-investigational drugs or devices.
The protocol amendment must be publicly posted for at least 5 business days prior to submission to the IRB. Posting may be on the sponsor’s website, a peer-reviewed scientific journal website, PubMed®, a government agency website (such as FDA), or another external, trusted site with a reliable URL.
The sponsor submits an explanation of why approval is not required with the revised protocol
According to the guidance, if the sponsor submits an explanation of why approval is not required with the revised protocol, then no prior IRB approval is needed for amendments involving changes to IRB-approved protocols.
This explanation must be reasonable and justified, and can be based on one or more of the following:
That the changes are minor or technical in nature, That the changes do not alter the risk/benefit balance of the protocol, or That the changes were made due to circumstances outside of the control of the investigator(s) or research team conducting the study.
The last point is an important one – it means that unforeseen events (like a device malfunction) can be taken into consideration when making changes to a trial.
For example, if a device needed in a trial malfunctions after participants have been recruited and before they have participated in the intervention portion of the trial, then researchers can replace it without needing IRB approval for these revisions.
Sponsors should submit amendments within 30 days of making them and notify investigators within 10 days after that date
Amendments should include a description of the change and when it was made. They should also include a description of the study design and changes to the protocol that were made since its approval by the IRB.
Amendments that do not involve changes to approved protocols do not need prior IRB approval if they meet these requirements. However, all amendments must be reviewed by the IRB before implementation.
Sponsors are required to notify investigators within 10 days after making an amendment, so investigators should always check for updates on amendments. Changes made due to safety concerns must be notified immediately.
Investigators are encouraged to ask questions about amendments so that they are aware of any changes that may affect their participation in the study. Questions about amendments can be directed to the study coordinator or research staff.
Investigators should keep copies of amended protocols and records regarding receipt, review, and compliance with them for at least 3 years after completion or termination of study participation or 1 year after notification by sponsor or institution of adverse events
Amendments to clinical trials may be required for a number of reasons. These include changes in the protocol methodology, regulatory requirements or guidance, and sponsor request.
Amendments that do not require prior approval by the IRB include those that:
• Do not alter any additional risks to study participants or changes in benefits to participants or the investigator’s responsibilities; and
• Are editorial or clerical in nature (such as correcting a spelling error).1
The IRB will evaluate any amendment requested by the investigator to determine if it requires prior approval. Investigators are encouraged to work with their local IRB to determine whether an amendment requires prior approval.
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