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  • 1.  Clinical Trial - Substantial amendments

    This message was posted by a user wishing to remain anonymous
    Posted 17-Jan-2023 09:33
    This message was posted by a user wishing to remain anonymous

    Hi Team,

    Can anyone please guide me on Clinical Trials - substantial amendments
    These amendments are similar to post approval changes? any set guidelines for regulated market/s? are they the part of Clinical trial application procedure OR to be submitted separately as variation?

    Any feedback would be greatly appreciated.

    Thanks and Regards.

  • 2.  RE: Clinical Trial - Substantial amendments

    Posted 18-Jan-2023 03:54
    Hello Anon,

    It depends on the jurisdiction you are asking about because most countries have individual requirements for reporting on and changes to clinical trials/investigations.  This also depends if you are talking about a drug or device.  And if a device, what type of device because as example in the United States there are Non-Significant Risk devices and Significant Risk devices.  While this does not depend so much on the substantial change being made, it can impact notification to Institutional Review Board (IRB) and/or FDA.  Many of the regulated countries do have processes for making substantial change/amendments to clinical trials, but would have to know the country.

    Richard Vincins ASQ-CQA, MTOPRA, RAC
    Vice President Global Regulatory Affairs

  • 3.  RE: Clinical Trial - Substantial amendments

    This message was posted by a user wishing to remain anonymous
    Posted 18-Jan-2023 08:40
    This message was posted by a user wishing to remain anonymous

    Thank you for your reply.

    I'm referring to drugs and biologics. Would like to know more on the general process, especially clinical trial amendment process in regulated market like US and EU.
    whether, an amendments to the clinical trials to be approved by FDA and/or IRB before implementation?

    Guidance on general process would be appreciated.

    Thanks and Regards.

  • 4.  RE: Clinical Trial - Substantial amendments

    Posted 18-Jan-2023 11:36
    Edited by Marissa Berry 18-Jan-2023 11:37
    In my experience, any protocol amendment, no matter how minor or substantial, should always be reviewed and approved by an IRB or ethics committee prior to implementation.

    With respect to the FDA, in general, smaller/more administrative protocol amendments don't need prior approval from the FDA (but should still be approved by an IRB). However, a good practice is to submit the updated protocol with your annual report (if you didn't already submit it at the time of the amendment), just to make sure the FDA has access to the current version of the protocol.
    As noted in 21 CFR 312.30, if your protocol amendment may significantly affect the safety of subjects (any phase), the scope of the investigation (phase 2 or 3), or the scientific quality of the study (phase 2 or 3), then you should submit the amendment to the FDA prior to implementation. Although it's not a specific regulatory requirement, most of the companies and colleagues I've worked with generally give the FDA a courtesy 30 calendar days to provide feedback on the amended protocol prior to implementation. You can note in the cover letter of your submission when you plan to implement the changes so the FDA knows that, if they have concerns, they should try to communicate them before that date.

    My EU experience is limited, so I will defer to the comments of others regarding protocol amendment submissions to EU health authorities.

    Marissa Berry, Ph.D., RAC
    Senior Manager, Regulatory Strategy
    Durham, NC
    United States

  • 5.  RE: Clinical Trial - Substantial amendments

    Posted 18-Jan-2023 07:42
    Edited by Damien Tiller 18-Jan-2023 07:42
    As Richard said above, it does depend on jurisdiction, but I wondered if these links from the UK HRA might help you. 
    Information about when you need to submit substantial amendments to a clinical trial including changes to the trial sponsor or legal representative, Investigational medicinal product certification and importation.

    Amendments are changes made to a research project after approval from a review body has been given. Find out whether you need to notify the review bodies from whom you have received approvals.

    Examples of substantial vs non-substantial:

    Damien Tiller
    Director of Quality
    Lindus Health
    United Kingdom

  • 6.  RE: Clinical Trial - Substantial amendments

    Posted 18-Jan-2023 09:56
    Clinical trials in the EU are currently regulated under REGULATION (EU) No 536/2014.  Under this regulation, a 'Substantial modification' requires submission of an amendment to the protocol, which means any change to any aspect of the clinical trial which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial. Sponsors tend to be conservative on interpretation of "substantial impact."

    Clinical trials in the US are regulated under 21 CFR 312. FDA does not use the concept of "substantial amendment" but 312.30 Protocol Amendments gives some examples of changes that would require submission of an amendment.

    A general difference between EU and FDA requirements for protocol amendments is that EU requires approval of a substantial amendment before implementation (unless it is for safety purposes), whereas FDA allows amendment changes to occur without prior approval.

    Glen Park PharmD
    Vice President, Regulatory Affairs and Quality Assurance
    New York NY
    United States