Clinical Trials & REMS in the Time of Corona: FDA & MHRA Advice and Guidance

A word on Corona

Well, we are living in the time of the Corona pandemic.  Coming from the pharmaceutical world, I find it interesting now that everyone from the public, academe and governments are looking to the pharmaceutical industry to 1) make and supply lots of masks, 2) make and supply lots of respirators 3) find better and faster tests for Corona including bedside PCR and fast serology 4) find a treatment/cure for Corona and a vaccine to prevent the infection in the first place.

Gone is the talk of evil drug companies, predatory pricing, capitalist profiteers etc. None of this is surprising.  The industry, not just for the good of humanity, but also to save their own lives and profits are indeed rushing to do this.  After all, the government doesn’t have factories to make masks or respirators. It is highly likely the industry will respond and do it well. Governments are already relaxing some standards and requirements for approval to get these products to the people asap.  Still, it may take many months and many lives but it will happen and a “new normal” will be reached.  Then the harping will start again about drug pricing, corporate greed etc. This is the human condition. This certainly does exist but the bottom line is that the pharma industry is a net contributor to the world.

Clinical Trials FDA

The FDA and MHRA (and others) have issued two documents on clinical trials now underway for non-Corona related clinical trials.  First the FDA issued a guidance entitled FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic Guidance for Industry, Investigators, and Institutional Review Boards  (See https://www.fda.gov/media/136238/download for the pdf).

The point of this guidance is to “assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic.”  Because of the emergency, no public comment was sought in advance but comments are still welcome.  FDA reminds readers that this is a guidance and is not obligatory.

The agency realizes issues may arise in clinical trials from quarantines, site closures, travel limitations, supply chain problems with drug product and COVID-19 infection in trial staff and/or subjects etc.  FDA realizes there will be protocol deviations and changes to protocols.  Several points are made:

On-going trials

• “Ensuring the safety of trial participants is paramount.” Changes and modifications should be customized for each circumstance. Participants must be kept informed of such changes.
• Sponsors, investigators and IRBs/ECs may determine that subjects should or should not continue in the trial.
• If subjects cannot get to the site for trial visits the sponsors should consider alternate methods for safety assessments including phone calls virtual visits, alternate locations such as labs or imaging centers. Determine if in-person visits are really necessary to ensure the safety of the subjects. Again, keep the subjects’ safety paramount.
• Participants who no longer have access to the drug product or site may need additional safety monitoring after withdrawal.
• Alterations in the protocol and processes should be customized to each protocol and local situation. If the study cannot be properly conducted, it may be necessary to stop the trial or even withdraw subjects.
• COVID-19 tests that may be mandated by local health care systems involving subjects in a trial do not need to be put into the protocol as amendments unless the sponsor is incorporating the data collected as part of a new research objective.Author’s comment: It is probably still worthwhile to mention such additional tests and results in the patient’s case records and note in the protocol (as an amendment perhaps) that such tests may be done and documented.
• Normally, changes in the protocol cannot be implemented till IRB and sometimes FDA approval is granted. However, if changes must be made to minimize or eliminate immediate hazards and to protect the life and well-being of subjects, the changes may be made before IRB and/or before filing and amendment to the IND or IDE.  However, such changes must be reported afterwards. Sponsors, investigators and IRBs should work together closely, early and frequently.
• New or alternative processes should be consistent with the protocol where possible and all changes should be well documented. Restrictions in the protocol related to COVID-19 should be explained noting duration of the changes and impact on all concerned.
• For drugs administered by the subject him/herself, alternate means may be made to get the drug to the subject. For situations where administration is done in a health care setting where changes are necessary, FDA should be consulted.
• For efficacy changes, consult FDA. See the guidance for further details.
• If the data management and/or statistical analysis plans are to be amended, the sponsor should consult with FDA. Prior to database lock, address how protocol deviations will be handled in the prespecified analyses.
• If on-site monitoring visits are not possible, sponsor should consider other means of remote monitoring.

Trials where policies and procedures are not yet in place

• Sponsors, investigators and IRBs should implement policy and procedures or revise existing ones to describe what will be done to protect subjects and to manage study conduct in the light of COVID-19 control measures. This should cover all aspects of the trial.  Protocol amendments may be required.

Clinical study report

• The report should note all measures implemented as a result of COVID-19 control measures.
• A listing of all participants affected with subject ID number and site with a description of the altered situation.
• Analyses and discussions should address the implemented contingency measures in the safety and efficacy sections.

Comments: All of this is very reasonable and understandable.  FDA is indicating it will be flexible and that changes to trials will be necessary and will alter analyses and conclusions.  How FDA will respond at NDA approval time regarding “weakened” studies remains to be seen.

Clinical Trials MHRA

On its blog, the MHRA on March 3, 2020 gave its advice.  It noted initially, similar to FDA above, that changes will be necessary due to Corona.  See:    https://mhrainspectorate.blog.gov.uk/2020/03/12/advice-for-management-of-clinical-trials-in-relation-to-coronavirus/ .   They note:

• There will be an increase in protocol deviations; please ensure they are well documented, to enable appropriate evaluation for the trial.
• An increase in protocol deviations in relation to Coronavirus will not constitute a serious breach, therefore there is no need to report this unless of course patients are being put at risk.
• Alternate mechanisms of monitoring and oversight will likely be required such as phone calls, video calls to ensure subject well-being. MHRA advises a brief risk assessment and documentation of the impact of this, with consideration of prioritization of critical activities such as safety reporting. Remote monitoring can be considered; however, this should not place an extra burden on trial sites, and subjects must consent to any sharing of their personal information outside the trial site.
• Prospective protocol waivers remain unacceptable. Do not omit eligibility requirements (inclusion and exclusion). Patient safety remains the priority.
• If the safety of a trial subject is at risk because they cannot complete key evaluations or adhere to critical mitigation steps, then consideration to discontinuing that subject must be discussed. This may apply to the whole trial in some cases.  Use of Urgent Safety Measures or temporarily stopping a trial or trial recruitment may be the way to proceed.
• Most temporary halts need not be submitted to the MHRA but this will be addressed in a further guidance by MHRA.
• Sponsors should consider the risk/benefit of conducting trials in medicines that act as immunosuppressants, for example in early phase healthy volunteer trials, where there is no therapeutic benefit to the volunteer, but taking part in the trials does pose a risk of infection.
• If processes require wet-ink signatures, consider alternative methods of demonstrating approvals, such as email confirmation. Inspectors will take a pragmatic approach to this, but you may want to consider an SOP deviation to cover this in the interim.

Comments: This is quite similar to FDA’s requirements.  Pragmatism on everyone’s part is either clearly stated or implied.  The goal is to preserve the integrity at the study where possible but the subjects’ health is paramount and must not be risked to maintain the trial.

Obviously, lots of judgment calls here.  Hopefully one has good rapport and relationships with the agencies, IRBs and investigators.  Be transparent, keep everyone informed. Document everything.  Repeat: Document everything. Protect the subjects.  Repeat: Protect the subjects.

REMS

FDA released a guidance on REMS  and Corona.  See: https://www.fda.gov/media/136317/download

FDA notes that “For a limited number of drugs that are subject to a REMS with ETASU, the REMS requires laboratory testing (e.g., liver enzyme testing) or imaging studies (e.g., magnetic resonance imaging).”

FDA recognizes that getting these tests done may not be possible if patients are sequestered or at risk by going to labs or imaging facilities.

For these situations, health care prescribers and dispensers “should consider whether there are compelling reasons not to complete these tests or studies during the PHE, and use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing and imaging studies. Health care providers should also communicate with their patients regarding these judgments, including the risks associated with it.”

Comments: Here too the FDA is indicating there is flexibility.  Sponsors and prescribers, dispensers and patients should consult and come to reasonable agreements on how each situation or even each patient should be handled.  Everything should be well documented and it is advisable to periodically let FDA know what is being done.

Overall Comments

Obviously, lots of judgment calls here.  Hopefully one has good rapport and relationships with the agencies, IRBs and investigators.  Be transparent, keep everyone informed. Document everything.  Repeat: Document everything. Protect the subjects.  Repeat: Protect the subjects.