Understanding the FDA’s Medical Products Clinical Trial Guidance amidst COVID-19

Conducting medical product clinical trials during the COVID-19 public health emergency presents unprecedented challenges. In light of the challenges presented by COVID-19, the Food and Drug Administration (FDA) issued guidance to assist clinical trial sponsors in protecting the trial participants safety while maintaining trial integrity and regulatory compliance.

The issue for clinical trial sponsors mirrors the conundrum faced by other businesses; how to operate effectively while reducing human-to-human contact to mitigate the spread of COVID-19. Human interaction, whether physical or virtual, is abundant during clinical trials. For example, human contact is often necessary to explain the clinical process to subjects, obtain a subject’s informed consent, administer the medical product, and monitor outcomes. FDA recently issued guidance on how to ensure the safety of trial participants, maintain compliance with good clinical practice, and minimize risk to trial integrity.¹

1. Suspending, continuing, initiating trials

There is no bright line rule for suspending, continuing, or initiating clinical trials during the public health emergency. Instead, FDA lists factors which should be weighed to make an appropriate decision regarding a clinical trial’s status. FDA recognizes that the safety of the clinical trial participants is central to any decision. Additional factors include: (i) whether a trial participant is benefiting from the product treatment; (ii) whether there are reasonable alternative treatments; (iii) the seriousness of the disease or condition being treated; (iv) and the risks associated with changing treatments. FDA recognizes in some cases the sponsor should consider discontinuing the trial for subjects who are not benefiting from the product while continuing the trial for those subjects who appear to be benefitting.

2. Managing protocol deviations and amendments

• Some protocol deviations due to COVID-19 may be unavoidable. Per FDA, all deviations should be documented. Also, FDA highlights regulatory provisions which allows sponsors to make immediate changes without first gaining FDA approval. For example, during Investigational New Drug (IND) clinical trial the sponsor generally may implement protocol amendments immediately to prevent imminent hazards to trial participants and subsequently seek formal approval from an institutional review board (IRB). Protocol amendments that are not required to prevent imminent safety risks to patients must first be submitted to the FDA and IRB prior to implementation.

See

• 21 CFR 312.30(b). Similarly, under an Investigational Device Exemption (IDE), a sponsor can make immediate changes to protect the life of trial participants in an emergency but must await FDA approval before implementing changes in a non-emergency scenario.

See

21 CFR 812.35(a).

3. Conducting remote clinic visits

As stated above, investigational plan or protocol changes generally can be made without prior FDA approval, if the change is intended to eliminate an apparent immediate hazard or to protect the life and well-being of the trial participants. Thus, sponsors may immediately switch from on-sites visits to telephone / video conference visits to curb the risk of COVID-19 infection.

4. Delivering investigational products to home

Many trial participants currently receive investigational products through a pharmacy or at the clinical site and then subsequently self-administer the product at home. In order to decrease the risk of COVID-19 exposure, FDA will also allow home delivery of investigational products if it will not raise any new safety risks. However, FDA’s regulations regarding storage conditions remain and must be adhered to and documented.

5. Switching to home infusion from a clinical trial site

FDA recognizes the possibility that trial participants may be unable to visit a clinical trial site to receive an infusion. FDA directed sponsors to consider the risk to trial participants who would otherwise miss investigational product infusions. However, FDA also directed sponsors to conduct a risk assessment for providing an alternative arrangement, which includes the nature of the investigational product and the potential risks to the participant and provider. For high-risk/complex investigational products (e.g., cellular therapy and gene therapy products), the FDA strongly encourages sponsors to consult the FDA.

6. Obtaining informed consent

Per FDA, the traditional method of receiving informed consent – using a signed paper copy of the consent form – is preferred. However, with COVID-19 limiting physical interactions, FDA has recommended alternatives in receiving the informed consent: (1) a sponsor may obtain a photograph of the informed consent document; and (2) a sponsor may receive verbal consent in the presence of a witness and have the witness sign and date an attestation to the verbal consent.

7. Remote site monitoring visits

The FDA will allow remote clinical outcome assessments (COAs) to assess performance outcomes (PerfO), interview-based clinician-reported outcomes (ClinRo), patient-reported outcomes (PRO), and observer-reported outcomes (ObsRO). However, sponsors seeking to switch to remote COAs must give general considerations to the following factors: (1) trial participant safety; (2) data quality and integrity; and (3) appropriate training for personnel and trial participants. Moreover, sponsors should give specific considerations depending on the COA type. For PerfO and ClinRO, the sponsors should consider: (1) appropriateness of the remote assessment for the type of clinical data being collecting; (2) special investigator training to administer the assessment; and (3) procedures for assessing and confirming trial participant safety and privacy. For PRO and ObsRo COAs, the sponsors should specifically consider: (1) potential to miss data when switching to remote assessment; (2) whether to use paper or electronic based assessment; and (3) that data collected through verbal administrations should not be considered a substitute for required safety monitoring throughout the trial.

8. Reporting serious adverse events (SAE) during clinical trials

• What are the reporting requirements if a trial subject is diagnosed with COVID-19? FDA regulations require sponsors to report

any

• serious adverse event (SAE) regardless of whether the adverse event is unrelated to the drug (i.e., due to COVID-19) or whether there is a causal relationship between the drug and the adverse event.

See

21 CFR 312.32. FDA notes that in order to properly determine whether the SAE is causally related to the drug or to COVID-19 or to a combination thereof, its is imperative to report all adverse events.

The FDA’s recommendations are suppose to remain in effect only for the duration of the COVD-19 public health emergency. However, over the last decade, we’ve seen the FDA slowly inch towards more flexibility in executing clinical trials. Should sponsors have success protecting trial participants while maintaining study integrity and proper documentation / reporting, then we may see some of these recommendations become permanent fixtures after the public health emergency. However, in all cases, the longstanding core principles of risk assessment, safety to participants, and data integrity will always be paramount.