Drug and Device Companies Should Plan for Rapid Changes to Interactions with IRBs/IECs, Clinical Trial Sites, and Human Study Subjects
The Food and Drug Administration (“FDA”) as well as the European Medicines Agency (“EMA”) and the national Heads of Medicines Agencies (“HMA”) issued new guidance[i],[ii] for industry sponsors, investigators, and Institutional Review Boards/Independent Ethics Committees (“IRB/IEC”), to anticipate potential modifications of ongoing clinical trials that may be required to ensure the safety of human subjects (“participants”) during the COVID-19 pandemic. These agencies recognize that the current COVID‑19 crisis presents risks of infection due to person-to-person proximity or contact, attendance limitations due to stay-at-home[iii] and self‑quarantine obligations, supply chain constrictions, and unanticipated demands on healthcare personnel, facilities, and resources. The intent of the guidance is to anticipate challenges in overseeing trial participants, administering investigational products, and adhering to protocol requirements in accordance with good clinical practice (“GCP”). FDA’s guidance document applies broadly to human drug, biological, and medical device products. The EMA/HMA guidance applies expressly to drug and biological clinical trials, but it should be instructive to medical device sponsors as well.
FDA’s and EMA/HMA’s guidance documents focus on actions that sponsors should consider. None of the regulators, however, announced that they are suspending or exercising enforcement discretion regarding the obligations of a sponsor or its oversight of investigators, the requirements for informed consent, or IRB/IEC review. Notably, the FDA guidance is silent regarding potential deviations from federal regulations that an IRB/IEC might consider in responding rapidly to changes in trial conduct proposed by a sponsor, including certain changes in informed consent. Our analysis identifies the key issues that a company sponsor should consider now for each of the company’s ongoing or about-to-be-initiated, regulated drug or medical device clinical investigations. Certain information concerning recent IRB/IEC actions also is set forth below.
Safety of trial participants
The overriding emphasis of the FDA guidance is ensuring the safety of clinical trial participants in ongoing trials, not inconvenience or expense for sponsors. FDA advises that all modifications to a sponsor’s current conduct of ongoing clinical trials should be driven by this consideration. In addition, sponsors should ensure that all trial participants are informed of changes to the conduct of the trial that could affect them. Among the recommendations in the guidance, the following are key considerations.
- Continuing or discontinuing recruitment, administration of test product to enrolled participants, and conduct of the trial: The most far-reaching issue that companies should consider, in consultation with investigators and a reviewing IRB/IEC, is whether the safety of participants is best served by halting recruitment, discontinuing test product administration, or suspending/terminating the trial. Although not cited by FDA, companies may consider obtaining input from enrolled participants. Sponsors also should take into consideration the specific circumstances of each clinical trial, including the nature of the investigational product and disease under study, the ability to conduct appropriate safety monitoring (including during product withdrawal, if applicable), and the investigational product supply chain. Because of the far-reaching implications of such decisions—including implications for product development, public notification on ClinicalTrials.gov, and potential disclosure to shareholders—sponsors should determine the most immediate needed action for each of the company’s ongoing clinical trials. Companies also should be aware that decisions may need to be updated as the COVID-19 pandemic escalates and local circumstances evolve.
- Changes in monitoring and ensuring the safety of participants: Since many participants may not be able (or may be unwilling) to come to protocol-specified, on-site visits, FDA advises that sponsors can consider altering their approach for monitoring trial participants. However, any alteration in on-site monitoring of participants specified in the protocol, such as changes to telephonic or other remote monitoring, must be sufficient to “fully assure” the safety of all trial participants, including carrying out procedures and testing critical for monitoring safety. Specific to the trial, sponsors may need to ensure additional safety monitoring for unplanned withdrawal of the active investigational treatment.
- Changes in monitoring for oversight of data quality: In addition to oversight of the welfare and safety of participants, sponsors are obligated to monitor[iv] the conduct of FDA-regulated clinical investigations to ensure the integrity and quality of data. This typically includes verification of some or all information submitted to the sponsor on case report forms against primary source documents maintained by investigators. In its guidance, FDA briefly advises that sponsors should consider using central and remote monitoring to maintain oversight of clinical sites. Neither the Investigational New Drug (“IND”) or Investigational Device Exemption (“IDE”) regulations narrowly prescribe how such monitoring should be done; however, FDA previously issued draft guidance[v] that encourages risk-based monitoring and centralized monitoring approaches. The restrictions of the COVID-19 pandemic may incentivize sponsors to implement off-site monitoring of data quality, including review of clinical source documents. In that instance, however, remote access to primary source documents, including healthcare facility electronic medical records, may require renegotiation of clinical trial agreements between a sponsor and site, as well as review of the informed consent document and participants’ HIPAA Authorizations to ensure such access is permitted and privacy protections are observed.
Changes to the protocol and protocol deviations
FDA reminds sponsors that “changes in a protocol [including informed consent] are typically not implemented before review and approval by [an] IRB[/IEC], in some cases, by FDA.” Sponsors should be aware that the guidance recommendations are entirely consistent with and do not waive any current regulatory requirements for modification of a protocol approved under 21 C.F.R. Part 312 for an IND, or 21 C.F.R. Part 812 for an IDE.
- Protocol change to eliminate an immediate hazard, including limiting participant exposure to COVID-19: Consistent with current regulations,[vi] the guidance clarifies that changes to a protocol or investigational plan to minimize or eliminate immediate hazards, or to protect the life and well-being of research participants, may be implemented without IRB/IEC approval or filing an amendment to the IND or IDE. Any such change must be reported to the reviewing IRB/IEC and FDA within 5 working days in accordance with applicable regulations. Notably, the guidance explicitly clarifies that minimizing or eliminating an immediate hazard includes limiting participant exposure to COVID-19 (i.e., exposure to the SARS-CoV-2 virus). The guidance urges sponsors and investigators to engage with an IRB/IEC as early as possible if urgent or emergent changes to the protocol, including informed consent, are anticipated in the context of the COVID-19 pandemic, and to prospectively develop procedures acceptable to the IRB/IEC to prioritize reporting changes in the protocol (protocol deviations) that may impact the safety of trial participants.
- Documentation of changes in study conduct, including missing protocol-specified data: FDA informs sponsors that it expects extensive new information to be collected if protocol-specified activities for participants are modified or missed related to the COVID-19 pandemic. The Agency advises that sponsors should document the reasons for any changes in processes not specified in the protocol, including “how restrictions related to COVID 19” led to (1) changes in study conduct, (2) the duration of changes, (3) which specific participants were impacted, and (4) how participants were impacted. In addition, if any prespecified assessment for an efficacy endpoint is not collected, the specific limitation imposed by COVID-19 should be documented.
- Case report forms: FDA expects that case report forms will “capture specific information” for missing information, such as drop out of participants, missed study visits or absent laboratory data, due to COVID-19. Implicitly, although not stated in the guidance, sponsors should ensure that such case report form data can be verified by the investigators’ source documents. For many sponsors, this may require urgent development of new case report forms and provision of instructions to investigators and monitors to ensure that this expectation is being met.
- COVID-19 screening procedures: FDA states that it will not consider COVID-19 screening procedures mandated by healthcare systems to be a protocol amendment that must be reported unless the sponsor is incorporating these data as a new research objective.
- Final clinical study reports: In the clinical study report or study-specific document for all trials impacted by the COVID-19 pandemic, FDA expects sponsors to describe (1) contingency measures implemented to manage study conduct; (2) a listing of all participants affected by the COVID-19 related study disruption and a description of how each individual’s participation was altered; and (3) an analysis of how contingency measures—including but not limited to discontinuation of a participant in the study and changes in procedures to collect critical efficacy and safety data—impacted safety and efficacy results.
- Consultation with FDA: The Agency advises that sponsors should consider consultation with the appropriate FDA review division regarding potential protocol modifications for the collection of efficacy endpoints, including but not limited to use of virtual at-a-distance assessment, delays in assessments, and changes in collection of research-specific specimens. Sponsors should also consult with FDA if proposed protocol changes will modify data management and statistical analysis plans (“SAP”); prior to database lock, sponsors should also explain in the SAP how prespecified analyses will address protocol deviations related to COVID-19.
Investigational product accountability
Both the IND and IDE regulations require that sponsors ensure each investigator maintains control of an investigational product—including administration to a participant under the investigator’s direct supervision—and keep records regarding disposition of the product. The guidance does not provide any general waiver of these obligations. For investigational products that are intended to be administered in a healthcare setting by the investigator, sponsors should consult the relevant FDA review division if plans for alternative administration are contemplated. (King and Spalding note: Sponsors also should consider state professional licensing and telemedicine laws, as applicable.)
COVID-19 disruption of clinical trials in the EU: What’s similar and different from FDA guidance?
The EMA/HMA’s guidance is similar to the FDA’s guidance. It contains a set of recommendations to ensure the safety of trial participants while preserving the quality of the trial data. It also advises about the communication of changes to the competent authorities.
The guidance has been prepared or endorsed by all relevant European authorities: the EMA (represented by the Good Clinical Practice Inspectors Working Group), the HMA (represented by the Clinical Trials Facilitation and Coordination Group (“CTFG”)), and the European Commission (represented by the Clinical Trials Expert Group (“CTEG”), a working group comprising ethics committees and national competent authorities (“NCA”)). However, this guidance only complements—and thus may be preempted by—measures that have been and will be adopted by individual European Union (“EU”) countries, because clinical trials are still authorized and supervised at the national level (until the application of the new EU Clinical Trial Regulation). Sponsors are therefore advised to check specific national legislation and guidelines on a trial-specific basis.
Important recommendations from the EMA/HMA guidance are summarized in the Appendix to this alert. Two noteworthy distinctions between the FDA and EMA/HMA guidance documents are:
- Initiation of new trials to test new treatments for COVID-19: In order to generate conclusive evidence and enable the rapid development of new COVID-19 treatments, EU countries expressly support the submission of large, multinational trial protocols for investigations. Sponsors also are encouraged to consider the submission of such applications for an accelerated Voluntary Harmonisation Procedure[vii] (“VHP”) assessment when possible. Developers of medicines or vaccines are invited to contact EMA as soon as possible with information about proposed development plans. EMA will provide a full fee waiver and a fast-track procedure for scientific advice in this context.
- Reimbursement of exceptional expenses: The EMA/HMA guidance advises that, if, in order to implement urgent measures for the protection of trial participants, expenses may arise that may be borne initially by the participants, such expenses should typically be subsequently compensated by the sponsor via the investigator. If additional financial compensation is provided to sites/investigators (e.g., to cover the cost of using couriers for investigational product delivery), this needs to be documented and performed according to national legislation. Handling of reimbursement of such expenses should follow national legislation and/or guidance.
The EMA/HMA guidance addresses a range of important considerations, and these are summarized in the Appendix. Not all recommendations of FDA and EMA/HMA are identical with respect to ongoing trials, protocol deviations, and monitoring. Hence, it is important to study the details relevant to each trial location.
IRB/IEC policies must be carefully monitored, in addition to regulatory requirements
Sponsors should remain aware that IRBs/IECs may adopt policy and procedural requirements that augment FDA and national Medicines Agency regulatory obligations at individual sites. Indeed, in recent weeks both academic medical center and commercial IRBs/IECs have published guidance specific to the trials under their authority. In various instances, the individual IRB/IEC requirements are notably more stringent than the considerations governmental guidance might enable.
As merely one example, some IRBs/IECs have classified research into “tiers” that can determine a trial’s fate at covered sites as the COVID-19 conditions rapidly evolve. Under this regime, “Tier 1” includes research that involves high direct potential benefit to research participants, and risk of serious or immediate harm if stopped. “Tier 2” includes moderate direct potential benefit to research participants, and some risk if stopped. “Tier 3” involves low direct benefit to research participants. Over the past two weeks, some institutions announced that they have advanced from contingency planning; to increasing screening; stopping on-site monitoring visits; implementing IRB/IEC triage procedures to manage workload; deferring enrollment of new participants except in Tier 1 and some Tier 2 studies; and now ceasing in-person interactions in Tier 2 studies except with IRB/IEC approval. Sponsors need to maintain very reliable communication channels with investigators and adopt processes to anticipate and monitor how IRB/IEC or institutional activities may rapidly affect ongoing clinical trials.
Take-home considerations for sponsors
The FDA and EMA/HMA guidance documents provide both a framework and impetus for sponsors of regulated clinical trials to immediately put into place—if they have not already done so—policies and procedures to protect trial participants, manage study conduct, and ensure data quality in response to escalating disruption by the COVID-19 pandemic. Policies and procedures, accompanied by personnel training, should be developed with a primary focus on the safety of trial participants and, at minimum, should address the impact on informed consent, study visits and procedures, data collection, adverse event reporting, and unexpected changes in investigators, study staff, and/or monitors. For contemplated changes in the conduct of a trial or protocol, sponsors must determine for each change if a protocol (investigational plan) amendment to the IND or IDE (for the U.S.) or a substantial amendment application (for Europe) is required, as well as potential IRB/IEC review and modification of the informed consent.
In addition to federal/national requirements, sponsors must ensure that policies and actions remain compliant with applicable state and local laws (e.g., professional licensing laws), and with regional and facility policies for management and control of COVID-19.
Regulators advise that sponsors should consider whether contingency measures are needed now to protect participants in ongoing clinical trials, including such strict measures as closure of recruitment, discontinuation of administration of test product to enrolled participants, or termination of participants in the trial. Sponsors should consider making these determinations—with potential input from investigators and reviewing IRBs/IECs—considering the nature of each investigational product, disease under study, ability to ensure appropriate safety monitoring for all participants, and the investigational supply chain that.
King & Spalding recommends such assessments be conducted in the framework of a written policy and procedure, with documentation of the decision-making. Decision-making also may require rapid revision of study documentation, review/revision of existing contractual arrangements, personnel training, and thoughtful recordkeeping. Decisions may need to be sequentially revisited as the COVID-19 pandemic evolves.
We appreciate that these are stressful, difficult, and potentially high risk decisions for sponsors of drug and medical device clinical trials. If you have questions regarding this new FDA or EMA/HMA guidance, require support for compliance, contractual analysis, or re-negotiation, or need urgent counsel regarding your ongoing clinical trials, please contact Chris Markus, Beverly Lorell, Nikki Reeves, Elaine Tseng, or Becka Paradis for more information. If you have questions regarding the implications of the recommendations in this guidance for trials with sites in the EU, please contact Geneviève Michaux.
[ii] EMA-HMA, Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic (Mar. 20, 2020), https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf.
[iii] At the time of publication of this Client Alert, 12 states have announced stay-at-home/shelter-in-place orders (California, Connecticut, Delaware, Illinois, Louisiana, Maryland, Michigan, Nevada, New Jersey, New York, Ohio, and Pennsylvania), and the number continues to evolve. In Europe, most of the EU countries and Switzerland impose total or partial home confinement.
[iv] 21 C.F.R. Part 312, Subpart D (Responsibilities of Sponsors and Investigators) and 21 C.F.R. Part 812, Subpart C (Responsibilities of Sponsors).
[vi] 21 C.F.R. §§ 56.108(a)(4), 56.104(c), 312.30(b)(2)(ii), and 812.35(a)(2).
[vii] Clinical Trials Facilitation Groups, Guidance Document for Sponsors for a Voluntary Harmonisation Procedure (VHP) for the assessment of multinational Clinical Trial Applications (version 4) (June 2016), https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2016_06_CTFG_VHP_guidance_for_sponsor_v4.pdf.
APPENDIX: EMA/HMA guidance related to clinical trial responses in the face of COVID-19
The EMA/HMA’s guidance contains recommendations to ensure the safety of trial participants while preserving the quality of the trial data. It also advises about the communication of changes to the competent authorities. Important considerations include:
- New clinical trials/new trial participants in ongoing trials: The feasibility and relevance of starting a new clinical trial or including new trial participants in an ongoing trial should be critically assessed by sponsors. Absolute priority should be given to clinical trials involving potential treatments for COVID-19 and COVID-19 related illnesses, or involving serious diseases with no satisfactory treatment option.
- Ongoing Clinical Trials: Sponsors should consider the most appropriate measures and agree with investigators thereon. Responsive measures could include the following:
- Conversion of physical visits into phone or video visits, postponement or cancellation of visits to ensure that only strictly necessary visits are performed at sites.
- Temporary halt of the trial at some or all trial sites.
- Suspension or slowing down of recruitment of new trial subjects.
- Extension of the trial duration.
- Postponement of trials or activation of sites.
- Closing of sites (without compromising patients’ safety and well-being of patients and data validity).
- If unavoidable, transfer of trial subjects to new or existing investigational sites away from risk zones, or closer to their home. An urgent need to open a new trial site may be implemented as an urgent safety measure (“USM”) and then confirmed through a substantial amendment. It is important that: trial subjects and investigators (both receiving and sending sites) agree on the transfer; the receiving site may access previously collected information/collected data for the trial subject; and any eCRF can be adjusted to allow the receiving site to enter new data. The impact on trial subjects should be considered and arrangements should be made for appropriate transportation.
- Conduct of critical laboratory tests, imaging or other diagnostic test for patient safety at a local laboratory (or relevant clinical facility for other tests) authorized/certified (as legally required nationally) to perform such tests routinely (e.g. blood cell count, liver function test, X-ray, ECG etc.) rather than at the site.
On the other hand, prospective protocol waivers remain unacceptable, and patients should not be included in trials without proper eligibility assessment and written informed consent.
If the principal investigator (PI) of a site is indisposed for a limited period, he/she may delegate parts of his/her duties temporarily to a sub-investigator. On the other hand, a permanent change in PI should be submitted to the national competent authority and ethics committees.
Changes should be well-balanced, taking into account the legitimate interest of trial sites in avoiding further burden in terms of time and staffing, be it understood that the trial subject’s overall well-being and best interests prevail over other considerations.
Compliance with the trial protocol should be ensured, provided that an ongoing benefit-risk assessment for the clinical trial and its subject is still possible. The sponsor must assess the impact of protocol changes on clinical data interpretability, and the overall evidence generation package could be subsequently discussed within scientific advice with regulatory authorities. Guidance on methodological considerations is being prepared by the EMA (CHMP, Biostats Working Party).
- Risk assessment: All decisions to adjust the conduct of a clinical trial should be based on a risk assessment that takes into account the added challenges due to the COVID-19. The sponsor is expected to perform a risk assessment of each individual ongoing trial and to implement measures that prioritize participant’s safety and data validity. Special attention should be paid to participants enrolled in ongoing clinical trials who may be determined as being a risk group for COVID-19 or who are in trials involving therapies which may increase such risk.
The sponsor should reassess risks as the situation develops. With the escalation of the pandemic, local circumstances may lead to a local change in risk assessment, which may require additional measures and an investigator-driven risk assessment.
- Communication with authorities: The relevant national competent authorities and ethics committees must be informed if the risk assessment leads to the following actions:
- When a new event is likely to have a serious effect on the benefit-risk balance of the trial, immediate actions may be required to protect the subjects against immediate hazard. These urgent safety measures may be taken without prior notification, but the information should be provided ex post to the national competent authority and ethics committee as soon as possible.
- If changes are likely to affect the subjects’ safety or well-being and/or the scientific value of the trial but do not require immediate action from sponsor or investigator, they can be submitted as substantial amendment applications. Sponsors are encouraged to take into account the limited capacity of assessors, and submit only high quality, complete applications containing only the necessary changes. Over-reporting should be avoided.
- Agreement with and communication to sites: Changes to trial conduct should be agreed with and communicated clearly to investigating sites. Changes and local implications should be clear (track change marking) to support implementation by sites. Agreements may be documented as e-mail exchange.
- Changes to informed consent:
- Clinical trial for a new treatment for the COVID-19: advice should be sought on alternative procedures to obtain informed consent because the physical consent cannot leave the isolation room and thus is not appropriate as trial documentation.
- Emergency situations” (trial subjects are incapable of giving their informed consent, for example because they are under intensive medical care): sponsors comply with Article 5 of the Clinical Trial Directive and national regulations. Informed consent of these patients or their representatives will be obtained later, as soon as feasible, if deferred consent in emergency situations is permitted under national law.
- New consent: If re-consents are necessary for the new urgent changes in trial conduct (mainly expected for reasons related to COVID-19), alternative ways of obtaining such re-consents should be considered during the pandemic e.g. contacting the trial subjects via phone or video-calls and obtaining oral consents supplemented with email confirmation. Any consent obtained this way should be documented and confirmed by way of normal consent procedures at the earliest opportunity when the trial subjects are back at the regular sites
Any validated and secure electronic system already used in the trial for obtaining informed consent can be used as per usual practice and in compliance with national legislation.
- Changes in the distribution of the investigational medicinal product (IMP): Changes in the distribution of the IMP may be necessary to remove avoidable visits to sites and to provide patients with needed treatments. Sponsors must assess the risks relating to the product and consider any alternative shipping and storage arrangements (without compromising blinding). Changes in distribution of IMP may include:
- Urgent shortage of IMP at some sites or transfer of trial subjects from one site to another site: the IMP may have to be redistributed between sites in accordance with GMP annex 13 (section 47). This should only be considered in cases where a direct distribution of the IMP to a trial site by the usual distributor is not possible or in the exceptional circumstance where a trial subject is transferred from one site to another. Sponsors should assess whether sites can handle and control such a re-distribution process. Re-distribution should follow a written procedure established in cooperation with the Qualified Person or the person responsible for distribution of the IMP, and sites should be provided with sufficient information to ensure that the process can be performed securely.
- Reduction of physical site visits: the IMP will have to be delivered directly to trial subjects during the COVID-19 pandemic. The delivery is generally expected to happen from investigator sites to trial subjects. IMP delivery directly from sponsor to trial subject is accepted in a few EU countries under this emergency situation (the sponsor should check the national guidance as it is likely that such measures can only be implemented under specified conditions and for a limited period).
- Changes to monitoring: Certain sponsor oversight responsibilities, such as monitoring and quality assurance activities, have to be re- assessed and temporary alternative proportionate mechanisms of oversight may be required. The extent of on-site monitoring, if it remains feasible, should take into account national and local restrictions, the urgency (e.g. source data verification can often be postponed) and the availability of site staff, and should only be performed as agreed with investigator sites. The burden of introducing any alternative measures for the site staff and facilities should be considered in order to strike an acceptable balance between appropriate oversight and the capacity of and possibilities at the site.
Possible temporary, alternative measures could include:
- Cancelling of on-site monitoring visits and extending of the period between monitoring visit.
- Implementing phone and video visits (without unnecessarily increased burden to the investigator site and taking into account trial participant integrity).
- Adapting the on-site monitoring plan when it is impossible to follow, supplementing it with (additional/increased) centralized monitoring and central review of data if possible and meaningful.
Remote source data verification (e.g. providing sponsor with copies of medical records or remote access to electronic medical records) is currently not allowed in most EU countries, and the provision of redacted/ de-identified pdfs files is not acceptable. However, several national competent authorities have started looking into possible temporary solutions related to remote access, provided that methods can be used that restricts access to trial subjects’ records. This should also be clarified with other relevant authorities (such as ethics committees and data protection agencies) and is consequently not allowed unless specific national guidance allowing it.
Results of adjusted monitoring/review measures should be reported to the sponsor in monitoring reports and in the clinical study report.
It is essential that robust follow-up measures are planned and ready to be implemented when the situation is normalized (e.g. an increased on-site monitoring for a period sufficient to ensure that the impact of reduced monitoring could be rectified and problems resolved or properly documented for reporting in the clinical study report).
- Protocol deviations: The COVID-19 situation is likely to introduce more protocol deviations than normal. We expect that the sponsor escalates and manages such protocol deviations in accordance with his standard procedures. A proportionate approach will be taken by the GCP inspectors when such deviations are reviewed during inspections and the subject is not put at risk. An increase in protocol deviations in relation to the COVID-19 situation will in itself not trigger the actions required by GCP § 5.20, but they will be assessed and reported in the clinical study report.
- Reimbursement of exceptional expenses: If, in order to implement urgent measures for the protection of trial subjects, expenses may arise which may be borne initially by the subjects, they should typically be compensated subsequently by the sponsor via the investigator. If additional financial compensation is provided to sites/investigators (e.g. to cover the cost of using couriers for IMP delivery), this needs to be documented and performed according to national legislation. Handling of reimbursement of such expenses should follow national legislation and/or guidance.
- Initiation of new trials aiming to test new treatments for COVID-19: The EU countries support the submission of large, multinational trial protocols for the investigation of two new treatments for COVID-19 . In addition, sponsors are encouraged to consider the submission of such applications for an accelerated Voluntary Harmonisation Procedure[i] (“VHP”) assessment when possible. Developers of medicines or vaccines are invited to contact EMA as soon as possible with information about their proposed development. EMA provides a full fee waiver and a fast-track procedure for scientific advice.