The United States Food and Drug Administration (FDA) has strict regulations regarding pharmacovigilance activities that are a part of post-marketing studies for drugs and medical devices that are required as part of a New Drug Application (NDA). The Code of Federal Regulations Title 21 contains various sections related to pharmacovigilance, adverse event reporting, and drug safety and these regulations are governed and enforced by the FDA. Some of the relevant regulations for pharmacovigilance include:

Title 21 CFR Part 314

Which includes post-marketing and pharmacovigilance activities that are required in an NDA such as periodic reports, individual case safety reports (ICSR), and electronic reporting formats. This part includes several subparts that are related to risk evaluation and mitigations strategies (REMS), adverse event reporting, dispute resolution, and any deviations.

Title 21 CFR Part 600

This relates to reporting requirements for adverse events related to biological products, vaccines, and blood products.

The FDA has released a guidance document in 2005 on “Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment” that provides recommendations and best practices for safety signal evaluations. It includes information for the development of case series, data mining from databases such as FDA Adverse Event Reporting System (FAERS) and Vaccine Adverse Event Reporting System (VAERS), labelling modifications depending upon incidence rates of the safety signal, and data collection and signal collection through non-randomized, observational studies such as pharmacoepidemiologic studies, registries, and surveys. It also emphasizes the importance for the development of a pharmacovigilance plan and specifies what elements need to be included in it.

Figure 1 shows the various regulations that are required to be followed by sponsors/manufacturers for pharmacovigilance activities.

Adverse event reporting

The FDA has the FAERS and VAERS databases for voluntary reporting of adverse events received from post-marketing studies, observational studies, or real-word evidence (RWE). These databases contain information reported by consumers or healthcare professionals and is used by the regulatory agency to make decisions regarding the use of the product or changes in labelling that may be needed.

Risk Evaluation and Mitigation Strategies (REMS)

The US FDA mandates the development of REMS programs for drugs with safety concerns to ensure that the benefits outweigh the risks. They are required to educate and inform healthcare professionals on safe prescribing information and are not intended to mitigate adverse effects but rather increase awareness about them.

Post-marketing surveillance (PMS)

PMS studies are an essential component for FDA-regulated drugs and medical devices and for a part of the product lifecycle. FDA programs such as Med Watch help to collect unexpected or previously unobserved adverse events not captured during clinical trials. They help regulatory agencies make decisions regarding the fate of the product, such as withdrawals, limited usage, or change in labelling conditions.

Signal detection and evaluation

Potential safety issues that are entered on the FAERS database are evaluated by the FDA to characterize the risk and determine if there is a casual relationship between the event and the product. Once an issue has been deemed to present a safety concern, the FDA is responsible for taking appropriate action and communicating the risk to healthcare professionals such that they can modify their prescribing patterns.

Inspections

The FDA’s Post marketing Adverse Drug Experience (PADE) compliance program monitors the manufacture/sponsors compliance with post marketing laws and regulations for FDA-regulated products. Noncompliance and deviations result in warning letters and regulatory actions.

Risk communication

The FDA website contains a Drug Safety Communications page that provides patients and healthcare professionals with up-to-date safety information on regulated products which includes adverse events and long-term side effects.

In April 2022, the FDA released a guidance document on the submission of post-marketing safety reports in an electronic format. It describes the submission process and timeline for individual case safety reports (ICSRs) to the FAERS system through the electronic submissions gateway (ESG) or safety reporting portal (SRP). It describes the procedure that involves setting up an account and password, details on unique identification numbers and periodic submissions of ICSRs, label submissions for unapproved prescription and nonprescription products, and ICSR submissions and attachments. The guidance also describes the acknowledgement of submission by the FDA to the FAERS database and contact information in case of any problems with the submission process. Submission methods such as physical submissions and guidelines for these are stated in case of non-functionality of the FAERS system. The format and content of waiver requests, reasons for waiver, and portal for submission are covered in this guidance.

Another guidance document on the electronic transmission of ICSRs for drugs and biological products was released in August 2022. This guidance describes technical requirements for submitting ICSRs to the FAERS database as per ICH E2B(R3) specifications along with incorporation of FDA regional data elements. File structures, data elements, formats, coding structures, medical terminologies, and transmission standards are described in this guidance. Additionally, requirements for expedited reporting, follow-up of ICSRs, and contact information in case of misinformation is also specified. The overall aim of this guidance is to ensure accuracy, consistency, and streamline the process for submission of ICSRs to the FDA allowing for safeguarding of patient health and well-being.

Therefore, it is required that all manufacturers, sponsors/investigators, and companies adhere to FDA regulations and comply with necessary standards. The current set of regulations help collect adverse event information that can provide feedback on the safety of the product. As electronic reporting is becoming increasingly popular, most of the new FDA guidances focus on the submission and format for electronic submissions to the FDA database which can facilitate exchange of information within the U.S. and globally allowing for patient safety.

Read More– US FDA Foreign Clinical Trial Data Requirements

References

1. FDA Regional Implementation Guide for E2B(R3) Electronic Transmission of Individual Case Safety Reports for Drug and Biological Products | FDA
2. Providing Submissions in Electronic Format — Postmarketing Safety Reports | FDA
3. CFR – Code of Federal Regulations Title 21 (fda.gov)
4.  21 CFR 314.80 – Postmarketing reporting of adverse drug experiences. – Content Details – CFR-2011-title21-vol5-sec314-80 (govinfo.gov)

The growing impetus for the conduct of clinical trials outside the United States for products and medical devices intended to be used in the US include multiple reasons such as increased accessibility to patient populations particularly in case of rare diseases, faster enrolments, reduced operational and clinical expenses, ethical or legal reasons, shorter trial timelines, and expertise in certain therapeutic or disease areas in other countries through the use of contract research organizations (CROs). These advantages have prompted sponsors to use clinical data from foreign sites conducted under an Investigational New Drug (IND) application and non-IND foreign sites to support clinical investigations or marketing approvals in the U.S. As per legal requirements, the Code of Federal Regulations (CFR), 21 CFR 316.106 (for drugs) and 21 CFR 814.15 (for medical devices), the following criteria must be fulfilled for foreign clinical data to be used to support marketing approvals in the U.S.:

• The foreign data are applicable to the U.S. population and U.S. medical practice;
• The studies have been performed by clinical investigators of recognized competence;
• The data may be considered valid without the need for on-site inspection by the FDA or, if the FDA considers such an inspection necessary, FDA is able to validate the data through an on-site inspection or other appropriate means.

Thus, ensuring the applicability and extrapolation of the data U.S. populations and adhering with regulatory conditions is vital when data from foreign clinical trials is used. However, challenges such as proper documentation standards and data quality, regulatory considerations, investigational product (IP) supply, safety monitoring, and personnel training are some issues that continue to plague foreign clinical trials. Of these, lack of data quality, accuracy, consistency, and completeness are the most common reasons for difficulties in using foreign data. The FDA has high standards and expectation for data that must comply with certain guidelines and regulations which may be hard to fulfil as the data collection practices and monitoring strategies maybe different in countries outside the U.S.

The FDA has released a guidance document entitled ‘FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND Frequently Asked Questions’ in March 2012. This guidance states that foreign studies conducted under an IND must comply with the requirements of the FDA for IND investigations. However, sponsors that do not choose to conduct a study under an IND must comply with the regulations under 21 CFR 312.120 which states the conditions for acceptance of foreign studies. In addition to CFR regulations, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guidelines also provide information on conduct and data required from multi-regional clinical trials (MRCTs) to prevent duplication and provide bridging information to extrapolate data from one region to another taking into account ethnical and regional factors.

 According to 21 CFR 312.120, FDA will accept support for an IND or application for marketing approval for a study not conducted under an IND if it is well-designed and conducted and if the following conditions as shown in the Figure below are met:

Figure. FDA conditions for acceptance of foreign clinical studies

Good Clinical Practice (GCP) guidelines

FDA requires that trials conducted for products intended to be used in the U.S. comply with GCP standards to ensure that the data collected are credible, accurate, and ethically procured. Compliance with GCP standards is necessary for protecting the rights and well-being of study participants by documenting informed consent that are required to be approved by independent ethics committees (IEC) that oversee that the trial is conducted under ethical considerations. Necessary data that is necessary for FDA approval is informed consent documentation, local regulatory approval, case report forms (CRF), detailed study protocols, data on safety events and adverse events reporting, statistical analysis plans and clinical study reports, quality assurance documentation such as standard operating procedures (SOPs) followed, audit and inspection reports, protocol deviations and their reasons, and documents to show Good Clinical Practice (GCP) training of personnel and documentation for compliance with GCP standards. Furthermore, supporting information should include a description of investigator’s qualifications and research facilities and chemistry, manufacturing, and controls (CMC) related to the drug substance and drug product. It is also required of the manufacturer/sponsor to delineate the location of the trials and provide data and documents on how the trials conformed with GCP regulations. FDA recommends the use of the electronic common technical document (eCTD) format with a submission letter to list out data in support of a particular clinical trial phase.

Onsite inspection and validation

Onsite inspection and audits are important when clinical trials are conducted outside the U.S. to ensure compliance with regulatory requirements and data standards that are necessary to obtain marketing approval in the U.S. Audits are done for quality assurance purposes and to protect the integrity of the participants. The probability of an audit increases when FDA has a reason to suspect fraud, mishandling of data, or violation of patients safety and welfare.  It is necessary to have audit-ready documents and reports available during inspections as well as audit certificates to facilitate quick and effective results and allow the auditors to assess where the data is insufficient or unreliable. Thus, data must be at hand during inspections and maintained systematically as per U.S. data standards.

Although conducting foreign trials may be a lucrative and practical option for U.S. manufacturers/sponsors, it is necessary that the data generated is up to U.S. regulatory standards if the product is to be marketed in the U.S. Along with audits, inspections, and GCP compliance, the FDA encourages pre-submission meetings between the sponsors and regulatory authorities to allow the trials to proceed smoothly.

Read More : FDA’s Clinical Data Standard Requirements for Clinical Trials

References

1)  Implementing Clinical Trials on an International Platform: Challenges and Perspectives – PMC (nih.gov)

2) E17 Step 5 on general principles for planning and design of multi-regional clinical trials (europa.eu)

3) FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND: Frequently Asked Questions | FDA

   Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be       Conducted Without an IND (fda.go