FDA Guidance on Providing Regulatory Submissions in Electronic and Non-Electronic Format

The U.S. Food & Drug Administration (FDA) issued a guidance on providing regulatory submissions in electronic and non-electronic format. This guidance pertains to submissions of promotional materials for human prescription drugs to the FDA made by manufacturers, packers, and distributors, whether the applicant or an entity acting on behalf of the applicant. Specifically, this guidance pertains to submissions made to the Office of Prescription Drug Promotion (OPDP) in the Center for Drug Evaluation and Research (CDER) and the Advertising and Promotional Labeling Branch (APLB) in the Center for Biologics Evaluation and Research (CBER). This guidance also explains certain aspects of electronic submission of promotional materials in module 1 of the electronic common technical document (eCTD).

Read the full guidance here

FDA issues guidance for Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations

FDA announced the availability of a new guidance entitled “Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations.” This guidance clarifies that certain provisions of the 2018 Requirements related to informed consent are not inconsistent with FDA’s current policies and guidances.  The guidance also reminds stakeholders that FDA’s current regulations for expedited review and continuing review must be followed for FDA-regulated studies.

The revisions to the Department of Health and Human Services’ (HHS’) Federal Policy for Protection of Human Research Subjects (45 CFR 46, Subpart A; “the Common Rule” or “2018 Requirements”) have created certain differences between FDA’s human subject regulations and HHS’ human subject regulations.  While FDA intends to undertake rulemaking to harmonize, to the extent practicable and consistent with other statutory provisions, its regulations with the 2018 Requirements consistent with Section 3023 of the 21st Century Cures Act, we recognize the potential for confusion in the interim for sponsors, investigators, and IRBs who are involved in both HHS-regulated research and FDA-regulated clinical investigations. This guidance is intended to clarify the impact of certain provisions of the 2018 Requirements on FDA-regulated clinical investigations.

The guidance is available to download on FDA’s website

FDA releases final rule on Acceptance of Data from Clinical Investigations for Medical Devices

Today the FDA issued both the final rule on “Human Subject Protection; Acceptance of Data from Clinical Investigations for Medical Devices” and the guidance document “FDA Acceptance of Clinical Data to Support Medical Device Applications and Submissions Frequently Asked Questions.”  The rule updates the FDA’s standards for accepting clinical data from clinical investigations conducted both inside and outside the United States to help ensure the protection of human participants, and to help ensure the quality and integrity of data obtained from these clinical investigations.

The final rule amends FDA regulations on acceptance of data from clinical investigations conducted outside the United States to reflect the increasing globalization of clinical trials and the evolution of clinical trial standards for protecting human subjects. The new rule requires that sponsors and applicants provide statements and information about how the investigations conform with good clinical practices (GCP). This applies to clinical data submitted to support investigational device exemptions (IDE), premarket notifications (510(k)), requests for De Novo classification, premarket approvals (PMA), product development protocols (PDP), and humanitarian device exemptions (HDE). The FDA believes that the requirements set out in the final rule provide flexibility for medical device sponsors conducting multinational clinical trials by allowing them to describe the standard for good clinical practice they followed. 

The final rule also amends the IDE, 510(k) and HDE regulations for FDA acceptance of data from clinical investigations conducted within the United States to require a statement regarding compliance with FDA regulations for human subject protection, institutional review boards, and IDEs. This change is intended to provide consistency across different submission or application types.

The guidance document “FDA Acceptance of Clinical Data to Support Medical Device Applications and Submissions Frequently Asked Questions ” is in question and answer format and provides clarifications and recommendations to help stakeholders ensure that studies conducted in the U.S. or foreign countries comply with the new rule and revised regulations.

Source: http://s2027422842.t.en25.com/e/es?s=2027422842&e=53010&elqTrackId=B1F0B909CCF90C71B9C490C37BFE6647&elq=887a7e7d03884941a318e7081318a575&elqaid=2487&elqat=1

Draft FDA Guidance on Electronic Records and Electronic Signatures in Clinical Investigations

FDA announced the availability of a draft guidance for industry entitled, “Use of Electronic Records and Electronic Signatures in Clinical Investigations under 21 CFR Part 11-- Questions and Answers.” The draft guidance provides recommendations to sponsors, clinical investigators, IRBs, CROs, and other interested parties on the use of electronic records and electronic signatures under 21 CFR part 11 in clinical investigations of medical products.

Read the draft Guidance here

Getting it Right the First Time

When updating product licence details, there are always areas in the variation submission processes which can cause validation issues or the generation of Notification with Grounds (NWG) letters, ultimately resulting in a rejection or delay.  These can be time consuming for the MAH (Marketing Authorisation Holder) and may impact on assessment timeframes.

Learn about the key themes and "show stoppers" which have emerged over the last 5 years in this post by the Medicines and Healthcare Products Regulatory Agency.


Source: https://medregs.blog.gov.uk/2017/04/21/getting-it-right-first-time/

EU releases updated Pharmacovigilance Monitoring Plan

The European Medicines Agency (EMA) has released an updated pharmacovigilance management plan to deal with the introduction and proliferation of unsafe medicines into the EU's pharmaceutical supply chain.
In its 13 August 2012 posting, EMA explained its plan, has been in operation for nearly three years and applies to all medicines approved within the EU, including those approved by the decentralized and mutual recognition procedures. The plan had recently been updated to reflect the EU's new pharmacovigilance legislation, which should allow regulators to responds to serious and potential threats even faster, EMA said.
"Although the management of the large majority of emerging public health concerns related to the use of medicines has been possible by applying so-called routine measures, in a limited number of cases, commonly described as 'crisis' situations, specific measures had to be taken to allow for an efficient management," EMA explained. "This has been possible through the availability of dedicated 'crisis' management plans at national level."

The Regulatory Network Incident Management Plan (RNIMP) in Theory

As part of the plan, EMA said it conducts continuous monitoring of serious adverse events to understand their effects on the broader healthcare system—a process it refers to as proactive incident management. By actively monitoring events, it said it hopes to prevent crises from occurring in the first place with the help of a flexible framework that allows for a coordinated and expeditious response.
The agency said signed Memoranda of Understanding between EMA and National Competent Authorities (NCAs) to share EudraVigilance data and other safety data are a strong component of the coordinated response portion of the plan.  "This should allow for a more global approach at EU level in relation to the management of 'crisis' situations," noted EMA.
While the plan is intended to cover a range of issues—quality, efficacy and safety concerns among them—EMA said the majority of cases, in its experience, concern pharmacovigilance issues. Many of these problems require an EU-wide response immediately to take a product off the market or conduct more targeted vigilance measures. EMA also noted that emerging issues may be elevated to an EU-wide response if they are deemed to be a serious potential threat.

The RNIMP in Practice

EMA describes the plan as consisting of two pillars of support: a dedicated management structure contained at the EU-wide level and a procedure administered by the former.
The management structure takes a bifurcated approach toward the exchange of information. A Rapid Alert system communicates urgent safety risks to regulators, while a Non-Urgent Information system funnels potentially serious incidences to the same. Both sets are reviewed by the Incident Review Network—a digital network of EU regulators from EMA, NCAs and the European Commission—which then recommends action to the EU crisis management team.
This crisis management team is composed of an EU Executive Task Force charged with confirming a crisis and initiating a response and an EU Operational Task Force charged with responding to the crisis and recommending changes to avoid the crisis in the future.
The entire RINMP involves a seven step process in which it monitors a threat, evaluates it, confirms the threat is a crisis, initiates and monitors a response, confirms the crisis has been abated and takes steps to determine how it could be prevented from happening again.
Pharmacovigilance Monitoring Plan

FDA Issues Final Rule on Clinical Investigator Disqualification

The U.S. Food and Drug Administration (FDA) announced an amendment that will expand the scope of clinical investigator disqualification.  Under this new regulation, if the FDA Commissioner determines that a clinical investigator is ineligible to receive one kind of test article (drugs, devices or new animal drugs), the investigator will also be ineligible to conduct any clinical investigation that supports an application for a research or marketing permit for other kinds of products regulated by FDA.  This final rule is intended to help ensure adequate protection of research subjects and the quality and integrity of data submitted to FDA.  This rule will become effective May 30, 2012.

The final rule is available using the following web link: 

Conducting Effective Clinical Investigator Audits


audit of clinical investigator sites is often related to monitoring activities.

Like the monitor, an auditor ensures that reported trial data are accurate and complete, and that the trial is conducted in compliance with Standard Operating Procedures (SOPs), Good Clinical Practice (GCP) and applicable regulatory requirements.

These activities help to ensure that the rights and well-being of subjects are protected, viable product candidates reach the public with fewer obstacles, and potential risk or liability to the Company is reduced: i.e., protect the patient, protect the product, protect the Company.

Although both the auditor and monitor share these directives, the auditor differs from the monitor in the scope and performance of their work.  Whereas an individual monitor may be concerned primarily with overseeing the progress of a clinical trial at a particular investigator site(s), an auditor is guided by the importance of the trial in submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s) with a particular trial or clinical program.  The scope of an audit also includes an assessment of monitoring activities as they relate to the conduct of the trial.

To perform this function, the auditor must be independent of the monitoring and QC (Quality Control) functions to reduce any potential bias from experience with a particular study or investigator site and appropriately evaluate the risks inherent to a particular clinical trial relative to concurrent clinical development activities.  It is from this vantage point that clinical investigator sites are selected for audit based on criteria defined in the audit plan for the trial.

Auditors are qualified and selected to conduct investigator site audits based on their training and experience.  An auditor must be proficient in the practice of audit conduct, particular aspects of the trial and interpreting relevant information to identify compliance trends.  Preparation for a clinical investigator audit typically includes a review of the Investigator’s Brochure, Protocol and amendments, Informed Consent Forms, CRF’s (Case Report Forms), CRF completion guidelines, monitoring reports, SAE (Serious Adverse Event) reports, site correspondence and other relevant documentation in the Trial Master File.  The audit should be scheduled such that the Principal Investigator (PI), Site Coordinator(s) and other key staff will be available during the audit.  The auditor(s) will discuss site performance and any identified issues with the clinical project team prior to visiting the site.

During conduct of an audit, auditors will perform a detailed review of site regulatory files, informed consent forms, study correspondence, investigational product/material accountability records, and selected patient files including a comparison of information recorded on source documents with data recorded on case report forms.  Interviews will be conducted with the Principal Investigator, Study Coordinator and other site staff to discuss trial roles and responsibilities as well as the conduct of study activities, including procedures for gaining informed consent.  An auditor should use appropriate interview techniques to gain additional information to identify potential issues and performance trends as well as the attitudes and behaviors that led to any identified data discrepancies or events observed.  For example, is the Investigator reluctant to admit or correct mistakes?  Is the data recorded deliberately misleading or is it the result of a limited number of staff taking on too large a volume of work?  

These observations may result in the discovery of protocol violations, discrepancies in data or differences between site staff description and performance of trial activities.    It is an essential part of effective audit technique not only to be able to relate individual observations and data points to identify trends and patterns that may seem hidden among individual discrepancies, but to interpret the value and context of these trends relative to the risks to data integrity and compliance for the trial as a whole. 

If illegal or unethical activity is indicated, the auditor should record their observations, safeguard evidence and obtain copies of pertinent records.  A key distinction between demonstrating fraud and misconduct on the part of an investigator is the ability to prove intent.  Records and testimony collected during an audit may prove essential to being able to make this legal distinction.

During the audit exit interview, audit findings are presented and specific questions asked by both the site staff and auditor(s) to ensure accuracy.  There should be no ‘surprise’ audit findings if an auditor has been communicating effectively with site personnel throughout the conduct of the audit.  The auditor should also communicate with investigators and site staff to identify any issues or concerns that may fall within the influence of the Sponsor.

As a representative of the Sponsor, it is important that an auditor carry out their work in a professional manner.  How an auditor conducts her/himself, both on site and in correspondence, could have a potential impact on the liability of the Company.  Inappropriate conduct on the part of the auditor may be subject to actions related to securities laws, antitrust laws, violation of due care, or even aiding and abetting.  In addition to the standards of ensuring confidentiality and avoiding conflicts of interest, an auditor should not make any promises to site personnel on behalf of the Sponsor or tell auditees how to do their work (thereby inheriting partial liability for work conduct).  

Audit reports may be notoriously dry and matter-of-fact, but this approach is both to mitigate legal liability and provide a report of site performance with limited bias.  

It is not enough, however, to just write an audit report and file it away.

Timely follow-up and correction of audit observations will help to keep site operations compliant and data accurate.

Particular site observations may indicate more general actions for the study that can improve the compliance, accuracy, speed and/or costs of conducting the trial.

Conducting effective clinical investigator audits requires auditors to maintain standards of professional conduct and proficiency to provide an independent, unbiased report to management on the conduct of a clinical trial.  Clinical investigator audits, as part of an overall quality oversight program, help to effectively manage the risks to trial subjects, ensure data integrity and limit potential regulatory or legal liability associated with the conduct of clinical trials.

FDA Guidance: FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND

FDA issued the following guidance, "FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND, Frequently Asked Questions."  The guidance is intended to clarify the requirements if 21 CFR 312.120 and it also provides recommendations for IND's or MAA"s on how to provide evidence of GCP compliance of a non-IND foreign clinical study. 


FDA Guidance: IND Applications for PET Drugs

FDA's draft guidance summarizes the investigational new drug application (IND) process for unapproved positron emission tomography (PET) drugs, makes recommendations on how to submit an IND, provides advice on investigational PET drug access options, and describes the process for requesting permission to charge for an investigational PET drug.  Read the guidance at www.fda.gov:  Investigational New Drug Applications for Positron Emission Tomography (PET) Drugs (PDF - 461KB)