|U.S. Food and Drug Admiinistration, Center for Drug Evaluation and Research Small Business and Industry Assistance (CDER SBIA)|
|As our society becomes more global, it has become increasingly clear that the U.S. Food and Drug Administration needs to take a more collaborative approach to our drug approval process. Today, drugs that are approved by the FDA to be marketed in the United States are developed both in and out of the United States. Of the 46,391 participants in the clinical trials that supported the 48 novel drugs approved by the FDA in 2019, 60% of the participants were located outside the U.S., showing the international nature of drug development. While many clinical trials have an international component, the marketing authorization, including the application and review process, varies from country to country. What also varies is what information is made available to researchers, industry and the public about the scientific basis for each drug approval. Regulatory agencies in different countries are governed by different applicable laws and have their own transparency standards. |
To realize the benefits and opportunities provided by a more transparent drug approval process, we must first identify, and address, some of the challenges facing the global drug development community. The FDA is committed to improving collaboration efforts with drug-approving regulatory agencies in other countries, and to increasing transparency related to the scientific basis for drug approval decisions. The FDA is working on multiple fronts to support these efforts and apply best practices.
In 2018, the Center for Drug Evaluation and Research (CDER) at the FDA implemented the Clinical Data Summary Pilot Program, a voluntary pilot program designed to evaluate whether disclosing certain information included within clinical study reports (CSRs) following approval of a new drug application improves public access to drug approval information. When a drug is approved, the FDA releases certain information that the agency used when reviewing the new drug application, including summaries written by our medical reviewers that capture their assessment of the data, the approved labeling or other requirements, and other important, relevant data supporting safe and effective use. This information is included in our drug approvals database, Drugs@FDA. These summaries provide important context on the basis for our approval decisions, but they are packaged in a format that can sometimes make it difficult for external audiences to extract and understand the detailed clinical evidence that supported the FDA’s approval decisions.
The pilot aimed to test a new process for selecting, redacting and posting on the FDA’s public website summaries of information that the agency uses in making marketing approval decisions. The overarching goal of the pilot was to assess the feasibility of improving access to summary clinical trial information about approved drug products for the drug research and development community, medical researchers and the public. With this pilot, we aimed to respond to stakeholders’ requests for greater transparency in the drug approval process and more access to usable information and evaluate whether disclosing certain information improved public access to drug approval information.
After receiving useful internal and external knowledge and feedback as part of the pilot program, we have decided to conclude the pilot. In the interest of increasing transparency in the drug approval process, the agency has learned many best practices through the pilot that we intend to apply to future efforts. For example, we found that there are significant inefficiencies in having multiregional disclosure requirements relating to often identical clinical data summaries. These inefficiencies multiply the transactional, administrative and redaction (because there are differing regional disclosure standards) costs, whether the costs are incurred by industry or a regional regulatory authority. These costs create barriers to programs to disclose clinical trial information which might be reduced if a centralized or regional approach could be achieved.
Through the CSR pilot, we also identified a potential approach that could facilitate a harmonized system for disclosing study reports. The general framework of this approach includes the following principles:
International Library: A centralized international library, managed by an independent organization, where information is made available to the public rather than each regulatory authority having its own system. MedDRA.org is an example of a successful model of international harmonization through use of an independent organization.
On-Demand: An on-demand system, where sponsors would automatically publish a limited number of documents in the international library, such as the summaries of clinical information and an index of study reports, should be considered. The public could request study reports of interest, and the sponsor would then prepare the report, protocol and statistical plan and add it to the library.
Standardized: Anonymization and disclosure standards would be established to satisfy the requirements of the participating regional regulatory authorities. Our ongoing, independent efforts to establish anonymization standards and best practices (e.g., PhUSE) will continue.
Voluntary: A sponsor could have the choice of committing to use the international library system to disclose study reports, protocols and statistical plans for all marketing applications or to follow the requirements of each region where they apply for authorization to market products.
While increasing international harmonization efforts to share clinical study reports is a long-term goal, in the short term we are assessing how the lessons learned during the pilot can be applied in our modernization efforts. For example, CDER’s Office of New Drugs, in consultation with relevant stakeholders, may consider whether posting of certain portions of the clinical summary data would improve transparency and enhance our integrated review activities.
As the pilot concludes, our harmonization and transparency efforts will continue. The FDA continues to invest in our work with our international partners. This work brings together regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug development.
We plan to keep stakeholders informed of any future projects in these areas, as appropriate, and we sincerely thank those who took the time to comment on and participate in the pilot. We will continue to look for ways to improve harmonization and transparency in the drug approval process as we move forward with our modernization efforts.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products. The Small Business and Industry Assistance program in the Center for Drug Evaluation and Research (CDER SBIA) provides guidance and information to regulated domestic and international small pharmaceutical business and industry through its website, email notifications, and workshops.
Jennifer Goldfarb, CCRP
Senior Director, Clinical Research Support Office
Children’s Hospital of Philadelphia
Grace Wentzel, CCRP
Director, Clinical Research Services
The Research Institute at Nationwide Children’s Hospital
Abstract: The study start-up process sets a study up for success or failure. This article provides an overview of study start-up, the players on the study team, and the infrastructure required for successful study start-up. Tools for the study feasibility assessment for dissecting and implementing the protocol and for ensuring compliance are described. Challenges to study start-up and solutions to those challenges are provided.
Continue reading Developing Effective Study Start-up Processes →
IRB Audits and Inspections
IRB audits can be conducted by federal agencies overseeing research such as the FDA or the Office for Human Research Protections, research bases, study sponsors, and IRBs. Pharmaceutical sponsors do routine monitoring of their studies at regular intervals. The Toledo Community Oncology Program’s research bases only audited the program every three years. This can make it difficult to know about mistakes made years earlier and to put quality assurance processes in place when needed.
Continue reading Steps to Ensure an A+ on Your IRB Audit (Part 2) →
Pamela Shoup, CCRP
Past Executive Director, Toledo Community Oncology Program
Current Research Manager and IRB Coordinator for the Toledo Clinic, Inc.
Abstract: A well-organized institutional review board (IRB) ensures excellent quality assurance in the regulatory area and enables the IRB to score an A+ on regulatory inspections conducted by the U.S. Food and Drug Administration (FDA). This article describes best practices in IRB management and tools to help prepare for an FDA audit. Lessons learned from experiences at the Toledo Community Oncology Program are highlighted.
Continue reading Steps to Ensure an A+ on Your IRB Audit (Part 1) →
Anatoly Gorkun, MD, PhD, Assoc CIPD
Scientific and Compliance Training, MedImmune
Abstract: Different professional training techniques can be used to achieve training goals. This article describes how to deliver efficient training sessions that benefit learners, evaluate training sessions, and use the evaluation results to make necessary improvements. Topics covered include learning styles, planning the training, different training styles, monitoring learning progress and adjusting the training, and bringing the training session to a close. Examples of training evaluation tools and their role in continual improvement of training for clinical research professionals are highlighted.
Continue reading Effective Training Delivery and Evaluation: Professional Approaches and Tools →
James F. Bush, Esq. 
In 2018, the European Union’s General Data Protection Regulation (“GDPR”) came into full force and effect. With the growth of international multi-center clinical research studies, U.S.-based research organizations and investigators will now be governed by the GDPR to the extent that they control or process Personal Data of EU citizens in the course of their research. While efforts to attain compliance with HIPAA and HITECH within the U.S. provide clinical researchers a head-start in attaining compliance with the GDPR, substantial additional efforts must be undertaken to avoid the risk of enforcement penalties for failure to meet the mandates of the GDPR in conducting clinical research. A basic understanding of the important rights granted to study subjects, the jurisdictional reach of the law, logistical and organizational considerations, and the possible risks of enforcement action is now an essential competency for those engaging in clinical research involving EU citizens. The goal of this paper is to provide a regulatory overview of the law and its effect on clinical research in order to enhance the competency of investigators, project managers, and decision-makers involved in such clinical research.
Continue reading An Overview of the General Data Protection Regulation (“GDPR”) for Clinical Research Organizations →
Associate Director, Clinical Documentation Management
Abstract: Regulatory agencies are advocating for sponsors to take risk-based approaches in various clinical trial-related activities, especially in the area of monitoring. Sponsors are looking at and beginning to use centralized monitoring. This article describes centralized monitoring, regulatory and industry expectations and initiatives related to centralized monitoring, the value of centralized monitoring in enhancing data quality in clinical trials, and use and documentation of centralized monitoring,
Disclaimer: The views and opinions expressed in this article are those of the author and should not be attributed to the Society of Clinical Research Associates or Regeneron Pharmaceuticals.
Continue reading The Value of Centralized Monitoring →
Amy Waltz, JD, CIP
Associate Director – Regulatory Affairs, Reliance, Outreach
Abstract: Understanding context is key to understanding the regulations and complying with regulatory requirements. This article explores the historical context and events that shaped the current human subjects protection regulations and how changes in human subjects research and public perception have impacted the proposed revisions to the human subjects protection regulations. The 2017 revisions to the Common Rule (45CFR46) and the impact of these revisions on government funded research are also addressed.
Continue reading The Changing Landscape of Human Subjects Research →
Abby Statler, MPH, MA, CCRP
Research Regulatory Quality Assurance Coordinator
Cleveland Clinic Cancer Institute
Abstract: In 2008, The Cleveland
Clinic Cancer Institute established a quality assurance (QA) program for investigator-initiated trials
(IITs). Over the past nine years, the program has become an integral part of
the Institute’s research department, supporting the growth of IITs while
improving the proficiency of regulatory operations. This article describes the
program’s objectives and discusses the operational strategies employed to
achieve these goals. Other clinical research sites are encouraged to consider
how components of the Cleveland Clinic Cancer Institute’s QA program may be
adapted to meet the needs of their organizations.
The research sponsored by Cleveland Clinic investigators supports the Foundation’s innovation initiatives, making it a top priority for the Institute’s leadership team. Thus, the development and implementation of the Cleveland Clinic Taussig Cancer Institute’s QA program was motivated by the organization’s commitment to effectively oversee the conduct of IITs. Launched in 2008, the Cancer Institute’s QA program was the first of its kind, specifically focusing on providing operational support for investigator-initiated trials.
Before the department was implemented, investigator-initiated trials had few operational resources, protocols required multiple revisions, Investigational New Drug Applications were submitted inconsistently to the U.S. Food and Drug Administration (FDA), and processes for effective essential regulatory documentation management had not been established. To date, the QA program has grown from one to five members, which has enabled the department to cohesively support the IIT profile while also improve the operations of industry-sponsored and cooperative group trials. In this article, I will outline the essential components of a QA program, discuss the challenges that our department faced during the program’s development, and highlight how the Institute’s commitment to quality has enhanced the Cancer Center’s conduct and initiation of clinical trials.
Continue reading Building a Quality Assurance Program for Investigator-initiated Trials →
Sarah Attwood, BSc
Director of Client Services
Abstract: Institutional review boards (IRBs) continue to be overburdened with
reports not required by federal regulations. It is important to understand the
difference between what the regulations require and what has become an industry
standard. Additionally, clinical research sites are often confused about
reporting requirements and err on the side of conservatism by over-reporting. By
clearly identifying regulatory requirements, the clinical research industry may
become more efficient and eliminate unnecessary work for sites as well as IRBs.
Study sites are over-reporting adverse events (AEs) and serious adverse events (SAEs) for studies conducted under Investigational New Drug (IND) applications. IRBs are required by the U.S. Food and Drug Administration (FDA) and the Office of Human Research Protections (OHRP) within the Department of Health and Human Services to review “unanticipated problems involving risks to participants or others.”
IntegReview IRB is a central IRB that reviews many protocols each year, just as institutional IRBs do. In 2016, IntegReview IRB saw an increase in the number of IND safety reports and a slight decrease in SAE reports. The reason for these changes is unknown. IntegReview IRB is seeing about a four-fold increase in IND safety reports, which is far above the increase in business.
IRBs receive many IND safety reports that are not related to the current protocol at the clinical researchsite. The reports could be about something that is happening in Asia or Europe, a different use of the drug, or a different research project. These reports must be processed, even though they are not under the jurisdiction of the IRB for the current study, creating information overload.
Continue reading Reducing Over-reporting to INDs and Increasing Efficiencies at Clinical Research Sites →