Table of Contents
Food and Drug Administration
Scott Gottlieb M.D. Served As FDA Commissioner From 2017 To 2019.
Clinical Trials Oversight
- OFFICIAL INACTION
A Science investigation shows that FDA oversight of clinical trials is lax, slow moving, and secretive—and that enforcement is declining.1)
FDA Biologics Safety Monitoring
The Biologics Effectiveness and Safety BES System was launched in October 2017 to expand and enhance CBER access to new and better data sources, methods, tools, expertise and infrastructure to conduct surveillance and epidemiologic studies. BEST is part of the Sentinel initiative and it promotes CBER's Office of Biostatistics and Epidemiology's (OBE) mission to assure the safety and effectiveness of biologic products including vaccines, blood and blood products, tissues and advanced therapeutics.
The vision for BEST is for it to be the pre-eminent resource for evaluating biologic product safety and effectiveness that leverages high-quality data, analytics and innovation to enhance surveillance, real-world evidence generation, and clinical practice that benefits patients.
BEST builds and expands upon activities undertaken as part of previous FDA collaborative studies for biologic product safety and effectiveness. *BEST’s objectives are to build data, analytics, infrastructure for an active, large-scale, efficient surveillance system for biologic products develop innovative methods to utilize electronic health records (EHR) effectively and establish automated adverse events reporting, utilizing natural language processing and artificial intelligence
BEST fulfills the requirements of the FDA Amendments Act of 2007 for an active postmarket risk and analysis system covering at least 100 million persons. It supports FDA’s broader mandate outlined in the 21st Century Cures Act. BEST also supports the reauthorization of the Prescription Drug User Fee Act *PDUFA VI by advancing post marketing drug safety evaluation through expansion of the Sentinel System and Integration into FDA regulatory activities.
Learn More about FDA’s Postmarket Surveillance Programs
FDA Contractor Surveillance RFI
In September 2017, FDA/CBER awarded two separate ~one-year contracts to IMS Government Solutions, Inc to launch a new pilot initiative within the CBER Sentinel Program called the Biologics Effectiveness and Safety (BEST) Initiative. The primary goals of the two initial contracts were 1) to develop a pilot system using electronic health record (EHR) data sources, the Observational Medical Outcomes Partnership (OMOP) Common Data Model, and Observational Health Data Sciences and Informatics (OHDSI) tools to conduct regulatory studies; and 2) to develop improved automated adverse events data collection and analysis techniques by using methods such as machine learning, artificial intelligence, natural language processing and others to conduct more sophisticated surveillance and automated adverse event reporting for blood and blood-derived products.
CBER plans to continue to develop additional active post-market risk identification and analysis systems as part of the Biologics Effectiveness and Safety (BEST) Initiative in the Sentinel Program by using new data sources, enhanced capabilities and expanded infrastructure with the goal of providing deliverables in a more cost-effective, efficient, and timely manner for all biologic products. CBER's BEST Initiative will build additional capacity for: 1) Data, tools and infrastructure for surveillance of biologics; and, 2) New, innovative approaches to conduct automated adverse event reporting for biologic products to include approaches and applications such as machine learning, artificial intelligence, natural language processing and others.
BIOLOGICS EFFECTIVENESS AND SAFETY (BEST) OBJECTIVES AND SCOPE
The primary goal of the future contract is to expand and enhance the current CBER capabilities with respect to data sources, infrastructure, methods, and tools and to conduct surveillance and epidemiologic studies that promote CBER's Office of Biostatistics and Epidemiology's (OBE) mission to assure the safety and effectiveness of biologic products including vaccines, blood and blood products, tissues and advanced therapeutics. This contract builds and expands upon activities undertaken as part of previous FDA collaborative studies for biologic product safety and effectiveness such as the Sentinel contract awarded to the HPHCI in 2014 and the contract awarded to IQVIA (formerly known as QuintilesIMS) in 2017.
The objectives of this contract are to (i) build operational infrastructure and provide FDA with indirect access to large-scale United States (U.S.) health care data including administrative and claims as well as electronic health records (EHR) data sources using a distributed data model and network which would require the use of a common data model (CDM), (ii) the capability and capacity to run queries and observational studies on the data sources for CBER-regulated biologic products, and (iii) develop semi-automated processes for medical chart review to augment manual review of charts.
The contractor shall provide a quality-checked and rapidly expanding distributed data network and a structured CDM that can accommodate granular clinical data in all care settings for blood, blood products, vaccines, tissues, and advanced therapeutics. Also, availability of longitudinal data for a large U.S. population and ancillary clinical data such as demographics, health care utilization, laboratory test results, blood transfusion, and geographic distribution are desirable characteristics for the data network of claims and EHR sources. The CDM requires to include a large library of clinical data elements with the capacity to expand the clinical data library and incorporate Information Standard for Blood and Transplant-128 (ISBT-128) and Codabar coding systems (a standard terminology for medical products of human origin).
The Contractor shall develop the tools and methods needed to conduct population-based safety and effectiveness studies of CBER-regulated biologics using a distributed network of databases and provide scientific expertise to design and execute simple and complex queries as well as execute complex epidemiologic studies in a timely manner. Also, the contractor shall develop semi-automated capabilities to validate clinical outcomes and exposures to reduce or replace manual medical chart review.
Overall, the contractor shall provide the capability and capacity in terms of data sources, tools and scientific expertise and operational management to run queries and observational studies in the form of simple and complex queries as well as complex epidemiologic studies, methods (semi-automated processes for medical chart review, link health care data of mothers and their infants, link claims and EHR data) and devise a Management Plan to manage the contract and produce milestones and deliverables according to the specified schedule.
The proposed FDA work may be conducted under a number of possible organizational structures and arrangements. The data holder(s) or other organization(s) may have their own team of epidemiologists, subject matter experts, bioinformaticians, programmers and others who are experienced in conducting post-market pharmacoepidemiological safety and effectiveness studies for drugs and biologics. Alternatively, the contractor may work with other organization(s) or academic partner(s) which has its own team or may assemble its own team of such experts, and that organization may serve as a Coordinating Center to manage the work. See Attachment 1, Draft IDIQ SOW.
It is anticipated that this requirement will result in the award of an Indefinite Delivery/ Indefinite Quantity (IDIQ) contract.
Place of Performance: Contractor's facility.
An Industry Day is scheduled for February 12, 2018. See attachment 2 for further information.
FDA Oversight Failure
2007 Report - Department of Health and Human Services - OFFICE OF INSPECTOR GENERAL THE FOOD AND DRUG ADMINISTRATION’S OVERSIGHT OF CLINICAL TRIALS
Data limitations inhibit FDA’s ability to effectively manage the BiMo program. Because *FDA does not maintain a clinical trial registry*, it is unable to identify all ongoing clinical trials and their associated trial sites. Further, because FDA does not maintain an IRB registry, it is unable to identify all IRBs. Even though FDA maintains six databases to track BiMo inspections, none includes complete information needed to track all such inspections
For example, ORA’s database does not include complete information for inspection events that occur after it completes its inspection. The center databases do not consistently track inspection information. Other factors hinder FDA’s ability to effectively manage the BiMo program. Centers and ORA inconsistently classify OAI and NAI inspections. FDA relies on *voluntary compliance* to correct violations of regulatory significance.
Uncertainty of timing and lack of coordination impede FDA’s ability to conduct BiMo inspections. In addition, FDA guidance and regulations do not reflect current clinical trials practices. We estimate that *FDA inspected 1 percent of clinical trial sites* during the fiscal year 2000–2005 period. FDA conducted 2,856 BiMo inspections that required a clinical trial site visit during the FY 2000–2005 period.
Because FDA cannot identify the total number of clinical trial sites, we used the NIH clinical trial registry to estimate the proportion of clinical trial sites the BiMo inspections reached. The centers conduct more inspections that verify clinical trial data than inspections that focus on human subject protections. *Seventy-five percent of the BiMo inspections during the FY 2000–2005 period were surveillance inspections, which generally target previously completed trials* and often focus on verifying the quality of clinical trial data. Also, FDA inspected few IRBs, which offer considerable oversight of human subject protections.
In 2007 the Department of Health and Human Services’ Office of the Inspector General released a report on FDA’s oversight of clinical trials conducted between 2000 and 2005. The report found that the FDA inspected only 1% of clinical trial sites.6 Inspections carried out by the FDA’s vaccines and biologics branch have been decreasing in recent years, with just 50 conducted in the 2020 fiscal year
Arie Menachem, whose experience at the Merck plant has not been previously disclosed, was part of a specialized FDA division called Team Biologics, an elite unit comprised of 14 investigators who inspect the 280 manufacturing plants that make vaccines and blood products for U.S. patients and ensure manufacturers follow the detailed rules such work requires…
On his first afternoon at Merck’s Durham plant, Menachem’s concern deepened when his FDA supervisor belatedly emailed him a 19-page document, sent to the agency from a confidential informant at the facility. The allegations described a biohazard nightmare. Workers appeared to be defecating and urinating in their uniforms, and feces had been found smeared on the floor of the plant’s production area, the letter alleged. In a sterile manufacturing plant, bathroom breaks can be difficult to take because they require additional time, which could serve as one possible explanation for the events inside the Merck plant…
Merck is no stranger to vaccine-related whistleblower allegations. In 2010, two Merck virologists filed a whistleblower lawsuit in the U.S. District Court for the Eastern District of Pennsylvania, alleging that company scientists, with the knowledge of Merck executives, used improper testing techniques and manipulated data to falsely claim that its M-M-RII vaccine had an efficacy rate of 95%. It did so, the lawsuit suggested, so that the vaccine could be relicensed by the FDA, and also bundled with a chickenpox vaccine to create a new vaccine product called ProQuad. The lawsuit claimed that Merck’s M-M-RII vaccine had a lower efficacy rate, which might have led to a resurgence of mumps. The case is still being litigated, and both sides have moved for summary judgment.