PRISM Identifies Vaccine Safety Issues

By: Azadeh Shoaibi, Ph.D., M.H.S.

The word “prism” might make you think of a triangular piece of glass that separates white light into a rainbow of colors.

Azadeh ShoaibiBut at FDA, it means a powerful, computer-based system that separates critical bits of information from vast streams of healthcare data in order to investigate adverse events and determine if there is a connection to a specific vaccine. And while the FDA prism–called Post-licensure Rapid Immunization Safety Monitoring System (PRISM)—might not have such a colorful name, it’s a bright light in the agency’s continual efforts to identify adverse effects in a timely manner.

PRISM is a cooperative effort between FDA’s Center for Biologics Evaluation and Research and its partners in the health care and medical insurance communities. It analyzes health insurance claims data from four national healthcare plans: Aetna, HealthCore (Wellpoint), Humana, and OptumInsight (United Healthcare).

Prism image

PRISM is a computer-based vaccine safety monitoring system that separates out critical information from vast streams of healthcare data. A part of the Sentinel Initiative of FDA, PRISM broadens the agency’s ability to monitor critical healthcare products in support of its mission to protect and advance public health.

Since it was first inaugurated in 2010, PRISM has made valuable contributions to public safety.

For example, FDA was able to use the system to reassure the public that there was no link between an influenza vaccine and increased risk of febrile seizure in children (convulsion or seizure brought on by a fever). Another PRISM study comprising more than 1.4 million doses of Gardasil doses found no evidence of venous thromboembolism after vaccination among females 9 to 26 years old. FDA also used PRISM to identify a link between a rotavirus vaccine (RotaTeq) and an increased risk of intussusception in infants.

These case studies, along with other information, were discussed at a public meeting in December called to discuss what the system has accomplished and how it’s used in the regulatory process. The purpose of the workshop was to describe the Sentinel Initiative (a national electronic system for medical product safety surveillance) and the PRISM program, illustrate how FDA uses PRISM for regulatory responsibilities, and discuss the future direction of PRISM, including its further integration into the regulatory review process.

Stakeholders, including manufacturers, academics, the public, and other federal agencies, who participated in the workshop had an opportunity to weigh in with their opinions about the system, discuss its limitations, and offer ideas for improving it.

PRISM is one component of FDA’s Sentinel Initiative, which monitors the safety of a variety of FDA-regulated medical products by examining information in electronic healthcare databases.

Sentinel performs what is called “active” surveillance, as opposed to “passive” surveillance. Passive FDA surveillance systems depend on industry, consumers, patients, and healthcare professionals to recognize and report suspected adverse events to an FDA web site, such as the Vaccine Adverse Event Reporting System (VAERS). This means that FDA might not become aware of potential problems related to a licensed product for months.

Unlike passive surveillance, Sentinel’s active surveillance lets FDA initiate its own studies using existing electronic healthcare data in a timely manner. Sentinel also lets FDA evaluate safety issues in targeted groups, such as children, or to evaluate specific conditions (e.g., heart attacks) that are not usually reported as possible adverse events of medical products through passive reporting systems.

So by adding an active surveillance capability to FDA’s toolbox, Sentinel broadens FDA’s ability to monitor the safety of a spectrum of licensed medical products in support of the agency’s mission to protect and advance public health.

Azadeh Shoaibi, Ph.D., M.H.S., is the Sentinel Lead at FDA’s Center for Biologics Evaluation and Research

CBER Laboratories in the Life Sciences-Biodefense Complex

By: Carolyn A. Wilson, Ph.D.

Wise management of research programs means more than selecting projects that will yield the most scientific information but also making sure that we are making wise use of the dollars we allot for research.

Carolyn A. WilsonThat’s why FDA’s Center for Biologics Evaluation and Research (CBER) thinks strategically when it plans research programs by the more than 70 principal investigators who work in our two-year-old laboratories in the Life Sciences-Biodefense Complex at FDA’s White Oak campus.

We ask ourselves how we can most efficiently – and cost-effectively – obtain the answers to our scientific questions that our regulators will need to achieve their mission of ensuring the safety, purity, and potency of biological products.  Products regulated by CBER include vaccines, allergenics (allergy diagnostics and treatments), cellular, tissue, and gene therapy products, and blood and blood products.

To sharpen our research planning we recently undertook a major evaluation of our center’s scientific and administrative strategies and programs with the assistance of an outside consulting firm.

The findings have enabled us to refine  our strategies for wringing the most new knowledge from every dollar we spend on regulatory science – the science of developing new tools, standards and approaches to assess the safety, efficacy, quality and performance of FDA-regulated products. These refinements to CBER’s research strategy include:

  • A Resource Committee that manages CBER’s annual budget, as well as a Regulatory Science Council that develops center-wide goals, guides office-level objectives, and oversees all research activities. These two councils will increase overall transparency of decision-making, make sure that research is prioritized, and aim to make budget planning more timely and responsive to our mission.
  • More direct control of funds by individual CBER offices and earlier allocation of that funding, and annual peer review of 25 percent of existing and new projects to ensure accountability for how they are run.
  • Systems to increase the transparency of CBER research and research funding, enhance management decisions, and facilitate tracking of funding allocated to activities and projects.
  • Elevating the culture of science through monthly presentations highlighting the public health impact and mission relevance of CBER research; biannual CBER-wide Science Symposium, providing opportunities for communication and potentially improved collaboration across all CBER research projects; and, enhanced prominence of CBER research fellows in the research enterprise.
jars of vegetables

Faulty home food preservation is one potential source of botulism. FDA scientists are developing methods that will help manufacturers to make a vaccine that will prevent this bacterial illness.

These research and administration refinements are helping us better identify and prepare for tomorrow’s needs.  And when you consider the approximately 70-80 research programs we have underway, we’re doing a lot. A few examples include:

  • Studying botulism toxoids (inactivated illness-causing chemicals released by bacteria) to support development of the first vaccine to prevent this potentially fatal infection. CBER scientists are designing new tests to predict what vaccine approaches may be protective. These tests may also help screen vaccines that protect against other toxins such as those from anthrax, as well as the plant-derived toxin ricin.
  • Determining the critical immune events that provide protective immunity to intracellular microbes (bacteria and parasites that live inside human cells). Based on this, FDA scientists will develop new measurements to predict protection that may help evaluate new vaccines for these microbes.

    Girl sneezing in a field of flowers.

    Allergies can turn nature walks into annoying sneezing fits. FDA scientists are developing new tools to help manufacturers produce more potent allergy shots and enhance their safety.

  • Developing new tools and data to help manufacturers produce more potent allergy shots and enhance their safety.
  • Helping to develop a test for cow intestine to ensure heparin harvested from this tissue is not contaminated with the agent causing the bovine transmissible spongiform encephalopathy (TSE, also known as “mad cow disease”), a known risk to humans. This would help to ensure a safe, reliable, domestic source of heparin, which is now obtained mostly from China.
  • Developing new methods and technologies for rapid-testing detection and characterization of emerging infectious pathogens that threaten the safety of tissue and tissue-based products. In the course of developing these technologies, the lab has found previously unidentified microbial contaminants in archived tissues used for these studies. These findings provide preliminary evidence to support the potential for application of rapid test technologies in evaluation of emerging infectious disease transmission risks associated with the implantation, transplantation, infusion, or transfer of human tissue.

As CBER continues to advance regulatory science in its Life Sciences-BioDefense Complex, our projects will adapt to new challenges that the science of biologics will inevitably pose to FDA. And CBER will address those challenges, keeping in mind both the public health and our fiduciary responsibility to make every research dollar count.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research

Stem cell therapy: FDA regulatory science aims to facilitate development of safe and effective regenerative medicine products

By: Steve Bauer, Ph.D.

One of FDA’s primary missions is to make sure that the products we approve are safe and effective. There is tremendous interest in the development of regenerative medicine, including numerous proposed products that rely on stem cells. Stem cells have the ability to generate more stem cells or to turn into more mature cell types such as nerve- or bone-producing cells. These properties make stem cells potentially well suited for use in regenerative medicine. They might be used in repairing heart, nerve, and brain damage or in treating diabetes and other diseases by repairing or replacing cells and tissues.

Steve Bauer

Steve Bauer, Ph.D., chief of the Cellular and Tissues Therapy Branch, Division of Cellular and Gene Therapies, in the Office of Cellular, Tissue and Gene Therapy at CBER.

Because stem cells can change based on their surroundings, whether during growth outside of the body or following injection into the body, ensuring the safety of effective regenerative medicine products can be challenging. One type of adult stem cell, the multipotent marrow stromal cell (MSC) — more popularly called the mesenchymal stem cell — is the subject of a great deal of research in regenerative medicine. These cells can divide repeatedly, making additional cells, and under the right conditions can be turned into a variety of more specialized and mature types of cells. Depending upon the culture conditions, these more specialized cells have the potential to produce cartilage, bone, and fat, and help with control of inflammation and immunity.

MSCs can be obtained from bone marrow and adipose tissue (fat) and can be grown outside of the body to produce the large numbers needed for many proposed clinical trials. Donated MSCs can also suppress the immune system in individuals who receive them, preventing their rejection and allowing cells from one donor to potentially treat many different people, unlike most other cells or tissues.

But there are still scientific questions to answer about MSCs. A particularly important set of questions is how the manufacturing of these cells outside of the body could affect their potential healing properties and their safety. FDA scientists believe that answering these questions will improve the way MSCs are characterized and thereby facilitate the development of products made from MSCs. For this reason, the FDA’s Center for Biologics Evaluation and Research assembled seven of its laboratories into a consortium to develop tests and techniques that will help answer these types of questions as these products move through the development process.

Using bone-marrow-derived MSCs from eight different human donors, the consortium has published scientific articles on the following topics:

  • Evaluation of the ability of human MSCs to suppress activation of certain types of mouse immune cells in order to reduce variation in MSC immune suppression assays that use T-cells from human donors who might have many different T-cells. The mouse cells come from a genetically modified strain in which all of the mouse immune T-cells are identical.
  • Creation of a large database of MSC proteins (a total of 7753) that enabled us to demonstrate the large variability among proteins from different MSC samples. This database will enhance our understanding of MSC biology and help define the variability among various MSC samples.
  • Identification of 84 proteins (14 identified for the first time) on the surface of MSCs that may be useful for tracking these cells as they grow, divide, and differentiate to produce specific tissues.
  • Development of techniques that enable scientists to quantify the ability of MSCs to multiply and to differentiate into specific cell types.
  • Identification of specific genes that distinguish aging MSCs grown in cell culture, which could facilitate development of tests that evaluate the quality of MSCs before they are used to treat patients.

These contributions are part of the overall effort of FDA to bring safe and effective stem cell-based therapies to the many patients who could potentially benefit from this type of regenerative medicine.

Steve Bauer, Ph.D., is the chief of the Cellular and Tissues Therapy Branch, Division of Cellular and Gene Therapies, in the Office of Cellular, Tissue and Gene Therapy at FDA’s Center for Biologics Evaluation and Research.