We’re Committed to Guarding Against the Intentional Adulteration of Food and Implementing the New Rule Efficiently

By: Scott Gottlieb, M.D.

The U.S. food supply is among the safest in the world. But to keep it safe we must recognize that our foods are vulnerable – not just from unintended contamination, but from those who would seek to deliberately do us harm.

Dr. Scott GottliebEnsuring that we’re prepared to minimize the risk of an intentional attack on our food supply is a goal that we share with the food industry and consumers.

The FDA Food Safety Modernization Act (FSMA) charges FDA with addressing the burden of foodborne illness by requiring that producers, importers and distributors of food take systematic steps to prevent contamination. Congress passed FSMA with a view of the unique risks posed by a global food supply. Six of FDA’s seven “foundational rules” for FSMA focus on the safe production, storage, and transport of human and animal food by addressing conventional food safety hazards

But a different reality shapes the seventh rule on Intentional Adulteration. This provision seeks to prevent acts of terrorism meant to harm and kill many people.

Food facilities covered by this rule (both domestic and foreign facilities that export to the United States) are required to implement — for the first time — a food defense plan that identifies vulnerabilities and ways to reduce the risk of intentional adulteration.

Congress directed FDA to focus its efforts to prevent intentional adulteration on the highest risks to the food supply. That’s why the Intentional Adulteration Rule primarily covers large food companies whose products reach many people.

Extensive analysis shows that some of the most significant risks are posed by an attack perpetrated by someone who has legitimate access to a facility, perhaps under the guise of an employee. This is why the new rule asks facilities to focus their efforts on processing activities that — if deliberately attacked by a rogue insider — could potentially result in widespread contamination of products.

FDA is committed to making the implementation of the Intentional Adulteration rule as practical and flexible as possible for the food industry. Even though the initial compliance date for the largest businesses is July 2019, more than a year away, I’m taking steps right now to fully understand stakeholder concerns and challenges, and address them.

As part of this fact-finding process, I recently visited the Nestlé Dreyer’s Grand Ice Cream facility in Laurel, Maryland. My FDA colleagues and I were taken on a tour of the facility, from the receiving dock to the production line to the packaging equipment. It was very helpful for me to see, first hand, the processes and practices that Nestlé has in place that could be used to guard against deliberate contamination.

Addressing Misconceptions

Having this kind of direct interaction with stakeholders is important. This is new regulatory territory for both FDA and industry. We need to make sure we implement these new requirements in a way that achieves its public health goal, without creating unnecessary burdens or costs on industry. From my interactions, I’ve come to believe that there may be misconceptions about how we’re expecting the food industry to implement this rule.

I want to use this opportunity to provide more transparency on our work.

Food facilities covered by the rule will be able to choose from a wide range of options to identify and reduce their vulnerabilities. They have the flexibility to tailor individual options that are cost-effective and make sense for each particular facility.

We recognize that many companies have already made significant efforts to reduce their vulnerability in response to terrorism concerns since the attacks of 9/11. These are important steps. And we believe these existing efforts can help food facilities meet many of the intentional adulteration rule requirements.

Existing measures may be in place for reasons related to business, food safety, and food defense. Many current steps companies take can become important parts of a food defense plan to meet the Intentional Adulteration requirements. However, we also know that there are some areas where additional measures will be needed.

We want to make sure these new measures can be implemented in a way that’s the least burdensome while achieving its intended, food protection purpose.

We agree with food companies that the “inherent characteristics” of food production equipment and processes should be considered when conducting a vulnerability assessment. At Nestlé, for example, vats of chocolate with hatches at the ground level can’t be opened without creating a flood of chocolate, which certainly wouldn’t escape notice. Our rules are meant to be practical. In this case, the inherent characteristics of chocolate vats make the ground-level hatches a low area of vulnerability. This means that mitigation steps may not be needed at this point of access.

During discussions with stakeholders, we’ve also heard that some people believe that plants might be required to construct vast enclosures for their equipment, invest in advanced computer systems, or reengineer whole processing lines.

That’s not the case. We want expectations to be clear to industry stakeholders.

We’ve also heard that some companies believe they’ll have to hire more workers for the sole purpose of observing other workers. We don’t believe that’s going to be the case.

Moreover, we’ve also heard concerns that implementing some food defense measures required under the rule may create conditions that negatively impact worker safety, food safety and food quality. During our extensive work with industry to develop the proposed rule, we’ve identified a variety of strategies that are very practical to implement and don’t impact food production or safety of any kind.

I want to be very clear about this point. Facilities will be given enough flexibility in selecting options for mitigation strategies that there should be no conflicts between food defense and food safety. We’ll work with any company that has those concerns.

And make no mistake, food safety is — and will remain — our first priority. In implementing the requirements of the intentional adulteration rule; we don’t want facilities to take any steps taken that could jeopardize food or worker safety.

I’ve also heard concerns expressed about the potential paperwork requirements associated with the rule and costs associated with monitoring the food defense protective measures required in the rule. We’ll provide examples of how to minimize paperwork and templates for recordkeeping so that costs are kept to a minimum.

We also expect that many of the options for monitoring can be incorporated into an employee’s existing responsibilities. And the frequency of monitoring for some strategies can also be kept to a minimum while still assuring the measures are working, thereby reducing costs.

Upcoming Guidance

Part of the feedback that we received during the Nestlé tour was the need for FDA to provide a guidance document to provide clarity on how firms can more easily meet the new requirements. That’s something we’re working on right now. We plan to publish this new guidance document well in advance of the initial compliance date in 2019.

We’ll soon be publishing the first chapters of this three-part draft guidance to focus on important questions that I’ve heard. Our hope is that this guidance will help manufacturers focus on those measures that have a meaningful impact on protecting food from intentional adulteration. We plan to publish the remaining two parts of the guidance this summer. The entire draft guidance will be available for public comment.

The first two installments of the guidance focus on the greatest concerns expressed by the food industry and the requirements that drive costs.

The first installment includes a simple, cost-effective way to identify the most vulnerable parts of the production process. It details numerous ways to guard against deliberate contamination, including some existing and cost-effective measures, as well as additional ways to monitor the operation to make sure that protections are working.

The second installment includes guidance on an additional, detailed, and flexible method to identify a facility’s most vulnerable points.

Finally, the third installment focuses on corrective actions, verifying that the system is working, how to reanalyze the plan and its parts, and record keeping.

Protecting Against an Inside Attacker

Importantly, the guidance will also address measures facilities can take to address the risk of an inside attacker. The rule identifies that the greatest risk comes from an inside attacker rather than from an outsider. The new measures require that the assessment of vulnerabilities must consider the potential threat from within a facility.

While the possibility of an inside attacker is hopefully not likely at a particular facility, we’re not talking about a theoretical danger. The threat landscape for intentional adulteration continues to grow regarding an inside attack even since the rule was finalized in 2016.

To take one vivid example: There was a recent report of a foiled terror plot in the United Kingdom that involved an employee at a food manufacturing plant who had been investigating ways to poison supermarket-ready foods.

FDA has worked on food defense assessments for more than a decade in collaboration with food manufacturers, universities, and government partners — including the intelligence and law enforcement communities. Our interactions with intelligence and law enforcement communities have repeatedly indicated that an inside attacker presents the greatest potential danger.

Some existing, protective measures in food facilities, such as perimeter fencing and general visitor protocols, are focused on thwarting an outside threat. These measures are also important. But they don’t address the full scope of risks, including an inside attacker, that must be considered when identifying a facility’s most vulnerable points.

The guidance document will provide examples of how to protect against an inside attacker using a range of measures that can be adapted to best meet individual facility needs. In many cases, food facilities will be able to leverage their existing protections.

Next Steps

Industry has also asked about the availability of training on these new requirements, both for food facilities and regulators. We’re working on both fronts to create training and technical assistance for food facilities that’s consistent with other FSMA-related training. And we’ll be training both federal and state regulators as well.

I was grateful to meet and learn from the professionals at Nestlé. I’m impressed by their commitment to food safety and food defense. I know that their efforts, and their commitment, reflect the ethic that’s in place at a lot of leading food companies.

We’ll continue to work through the issues raised by food manufacturers covered by the Intentional Adulteration rule. We need to make sure we implement these requirements in a way that’s cost-effective and efficient. Safeguards that are too costly to put into place, or are too hard for firms to adhere to, don’t work. They don’t meet their purpose.

I look forward to continuing to engage personally in this dialogue. Keeping food safe from contamination during production, storage and transport remains a primary focus of the FSMA rules. And food defense is an important component of achieving that goal.

While intentional adulteration is unlikely, a successful attack could have devastating public health consequences. FDA and the food industry are committed to the overarching goal of protecting consumers from these and other risks. I look forward to partnering with industry to ensure that appropriate measures are in place to give us all confidence that the food supply is as safe as possible from hazards of all kinds.

Scott Gottlieb, M.D., is the Commissioner of the U.S. Food and Drug Administration

FDA Blood Supply and Demand Simulation Model Could Help Nation Prepare for Emergencies

By: Arianna Simonetti, Ph.D., and Richard Forshee, Ph.D.

Keeping the nation’s blood supply and demand system working efficiently can be a matter of life and death. That often means moving blood to meet critical needs when an area of the country experiences shortages. In fact, ensuring that blood gets to where it is needed, when it is needed, during emergencies is an important part of national security preparedness, and part of FDA’s mission.

Arianna Simonetti

Arianna Simonetti, Ph.D., is a Mathematical Statistician at FDA’s Office of Surveillance & Biometrics, Division of Biostatistics in the Center for Devices and Radiological Health

That’s why FDA developed a blood supply model that estimates the amount of blood available in the system during both routine conditions and emergencies. This model is designed to help public health officials effectively plan strategies that will minimize any disruption of the blood supply should blood collection efforts be reduced as a result of an emergency. The model has the advantage of being easily customized to explore various “what-if” scenarios, so it could assist in the development of sound regulatory policy and strategic planning for emergency preparedness and medical responses requiring blood transfusions.

The model estimates how much blood is available during two types of emergencies—a pandemic influenza outbreak and a mass casualty event caused by the detonation of an improvised nuclear device. Either scenario could threaten the blood supply in two ways—by reducing the number of people available to donate or by increasing the amount of blood needed to respond to such an emergency.

Richard Forshee

Richard Forshee, Ph.D., is Associate Director for Research at FDA’s Office of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research

To our knowledge, this model is the first attempt to estimate how much blood would be available for the U.S. blood system during potential national emergencies.

One of the challenges in dealing with an emergency is that red blood cells (RBCs) have a relatively short shelf life. The model allows us to calculate the supply—and the potential for shortages—based on how long RBCs have been in storage.

An earlier model designed by our group provided overall national daily estimates of the number of RBC units available in the demand system. Our new, inter-regional model divides the U.S. blood supply into four regions: East, West, South, and Midwest. This gives us a more fine-tuned look at the blood supply system’s response to emergencies by tracking the collection and transfer of blood across the different regions. It can also give us a snapshot of the blood supply at any time and in any region. This suggests that the model could help in planning for emergencies that trigger higher demands of blood in potentially affected regions.


Blood Availability: A Model of Supply and Demand

The amount of blood that is collected and used in different regions of the country varies. The FDA model of the U.S. blood supply enables public health officials to estimate the availability of blood in each region at any given time. This helps minimize disruption and avoid shortages in the blood supply.The amount of blood that is collected and used in different regions of the country varies. The FDA model of the U.S. blood supply enables public health officials to estimate the availability of blood in each region at any given time. This helps minimize disruption and avoid shortages in the blood supply.In the South, as shown in the example above, the amount of blood donated in a region may be less than the amount needed for transfusions in that region. This potential shortage in donations can be mitigated by blood transfers from other regions, as indicated by the arrows. The FDA model accounts for blood transfers among regions based on data provided by America’s Blood Centers, which collects about 55% of the U.S. blood supply.In the South, as shown in the example above, the amount of blood donated in a region may be less than the amount needed for transfusions in that region. This potential shortage in donations can be mitigated by blood transfers from other regions, as indicated by the arrows. The FDA model accounts for blood transfers among regions based on data provided by America’s Blood Centers, which collects about 55% of the U.S. blood supply.

To build a model that reflected actual blood collection and use in the four regions as closely as possible, we went to real-world sources of data. For example, we used the daily report on the national blood supply produced by America’s Blood Centers to determine how much blood was available in each region. To track blood use in each region, we calculated regional daily RBC units transfused from the 2007-2012 Center for Medicare and Medicaid Center for Medicare and Medicaid Services database. We also used national estimates of blood collections and use from the 2011 National Blood Collection and Utilization Survey. Using this information, the model estimates the average number of RBC units available each day for each region.

To create our scenario for a pandemic, we used data on the outbreak of Pandemic A(H1N1) influenza from the Centers for Disease Control and Prevention and the weekly flu-like activity levels reported by the states.

Guided by a previously-developed computer model simulating the effect of a pandemic on blood donations and blood supplies in Germany, we ran a simulation on how the pandemic could affect the inter-regional supplies of blood in the U.S. One important finding was that the new model estimated that 541,000 RBC units were lost overall and that the South region had the highest percentage of blood lost (15.5%), while the East region had the lowest lost (13.8%), compared to the levels at the beginning of the pandemic.

For our simulation of the demand for RBC units needed following a mass casualty event caused by an improvised nuclear device, we used data on the expected casualties from each type of injury from a previous study. Our own inter-regional simulation let us predict the effect of such an event on the U.S. blood supply. For example, we saw that if the event occurred in the East region, given the current data available, this area of the country rapidly recovered to its original level of blood supply due to increased blood transfers from other regions.

The FDA model showed that, based on current levels of blood collection, use, and other factors, the U.S. blood supply and demand system is flexible and reliable enough to respond to these events.

But our simulation model is just an attempt to replicate the workings of the U.S. blood supply and demand system under various circumstances. Our conclusions could change if patterns of blood donation and use change. However, our experience with this model thus far shows that, as we add more accurate and current data and, make it available to planners, it could help the nation prepare for disruptions of blood collection and demand.

Arianna Simonetti, Ph.D., is a Mathematical Statistician at FDA’s Office of Surveillance & Biometrics, Division of Biostatistics in the Center for Devices and Radiological Health

Richard Forshee, Ph.D., is Associate Director for Research at FDA’s Office of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research

FDA is Using Innovative Methods to Prevent Illegal Products with Hidden Drug Ingredients from Entering the United States

By: Scott Gottlieb, M.D., Melinda K. Plaisier, M.S.W., and Michael Kopcha, Ph.D., R.Ph.

One of the Food and Drug Administration’s important public health functions is to closely monitor the FDA-regulated products arriving at the nation’s international mail facilities (IMFs) every day to prevent unsafe, counterfeit, and unapproved products from entering the country. This sometimes includes interdiction of illicit products, in support of the U.S. Customs and Border Protection (CBP).

Dr. Scott Gottlieb

Scott Gottlieb, M.D., Commissioner of the U.S. Food and Drug Administration

Given the volume of mail, the increasing sophistication of bad actors, and the amount of time it takes to inspect just one package, this is an increasingly challenging task. FDA is taking new steps to increase the scope and effectiveness of this mission. One tool that FDA has deployed is advanced screening technologies that can allow FDA inspectors to screen packages containing suspected drug products more efficiently and reliably.

According to a January 2018 report by the U.S. Senate Permanent Subcommittee on Investigations, in just three years from 2013 to 2015, the number of packages processed by the nation’s nine IMFs nearly doubled. Today, these combined facilities receive more than 275 million packages a year. Most of the mail arrives without advanced or specific identifying information. As a consequence, we have no way of knowing exactly how many packages contain FDA-regulated products.

What we do know is that every year thousands of packages are found to contain FDA-regulated products and a surprising percentage of those products are illegal. These products come in all different shapes and forms – some with sophisticated packaging and others in nondescript plastic bags.

They include unapproved products; counterfeit or substandard drugs; and purported dietary supplements being sold for weight loss, sexual enhancement, bodybuilding or pain relief. Many products promoted as dietary supplements contain potentially dangerous undeclared drug ingredients. Any package initially suspected of containing controlled substances is immediately referred to the U.S. Drug Enforcement Administration. Still, FDA is seeing an increase in the number of packages containing opioids including tramadol, codeine and morphine, making FDA’s investigators the last line of defense for drugs that may not be easily identified as narcotics.

Melinda Plaisier

Melinda K. Plaisier, M.S.W., FDA’s Associate Commissioner for Regulatory Affairs

Last year, FDA increased the number of investigators it has in the IMFs from 8 to 22 full time employees; taking the number of packages FDA is able to open and screen from 10,000 a year to 40,000. These are packages that our partners at CBP have flagged for additional screening in order to intercept and detail what are believed to be nefarious products prior to refusal of admission and possible destruction.

To do so, based on current laws, FDA must first establish that the products are drugs based on their intended use, then determine if the drug is subject to refusal of admission. This requires documenting the contents, which can be a labor-intensive process. Some of the packages may contain loose pills without any packaging or contain hundreds of small internal packages. Screening a single package can take about 20 minutes, while packages that contain multiple products or large quantities can take much longer. This limits the number of packages that FDA is able to inspect. CBP will only pull for inspection the number of packages that FDA is able to complete in a given day. CBP and FDA target the highest risk packages for physical inspection. This is where good intelligence work is key. But packages that can’t undergo a physical inspection will typically be sent on to their recipient. The more that FDA can improve the efficiency of its process, its authorities, and the tools that it uses to evaluate products; the more higher-risk packages that the agency is able to subject to vetting.

Although the agency’s professional staff works hard to examine and document suspicious contents, FDA investigators are only able to inspect a fraction of the incoming international mail packages. It’s estimated that FDA is able to physically inspect less than 0.06 percent of the packages that are presumed to contain drug products that are shipped through the IMFs. Recognizing these hurdles, we’re doing all we can by increasing our existing resources, working more efficiently and identifying innovative ways to extend our efforts.

In addition to tripling the size of our staff, we’ve invested in, and would like to enhance, our screening equipment at the IMF locations and laboratory equipment for the forensic confirmations needed – all of which serves to increase efficiency and strengthen our ability to more quickly identify and assess suspect products entering through IMFs. FDA’s current analytical process requires sending samples to an FDA laboratory for analysis. It can take days or weeks to get results and during that time products would have to be held within the IMF’s limited space, restricting the number of products that can be tested by FDA.

Michael Kopcha

Michael Kopcha, Ph.D., R.Ph., Director, Office of Pharmaceutical Quality at FDA’s Center for Drug Evaluation and Research

One of the most promising technical developments is the successful use of various portable screening devices that will allow us to rapidly test for unsafe ingredients at the IMFs with similar reliability and accuracy as the current laboratory methods. FDA recently concluded a successful six-month pilot at two IMFs, testing whether we might be able to increase the number of packages we screen by making use of a portable screening device called an ion mobility spectrometer. This is the same technology used by airport security to swipe your luggage for explosives and by prisons to screen visitors for illegal narcotics. The device works by comparing the chemical signature of the unknown substance against the chemical signatures of known compounds in a process that takes less than 30 seconds.

For the pilot, the device was loaded with a custom-built library of pharmaceutical compounds to test whether products marketed for weight loss and sexual enhancement contained undeclared drug compounds such as sibutramine, phenolphthalein and sildenafil. These compounds have significant safety concerns and are often counterfeited; and are commonly found within packages coming into the IMFs. When criminals secretly spike products with these compounds, consumers do not know that they are at higher risk of harm from the products.

An astonishing 65 percent of the samples we screened tested positive for the presence of undeclared pharmaceutical ingredients, results that were confirmed in a FDA laboratory. Based on these results, we’re able to demonstrate that the device was reliable, efficient, and produced valid results. As a result of this pilot, we’ve decided to expand the use of this new technology and add devices at two additional IMFs. Our aim is to refine our use of this device, and eventually install it in all nine of our IMF facilities so that our staff can more quickly determine whether products contain undeclared drug ingredients.

This is a significant milestone.

The scanner’s methods are flexible enough to be used to detect the presence of an active ingredient in a drug product or to identify active ingredients in counterfeit drug products, simply by adding new pharmaceutical libraries developed by FDA laboratories. This will allow the agency to more quickly identify and respond to emerging issues. Already we’re actively working on developing an opioid screening method for the device. We hope to initiate a pilot study using this method very soon.

As we advance the science behind rapid, deployable, screening methods, we aim to shift the paradigm of how FDA screens products; increasing the effectiveness of our oversight. It’s an example of the creative measures we’re taking to keep harmful products out of the U.S. marketplace.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Melinda K. Plaisier, M.S.W., is FDA’s Associate Commissioner for Regulatory Affairs

Michael Kopcha, Ph.D., R.Ph., is Director, Office of Pharmaceutical Quality, at FDA’s Center for Drug Evaluation and Research

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Read more: U.S. Food and Drug Administration and the International Mail Facilities

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FDA’s New Pilot Program Aims for More Transparency about New Drug Approvals

By: Janet Woodcock, M.D.

When FDA approves a new drug, it has been found safe and effective when used under the conditions described in the label. Although this concept seems simple, the execution can be complex. Many factors are involved in weighing the benefits a drug can provide against the risks associated with its use. To that end, after we approve a new drug, we also want to make sure the scientific community and the public can understand why we approved it. This can help inform future drug development and, in turn, may facilitate the approval of additional safe and effective medicines.

Janet Woodcock, M.D.One way we explain the “why” behind a drug approval is by sharing information from the clinical trials that supported the approval decision. This information is usually discussed in FDA review documents authored by our physicians and other scientists. But often there is no complete description of the important efficacy trials, including the trial protocols, descriptions of any modifications made during the trial itself, and an explanation of all of the results. That’s why we launched the Clinical Data Summary Pilot in January. During the pilot, we will post key portions of the Clinical Study Reports (CSRs) – documents that sponsors create for FDA on each of their clinical studies. These portions would contain complete summaries of the study results, the protocol and protocol amendments, and the statistical plan. FDA plans to release these portions of the CSRs for the pivotal studies that supported the approval. The reports will be redacted by FDA to exclude confidential commercial information, trade secrets, and personal privacy information. FDA will not release patient-level data. Our goal is to share more directly complete summaries of the clinical trial information we have evaluated to determine whether a drug is safe and effective.

Currently FDA posts its review documents on line – material we call drug approval action packages. While the action packages include a significant amount of information pulled in from the sponsor’s application, that information is frequently separated into different sections and does not provide a complete summary of the results of any given study. This makes it difficult for academic researchers, regulators in other agencies, and other stakeholders to gain an in-depth understanding of the studies supporting approval. By providing the CSRs we hope to:

  • Enhance the accuracy of information used in scientific publications;
  • Increase stakeholders’ understanding of the basis for FDA’s approval decisions; and,
  • Inform physicians and other healthcare providers about the detailed results that regulatory decisions were based on.

The pilot will post the CSRs from up to 9 approved new drug applications of participating sponsors. We hope that reviewing the CSRs will help the scientific community better understand the information FDA used to evaluate an application and make an approval decision. At the end of the pilot we plan to seek comment from the public through a Federal Register notice to hear first-hand how the information was accessed and used. We hope to hear from a wide variety of stakeholders!

Our first pilot participant is Janssen Biotech for the approval of Erleada (apalutamide), the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer, as well the first to use the clinical trial result, or endpoint, of metastasis-free survival. Today we posted the CSR of the pivotal study with the regular action package. It’s a novel drug and we believe the CSR information, together with the FDA review, label, and other supporting documents, will facilitate a deeper understanding of how we reached our approval decision.

As an added benefit, our pilot program can help with global alignment, as our counterparts at the European Medicines Agency are similarly working to make information about their approvals more accessible and easier to understand.

The Clinical Summary Pilot is one of many efforts underway that require FDA working with industry to advance science. Now that it’s launched, we look forward to collaborating with sponsors who have an active or forthcoming NDA at FDA and who wish to participate in the pilot. For more information, visit the Center for Drug Evaluation and Research’s new pilot program page on our website.

Janet Woodcock, M.D., is Director of FDA’s Center for Drug Evaluation and Research

Predicting Stem Cell Activity to Ensure Safe and Effective Therapies

By: Steven R. Bauer, Ph.D.

We can admire an individualist for being independent and self-directed. But these traits can be disruptive and troublesome when they’re shared by cells called mesenchymal stem cells (MSCs). When these cells (also called human multipotent stromal cells, or MSCs) are being prepared for use as therapies to treat human diseases or medical conditions, what’s important is predictability.

Steve Bauer

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

MSCs are called ‘multipotent’ because they can produce more than one type of specialized cell of the body, but not all types. For example, they will respond to various types of substances called growth factors by differentiating − or specializing − into cartilage, bone, or fat. MSCs may also help the body control inflammation by suppressing immune cell functions. These processes, immunosuppression and differentiation, justify MSC use in regenerative medicine clinical trials investigating their use to protect, restore, or repair tissues in the body.

But there’s a catch. As of January 2018, no MSC-based clinical trials have resulted in FDA-approved treatments. One significant challenge is ensuring that the MSCs will work together to perform the same desired function when they are administered to patients. So FDA scientists have been developing ways to predict whether specific populations of MSCs intended for use as a therapy are made up of individualists or sufficient numbers of team players. It turns out that MSCs are very responsive to their environment. In a lab-based manufacturing process, MSCs are exposed to an environment very different from the body — one that could change the way they respond to growth factors and one that could result in MSC preparations with lots of unexpected – and undesirable – individualism. Additionally, this might change the way the cells behave after they are put into a patient. For example, they might not suppress inflammation very well, might form tissue where it isn’t wanted, might form the wrong tissue, and even form tumors.

Recognizing these potential issues, FDA’s MSC Consortium is trying to develop methods that would predict with more certainty how manufactured or isolated MSCs will behave in patients.

My own laboratory has been developing ways to predict the behavior of MSCs that have been stimulated by growth factors. Our study has involved identifying changes in the size and shape (or morphology) of stimulated MSCs that may predict their future behavior. We call this approach functionally-relevant morphological profiling. It’s made possible by powerful imaging technologies that make it practical for us to routinely monitor and analyze the changes in the size and shape of many thousands of cells in a matter of hours.

Stem Cell lab photo

Human multipotent stromal cells undergo morphological changes after being stimulated by growth factors. FDA scientists have demonstrated that these changes can predict the ability of the cells to develop specialized properties that might support their use in regenerative medicine clinical trials.

Why are sizes and shapes so important to predicting MSC activity?

Think of it this way: you can tell the difference between basketball players and baseball players by looking at their uniforms. And you know what kind of behavior you can anticipate when they’re playing their respective games. Likewise, morphological profiling can help scientists predict whether stimulated MSCs are going to differentiate into specific cells that do specific tasks.

We’ve used this approach to follow MSCs that were stimulated to undergo a process called mineralization, the laying down of minerals that support bone growth. Previously, we had to wait for over a month to see if stimulated MSCs would mineralize. But, by using our profiling method, we can predict with over 90 percent certainty on day three whether the stimulated cells would mineralize by day 35.

In another study, we measured more than 90 morphological features — including their sizes and shapes, and the shapes of internal structures — of stimulated MSCs. Based on our knowledge of the changes in the size and shapes of MSCs that go on to develop immunosuppressive activity, we could predict which MSCs would suppress a certain type of immune cell (T cell). Immunosuppression makes these stimulated MSCs potentially effective treatments for inflammatory diseases, such as Crohn’s disease (chronic inflammation of the intestine), and multiple sclerosis (loss of nerve cell signaling).

In short, this type of profiling allows us to measure the extent to which there are similarities or differences in these cell preparations and to compare our findings with the profile of specific cell types associated with the biological functions we are seeking. That may help us predict whether the cells will perform the function we want if they are administered to patients.

MSC-based therapies are not available yet. But the ability to predict specific functions of different preparations of MSCs in the lab may be a big step toward getting safe and effective FDA-approved treatments to patients. We think our work is widely applicable to a variety of potential stem-cell based products, and it will help us determine if new techniques for stimulating MSCs to differentiate will produce safe and effective therapies.

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

The FDA Grand Rounds on March 8 features Steven Bauer discussing his research.