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 Cellular, Tissue and Gene Therapy 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 Cellular, Tissue and Gene Therapy at FDA’s Center for Biologics Evaluation and Research.

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