At the Center of Innovative Safe and Effective New Biologics

By: Karen Midthun, M.D. 

We’ve all read news reports of research achievements that promise exciting and powerful new treatments such as gene therapies to treat diabetes and cell therapies to rebuild failing hearts.  

These medical products are biologics and may seem like the stuff of science fiction. But they could transform the way doctors treat certain illnesses and conditions. Other, more traditional biologics, such as vaccines and blood products, may play an important role in protecting against bioterrorism

As the part of FDA that has regulatory authority over many of these products, the Center for Biologics Evaluation and Research (CBER) plays a critical role in their development through its regulatory oversight and research. CBER comprises a variety of offices, including three product offices responsible for 1) gene, cell, and tissue therapies, 2) vaccines and allergy products and 3) blood and blood products. 

Biologics differ from chemically manufactured drugs; they are usually derived from living sources (humans, animals, microorganisms). Work in this field is demanding because of the unique challenges biologics pose to manufacturers as well as to the reviewers at CBER. For example, the sensitive makeup of some biologics (e.g., DNA and cells) means they can’t be sterilized, so great care is needed in manufacturing them. In addition, biologics are complex and often based on new scientific knowledge that CBER reviewers must be familiar with. 

One way CBER meets the challenges of reviewing these products is by conducting its own research, which creates new knowledge and helps advance development of innovative medical products. CBER shares this knowledge by publishing results in peer-reviewed journals, drafting guidance documents to assist in product development, and sharing information through global collaboration and conferences with colleagues in research institutes, government agencies, industry, and stakeholders. Scientists at CBER can bring this added knowledge to their review of new products. CBER research  enhances CBER reviewers’ ability to evaluate a product’s safety and effectiveness—and to spot problems in product development that might not be recognized by manufacturers. 

Thanks to all of this work, CBER has approved important new products over the past couple of years, including 1) the first over-the-counter test that enables consumers to determine their own HIV (the AIDS virus) status in about 30 minutes—in private, 2) five stem cell products derived from cord blood (placenta-umbilical cord) for use in rebuilding the populations of blood forming cells and the immune system; 3) three influenza vaccines that protect against four strains of influenza virus rather than the previous limit of three strains, and 4) two other influenza vaccines, which are produced using mammalian cells or insect cells, rather than with eggs, as is customary. These two new production techniques for influenza vaccine offer the potential for faster startup of the manufacturing process than egg-based manufacturing, as well as the ability to rapidly address an unexpected, spreading epidemic. These vaccines also offer an alternative for individuals who are allergic to egg products. 

Importantly, CBER’s product safety efforts don’t stop after a product goes to market. The Office of Biostatistics and Epidemiology works with collaborators such as Medicare and the FDA Sentinel program on projects that can help evaluate whether certain adverse reactions are caused by approved treatments. 

As medical innovation accelerates in the 21st Century, CBER will continue to be at the forefront of ensuring the development of innovative safe and effective biologics. 

Karen Midthun, M.D., is Director of FDA’s Center for Biologics Evaluation and Research

Resolving Disputes Concerning FDA and Medical Devices

By: David S. Buckles, PhD, FACC, and Lawrence “Jake” Romanell 

Disagreements are inevitable in science, medicine – and even life. As part of a regulatory agency committed to public health, the FDA’s medical devices center occasionally confronts scientific and policy disagreements among our staff and with the various stakeholders we strive to serve. 

Disputes can occur at any stage of a particular interaction, from an initial inquiry or pre-submission review to a final regulatory decision on an application or submission.

David S. Buckles, PhD, FACC

As Ombudsmen for FDA’s medical devices center, our office investigates complaints from outside the FDA and facilitates the resolution of disputes between FDA’s medical devices center and the industry we regulate. Since part of our job is maintaining impartiality and neutrality, we are a good starting point if you have a complaint, question, or dispute of a scientific, regulatory, or procedural nature. Given the inevitably of disputes, what we find important is how we deal with those disagreements. 

Legislation passed last year by Congress introduced the term “significant decision” to our regulatory lexicon and included certain expectations of how we are to deal with disagreements over such decisions. FDA has proposed its interpretation of what constitutes a “significant decision” in a question and answer draft guidance document, entitled, “Center for Devices and Radiological Health Appeals Processes: Questions and Answers about 517A.” This draft guidance is available for public comment. We believe that when it comes to disputes, all stakeholders play an important role in resolution. Therefore, we strongly encourage interested parties to provide comments and suggestions to improve our appeals process to help us meet our goal of providing a fair, equitable, predictable and transparent means for seeking resolution of disputes. 

In our current experience, differences of opinion that arise before a final decision is reached can usually be resolved through discussion, or even, occasionally, mediation. If interactive discussion with a lead reviewer, team leader or Consumer Safety Officer does not move the ball forward, we have found that outreach by the stakeholder to engage Branch and Division management in the discussion usually has a good chance of success. We have never yet had a senior manager turn us down when we’ve asked them to take a look at a situation, and we strongly encourage stakeholders to make a good faith effort to connect with management at least through the Division level before considering more formal approaches. 

Lawrence "Jake" Romanell

When discussion and interaction through the Division level fails to resolve a dispute, stakeholders usually have several options. By far the most common approach is to request internal agency supervisory review as provided in the Code of Federal Regulations, at 21 CFR 10.75. When a request is made for internal agency review of a decision of an FDA employee, the decision is subject to review by the FDA employee’s supervisor. Generally, such a request for internal agency review is filed with the manager at the next organizational level above the level that either signed the document in dispute or was substantively involved in the decision. 

In the past several years FDA’s Center for Devices and Radiological Health has come a long way in standardizing the appeal process and setting consistent expectations, both internally and externally, to ensure that stakeholders with a legitimate dispute receive a fair and impartial hearing by senior management. Our updated guidance documents will make our process even more clear—and clarity helps make for smoother decisions. 

Wasn’t it Gandhi who said that honest disagreement is often a good sign of progress? 

David S. Buckles, PhD, FACC, and Lawrence “Jake” Romanell, are in FDA’s Center for Devices and Radiological Health, Office of the Ombudsman

Why FDA Proposes an ‘Action Level’ for Arsenic in Apple Juice

By: Michael R. Taylor, J.D. 

FDA has always been—and will always be—committed to making sure that the food you eat is safe for you and your family. It’s a challenging job in today’s complex, global marketplace. 

One of those challenges can be summed up in one word: arsenic. This chemical element is found in the Earth’s crust. It’s everywhere in the environment and can be found in water, air and soil, in both organic and inorganic forms. Human activities also can introduce arsenic into the environment. That means that it can also be found in some foods and beverages. 

Today, FDA is acting to help ensure that consumers do not come in contact with apple juice that has levels of inorganic arsenic that exceed 10 parts per billion. That’s the same level that the Environmental Protection Agency (EPA) has set for drinking water, which is consumed in much greater quantities. 

FDA tests hundreds of foods and beverages for all kinds of potentially harmful substances, and we have been monitoring the levels of arsenic in foods for decades. Of the two forms of arsenic, we worry about the inorganic kind because long-term exposure can be harmful. 

The agency has always found that the amount of arsenic in apple juice is generally low—much lower, in fact, than the levels allowed in drinking water. Consumer Reports did an important story highlighting its own testing. And in 2011, we substantially increased testing and analysis of apple juice to continue and enhance our monitoring efforts. 

We found that our original belief was correct, that the levels of inorganic arsenic in apple juice are too low to cause immediate or short-term health damage. Working with colleagues in EPA, the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC), we then looked at potential risk from long-term exposure. 

That risk assessment helped lead us to the “action level” of 10 parts per billion. We believe that this action level will keep any apple juice that may have more inorganic arsenic than that out of the marketplace.  

We will continue to remain vigilant, work with the food industry, and take regulatory action when appropriate to minimize as much as we can the presence of arsenic and other unwanted contaminants in our food supply. 

Michael R. Taylor, J.D., is Deputy Commissioner for Foods and Veterinary Medicine

Inspiring Young Voices on Type 1 Diabetes

By: Margaret A. Hamburg, M.D.

As FDA Commissioner I frequently learn about exciting and promising new developments in science and medicine to treat disease and improve lives. Some involve advances in science and technology and others relate to the development of improved ways of doing business that promote innovation. But the most inspirational moments relating to these developments are when I have the chance to meet with people who deal personally with the challenges of a particular disease or condition and to hear first-hand what is needed in terms of education and research and development, as well as the difference that FDA’s work can make in their lives.

Earlier this week, I had just such an opportunity, when I met with officials and representatives from the JDRF, formerly known as the Juvenile Diabetes Research Foundation, who were in town for their annual Children’s Congress. 

It was a delight to meet with the group’s President and CEO, Jeffrey Brewer and several other top officials of the organization, with whom FDA has a strong working relationship. But the highlight of the meeting was when we heard from three children with diabetes and their parents who accompanied the group’s leaders. Ten year old Willa Spalter from California, nine year old James Cravero from Iowa, and thirteen year old Fallon Blackbull from New Mexico were among 150 children who were in town to meet with government officials and share their stories of life with diabetes in order to stimulate efforts to develop policies to cure, treat and prevent the disease.

These eloquent and inspiring young people offered compelling personal stories about their struggles with the disease, which, shockingly, included having it properly diagnosed. In fact, the doctors failure to diagnose their disease until the symptoms became life-threatening highlights the very real need for more education, not simply of the public or Congress, but of the medical community itself.

As I listened to these young people I was pleased to learn how FDA’s work is making a difference in their lives and the lives of others with juvenile diabetes. Perhaps most exciting are the remarkable strides being made to develop a safe and effective “artificial pancreas.” This innovative device type automatically monitors blood glucose and provides appropriate insulin doses in people with diabetes who use insulin. It can be life-changing for individuals with insulin-dependent diabetes, helping them reduce dangerously high and low blood sugar levels and lowering the risk for future diabetes-related complications.

To advance the development of this revolutionary type of system, we have worked to foster discussions between government and private researchers and have sponsored public forums to promote rapid and efficient development of artificial pancreas devices.  Additionally, at the FDA we have prioritized the review of artificial pancreas research studies and have provided clear guidelines to industry on performance and safety standards for these systems — efforts that we hope will shorten overall study review time and ultimately get these devices into the hands of researchers and users more quickly. Most recently, we approved clinical studies for artificial pancreas devices to take place at diabetes camps this summer. This is a major milestone, as it will represent the first time in the U.S. that we have been able to study artificial pancreas devices in camp settings, where children participate in camp activities and wear the artificial pancreas during the day and night.

It was gratifying to hear how Willa, James and Fallon each participated in trials related to the artificial pancreas. They know better than anyone the benefits that come from pushing this agenda and making sure the best science is available to take on juvenile diabetes. 

I am so pleased to have had the opportunity to meet with these three courageous and inspiring young people. Hearing their stories and watching how they bravely and competently manage their diseases will provide me and my colleagues additional motivation in our work on behalf of these and other children.

Margaret A. Hamburg, M.D., is Commissioner of the U.S. Food and Drug Administration

FDA, Small Businesses, and the Common Goal of Advancing Public Health

By: Margaret A. Hamburg, M.D.

When federal agencies celebrated “Small Business Week” last month, FDA had special reason to pay tribute. It is well known that the U.S. biomedical industry plays an essential role not only in advancing the health of individuals, but also the health of the overall economy. Less well appreciated is that small businesses account for much of this activity.  A new FDA report issued to Congress this week describes the multitude of ways we work with small businesses to support their innovative ability to craft new treatments, medicines, and devices that improve the health of all Americans. 

Margaret Hamburg, M.D.The outreach efforts described in this report are vital, because small businesses not only have a unique role but also unique needs in their involvement with a regulatory body like the FDA. That’s why we’re working on a number of fronts to strengthen the ability of small businesses to engage and to help ensure that they are not disadvantaged by their size.

One way we do this is by reducing or even waiving user fees for small businesses that meet certain criteria. Sometimes a startup company might have a groundbreaking product, but lacks the financial resources to cover the full cost of user fees, which are paid to the FDA to help cover the cost of product reviews. Encouraging this kind of small business innovation is the reason FDA participates in the Small Business Innovation Research (SBIR) Program, which funds research and development projects that have potential for commercialization and public benefit. Since 2008, FDA has awarded 36 SBIR grants with the average grant being just over $170,000. Small businesses are also eligible to apply for more broadly available FDA grants, such as Orphan Product Grants, which address rare diseases and disorders, and are tailored to meet the focus and needs of small firms.

Perhaps even more important to small businesses than funding is information. FDA works hard to maintain a variety of communications with small businesses. Seminars, webinars, and workshops open to, and often specifically designed for, small businesses are offered throughout the year free of charge. Links to these event listings can be found in Appendix D of the report. FDA’s product centers also have dedicated small business offices that give companies direct points of contact, which are identified in our new report. These offices provide technical support and education to small companies, hold meetings to hear the views and perspectives of small businesses, develop informational materials, and provide an accessible channel through which small businesses can acquire information from FDA. I hope small businesses will take advantage of these resources and reach out to FDA’s small business contacts.

Small businesses also benefit from early communication with FDA during the product review process. This early communication is especially valuable in FDA’s Rare Disease Program in which most product sponsors are small firms and the product evaluations can be particularly complex for companies with limited resources. Our centers have found that early communication between FDA and product sponsors gets safe and effective products to consumers faster. 

I encourage you to read the report for more information on how FDA promotes innovative research by small businesses, protects small businesses from unreasonable regulatory barriers, and thereby allows American ingenuity to thrive.

Margaret A. Hamburg, M.D., is Commissioner of the Food and Drug Administration

Looking Back and Looking Ahead: FDASIA’s One Year Anniversary

By: Margaret A. Hamburg, M.D. 

One year ago today President Obama signed into law the Food and Drug Administration Safety and Innovation Act, bipartisan legislation reauthorizing user fee programs for innovator drugs and medical devices and establishing two new user fee programs for generic drugs and biosimilar biological products. 

Margaret Hamburg, M.D.Coming at a time of continuing budget restraints, this steady and reliable source of funding is essential to support and maintain FDA’s staff of experts who review the thousands of product submissions we receive every year, and do so in a timely and thoughtful manner. Over the years, our user fee programs have ensured a predictable, consistent, and streamlined premarket program for industry and helped speed patient access to new safe and effective products. 

One of our major undertakings since last July has been putting in place the infrastructure for a new generic drug user fee program that will expedite the availability of low-cost, high quality generic drugs. The program has already achieved several significant milestones, including reducing the backlog of generic drug applications, enhancing review efficiencies, and streamlining hiring. Likewise, reauthorization of the medical device user fee program has helped to expedite the availability of innovative new products to market, and the program has already seen a decrease in the application backlog for device submissions. 

But user fees are by no means the only focus of the 140-page law. Additionally, FDASIA includes provisions to strengthen the drug supply chain, enhance engagement with FDA stakeholders, address the problem of drug shortages, and promote innovation. 

Since last July, FDA continues to meet its FDASIA milestones, and is on track to implement more provisions very soon. Consider some of our more significant accomplishments. In the area of innovation, we launched the new breakthrough therapy designation for drugs that may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases and published guidance on the use of this and all of our expedited programs. In the area of engagement, we initiated the Patient-Focused Drug Development Program. The objective of this five-year effort is to more systematically obtain the patient’s perspective on a disease and its impact on patients’ daily lives, the types of treatment benefit that matter most to patients, and the adequacy of the available therapies for the disease. We have already held patient meetings on three major diseases and another is scheduled in September. 

Also, FDASIA is helping FDA take important steps to address the challenges posed by an increasingly global drug supply chain in which nearly 40 percent of finished drugs are imported and nearly 80 percent of active ingredients come from overseas sources. FDA has been able to halt food and devices from distribution if an inspector believes they are adulterated or misbranded, but the agency lacked this authority for drugs. FDASIA has extended the agency’s administrative detention authority to include drugs as well, and the agency is taking steps to implement this authority. In addition, earlier this year the agency pushed for higher penalties for counterfeiting and intentionally adulterating drugs before the federal sentencing commission – and succeeded. These are the first of several provisions that we must implement under Title VII, the section of FDASIA that strengthens FDA’s authorities over the drug supply chain. Later this week I hope many of you will join me at a public meeting to discuss how we might implement some of the other portions of this important section. 

To help the public keep track of our progress on these and other provisions, we’ve established a FDASIA web portal that includes a link to our three year implementation plan, which we intend to update on a monthly basis. 

Implementing FDASIA is a massive undertaking, requiring detailed planning to integrate these tasks with the rest of our workload. FDA is committed to implementing the requirements of FDASIA in a way that provides lasting improvements to public health, and we will meet these objectives as quickly as resources allow. 

Margaret A. Hamburg, M.D., is the Commissioner of the Food and Drug Administration

Working together for new solutions to cancer in children

By: Margaret A. Hamburg, M.D. 

One of the greatest pleasures I have as FDA commissioner is the opportunity to meet with so many who are making a real difference in the world of health care, including researchers, doctors, drug industry leaders, foundations, and advocates for patients and families, including most recently the Alexandria Summit for Oncology. 

The group’s two-day meeting in New York City addressed a range of topics related to the challenges and advances in treatments for cancer and featured many of the leading scientists and researchers in the field, including my colleague Dr. Richard Pazdur, the director of FDA’s Office of Hematology and Oncology Products. 

Last night I had the chance to speak to the group about developments in treating pediatric cancer. I was joined by Nancy Goodman, a passionate and effective advocate, who is the founder of a patient advocacy group called Kids and Cancer. Nancy is helping to influence discussion on this topic, and her inspiring work gives enduring meaning to the life of her son Jacob, who died of cancer in 2009. 

Pediatric medicine is an area that has long faced historic obstacles, the result of the tension between our eagerness to respond as quickly as possible to treating and developing treatments for diseases in children, and our desire to protect children from potentially dangerous side effects, particularly in the early stages of research when effectiveness is not fully known. 

Today, we are in the midst of some exciting advances in the development of improved and better treatments for cancer that we expect can and will translate into new treatments for children with cancer. Scientific progress isn’t the only reason for these advances.  Regulators, researchers and industry are also thinking and acting in new ways that are allowing us to accelerate our investigation and approval process.  

Over the past 20 years we have evolved from a view that we must protect children from research, to a view that we must protect children through research, in order to assure their access to new and effective medications. Research studies are the only way to truly determine the safety and efficacy of medication in children and to avoid possible harm when children are given drugs approved only for adults. 

Recent laws have created new mechanisms to prioritize drug research and development for children, resulting in a dramatic increase in pediatric drug trials. We are already seeing progress, with more drug companies hiring pediatric experts, and some large pharmaceutical companies developing pediatric centers of excellence. 

FDA is working to promote earlier consideration and approval of treatments for children. But increased emphasis is also needed on discovery and development, which must come from the industry and the academic research community. The potential offered by our science has never been greater. We want to turn this potential into expanded treatments, new drug availability, and hopefully new cures. That’s why the enthusiasm and creativity this Summit generates is so promising. 

Margaret A. Hamburg, M.D., is the Commissioner of the Food and Drug Administration

 

“Breakthrough” Designation … Another Powerful Tool in FDA’s Toolbox for Expediting the Development and Review of Promising New Drugs for Serious Conditions

By: Janet Woodcock, M.D.

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

In fiscal year 2012, FDA approved 35 novel new drugs, also known as “new molecular entities.” Among these new products were drugs to treat patients with unmet medical needs, such as a groundbreaking treatment for a form of cystic fibrosis, the first FDA-approved human cord blood product for hematopoietic reconstitution, used to help patients with blood forming disorders, and the first drug to treat advanced basal cell carcinoma (a form of the most common skin cancer).

To enable our ongoing efforts to bring innovative drug products to the public as efficiently as possible, FDA relies heavily on several expedited development and review tools such as fast track designation, the accelerated approval pathway and priority review designation. For instance, 56 percent of the novel drugs approved by the Center for Drug Evaluation and Research in calendar year 2012 used some combination of these tools to speed promising therapies to patients with serious conditions. And any given drug may have received multiple expedited program designations. (See a brief summary of how each of these tools helps FDA shorten the development and review of promising new therapies.)

In July 2012, a provision in the new law called the Food and Drug Administration Safety and Innovation Act, or FDASIA for short, gave FDA another powerful expedited development tool, known as the “breakthrough therapy” designation. This new designation is now helping FDA assist drug developers expedite the development of new drugs with preliminary clinical evidence that indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. Although the designation is not yet even a year old, FDA has received 62 requests to grant this new designation to products under development. We have been very active on this subject, meeting with companies and discussing ways to expedite the drug development process for drugs that show striking early results. We have already granted the breakthrough designation to 20 potential innovative new drugs that have shown encouraging early clinical results.

Drug developers should have a clear understanding of all of FDA’s expedited development and review tools. To help industry better understand each tool, including when the tools can be used and the features of each, we have just published an industry draft guidance titled Expedited Programs for Serious Conditions — Drugs and BiologicsAmong other important information, the draft guidance describes FDA’s policies and the threshold criteria for each expedited program, defines and discusses important concepts, including serious condition, unmet medical need, and available therapy, and provides some general considerations for products utilizing an expedited program, such as manufacturing and product quality, nonclinical considerations, and clinical inspection considerations.

The breakthrough therapy designation gives us another tool in our “toolbox” to help expedite the development and review of new drugs to treat patients with serious medical conditions and little or no treatment options. We’ll continue to use the new breakthrough therapy designation and our existing tools to help make our expedited programs even more effective.

We’ve said it before — and I believe it’s worth repeating — our decision-making on whether to approve a drug always involves an evaluation of many factors, such as the seriousness of the disease.  However, ultimately any drug approved must show that its benefits outweigh its risks and regardless of which expedited development or review program or programs are used, FDA does not compromise its safety or efficacy standards in exchange for rapid approval. Like all drugs we approve, those approved after having been designated as breakthrough therapies will meet our usual rigorous standards for safety and effectiveness.

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

The Road Ahead for Ensuring Access to Quality Drugs for All Americans … New Laws Under “FDASIA” Will Help Pave the Way

By: Howard Sklamberg

In January, I became director of FDA’s Center for Drug Evaluation and Research’s (CDER) Office of Compliance, giving me the responsibility – and great privilege — of playing a lead role in FDA’s work to help protect the American public from unsafe and ineffective drugs. It’s a big job, filled with many challenges.

Fortunately, after three years of service with FDA, most recently as the agency’s deputy associate commissioner for regulatory affairs (our field operation), and 12 years before that as a prosecutor with the Justice Department, I feel prepared to help the agency meet these challenges head on.

I’d like to take an opportunity to share my priorities, as well as my views and perspectives on the goals and challenges ahead for FDA, as we continue to work to ensure access to quality drugs in the United States.

Tragically, last October’s outbreak of fungal meningitis from contaminated methylprednisolone injections that killed over 50 Americans and sickened hundreds more directed FDA’s attention to the immediate public health priority of evaluating the quality of sterile compounded drugs and preventing further incidents. Our efforts have included proposing a new legislative framework for federal oversight, inspecting high-risk compounding facilities that produce sterile drugs, and working more closely with our state partners.

As important as our efforts are in the compounding arena, our compliance challenges extend to many other critical areas, many of which are related to the new and growing global marketplace for pharmaceutical products.

Today, nearly 40 percent of the drugs Americans take are imported and nearly 80 percent of the active ingredients come from overseas sources. A growing number of clinical trials that test the safety and effectiveness of potential new drugs are also moving overseas, making FDA oversight more challenging. Counterfeit drugs are proliferating around the world and sometimes even entering the U.S.supply chain. The ever burgeoning worldwide use of the Internet continues to spawn avenues for illegal online sales of medicines of unknown safety and quality. Also, poor manufacturing practices that lead to facility shut-downs often contribute to shortages of important drugs. We must ensure that wherever drugs are made, wherever their ingredients are from, or wherever and however they are tested and sold, that they meet FDA’s strict standards of quality and that they remain in adequate supply.

Despite these challenges, there’s good news. The Food and Drug Administration Innovation and Safety Act of 2012 (FDASIA) gave FDA powerful new tools to enhance our compliance and enforcement activities including stronger authorities and funding to support the inspection of foreign manufacturing facilities. For example, FDASIA facilitates our ability to partner with and work more effectively with foreign regulatory agencies. FDASIA also gave FDA more authorities to control the drug supply chain.

However, laws on the books do not automatically translate into effective change without effective implementation and enforcement of these laws. So, in addition to continuing our critical work with Congress on appropriate and effective oversight of compounding that exceeds the bounds of traditional pharmacy compounding, my other key priority is to work to implement FDASIA’s provisions, keeping CDER focused globally and armed with the best set of tools possible to do the job. Although we have much more work to do, a vision of enhanced capabilities of ensuring quality drug products for the American public is well in sight.

I have the distinct privilege and responsibility of being part of a fantastic team of dedicated FDA staff that’s really making a difference, and I look forward to continuing to serve the American public in working to ensure access to quality drugs.

Howard Sklamberg is Director of FDA’s Center for Drug Evaluation and Research’s Office of Compliance

When Conduct Becomes a Crime

By: John Roth 

In my last post, I explained how FDA’s Office of Criminal Investigation (OCI) works when a small portion of the industry fails to adequately respond to regulatory action. For Abbott Laboratories and Amgen, the price for regulatory malfeasance was high:  $1.4 billion – yes, billion — paid in criminal and civil penalties to the United States. 

Sometimes, however, the conduct of entities evinces such a complete disregard for the health and safety of the public that a criminal response is necessary. 

A case that still resonates with the FDA and law enforcement community involves the OCI investigation of the conduct of Synthes, a medical device maker, in the marketing of a bone cement product called Norian XR. The product was cleared by FDA for use in certain instances, but was specifically rejected for the use Synthes wanted: injection into the spine as part of a mixture. 

In fact, the FDA-approved label specifically warned against such use. Rather than attempt to get FDA approval through scientifically-validated clinical trials (at a cost of about $1 million, and taking about three years), Synthes decided to convince doctors to perform the procedure and then publish the results, notwithstanding the risks. And certainly, Synthes had reasons to understand the risks. Before the marketing program began, pilot studies showed that the bone cement reacted chemically with human blood in a test tube to cause blood clots. The research also showed, in a pig, that such cement-caused clots became lodged in the lungs.  

Nevertheless, Synthes executives plunged forward with a plan to conduct what amounted to an unauthorized clinical trial of the use of Norian to treat vertebral compression fractures of the spine. Equally appalling, the company marketed uses of the product in contravention of a “Black Box” warning — the most serious warning the FDA can require. 

The ensuing tragedy was inevitable. Three patients injected with the medication died on the operating table. 

Despite this, the company did not recall the product from the market, an action which would have required them to disclose details of the three deaths to the FDA. Equally egregious, Synthes officials deliberately misled the FDA during an official inspection in May and June 2004. 

After painstaking and complex work by OCI investigators, working with their colleagues in FDA’s Office of Regulatory Affairs and the scientists and public health experts in FDA’s Center for Devices and Radiologic Health, in 2010, Synthes pled guilty and paid the maximum fine allowable by law — in excess of $23 million for the company and its corporate parent. In 2011, four executives were convicted and sentenced to prison terms. 

Another similarly tragic case of reckless conduct involved ApotheCure, a compounding pharmacy in Dallas that shipped colchicine injectable solution to a medical center in Portland, Oregon. Colchicine is used to prevent gout attacks and relieve the pain of gout attacks when they occur. In 2007, three patients, within hours of receiving the drug, died. 

FDA testing of vials selected from the shipment revealed some vials as super potent — containing over 640 percent of the level of the drug that was declared on the label. Others were sub potent, containing less than 63% of the declared strength. After an OCI investigation, the pharmacy and its owners pled guilty to criminal charges in 2012. 

The penalties imposed on these two firms, Synthes and ApotheCure, and the responsible individuals cannot bring back the lives of those six innocent individuals. But OCI’s determined work produces results, and as I noted in my first post, “gives the FDA unique fact-finding tools and provides for strong, industry-wide deterrence.” We trust our forceful actions, then and now, continue to deter other companies and individuals from such reprehensible conduct. 

John Roth is Director of FDA’s Office of Criminal Investigations