FDASIA at Year Two

By Margaret A. Hamburg, M.D.

Margaret Hamburg, M.D.Anniversaries are a time for stock-taking and today, on the second anniversary of the Food and Drug Administration Safety and Innovation Act or FDASIA, I’m pleased to report on the progress we’ve made implementing this multi-faceted law.

To date, we have completed nearly all of the deliverables we had scheduled for the first two years after FDASIA became law. And many of the new authorities under FDASIA are already having a positive impact on health. It’s difficult to cover all of our FDASIA work, but here are some highlights:

Preventing Drug Shortages: Drug shortages, which can have serious and immediate effects on patients and health care professionals, reached an all-time high in 2011, the year before FDASIA was enacted. In response to a Presidential Executive Order in December of that year, FDA issued an interim final rule to amend and broaden FDA regulations requiring certain manufacturers to give early notification of production interruptions that could cause drug shortages. FDASIA further broadened this requirement by requiring that other prescription drug manufacturers provide notification and also gave FDA additional authorities. In October 2013 FDA proposed a rule to implement these authorities and issued a strategic plan for addressing drug shortages. So far, with the help of early notifications, FDA was able to prevent 282 shortages in 2012 and 170 shortages in 2013. The number of drug shortages that did occur has also declined.

Promoting Innovation: FDASIA includes many provisions designed to encourage innovation. We have held meetings on the use of meta-analyses in drug applications; put in place a plan for implementing a benefit-risk framework for drug reviews, and issued a variety of guidance documents covering such topics as drug studies in children, abuse-deterrent drug development, antibacterial drug development and expedited review and development programs for serious diseases.

This latter guidance provided information that sponsors needed to know about our new Breakthrough Therapy designation that was part of FDASIA. This option exists for new drugs intended to treat a serious or life-threatening disease that, preliminary clinical evidence suggests, could provide a substantial improvement over available therapies. As of June 23, we had granted 52 requests for this designation, and of those, approved four new drugs and two new indications for previously approved drugs.

As part of our implementation of the FDASIA-related provisions related to medical devices, we proposed a strategy and recommendations for a risk-based health information technology (health IT) framework that would promote product innovation while maintaining appropriate patient protections and avoiding regulatory duplication; issued a proposed rule for implementing FDASIA’s streamlined new procedures for reclassifying a device; and published a final rule on a medical device unique identification or UDI with implementation in accordance with the timetable set in the law. UDIs will help the FDA identify product problems more quickly, better target recalls and improve patient safety. The riskiest medical devices will start bearing their UDI by September 24th.

Establishing and Strengthening User Fee Programs: An important element of FDASIA was reauthorizing user fees for prescription drugs and medical devices and creating new user fee programs for generic drugs and biosimilar biological drugs. User fees on some types of applications offer an important source of funding to support and maintain key activities, including FDA’s staff of experts who review the thousands of product submissions we receive every year. Since FDASIA took effect, review times for medical devices have been declining.  Our prescription drug user fee program is meeting or exceeding almost all of our performance goals agreed to with industry. We have acted on 54 percent of the generic drug applications, or amendments and supplements to generic drug applications which were pending in our inventory as of October 1, 2012. This helps ensure that consumers can have access to more low-cost drugs. And we have been able to provide advice concerning most of the 93 submissions from companies who are developing biosimilar biological drugs under a pathway that could also ultimately lower costs for consumers.

Enhancing Patient Engagement: A hallmark of FDASIA was a series of provisions intended to tap the patient perspective. Our Patient-Focused Drug Development Program allows us to more systematically obtain the patient’s perspective on a disease and its impact on the patients’ daily lives, the types of treatment benefit that matter most to patients, and the adequacy of the available therapies for the disease. In accordance with FDASIA, we have held patient meetings on eight diseases and have plans for meetings on 12 more. We have learned a great deal from patients in terms of their views of the symptoms of their condition, their feelings about how it affects their life, and their thoughts on ideal treatments and on participation in clinical trials to aid future drug development.  A FDA Voice blog post on patient reports captures these patient perspectives and much more.

Finally, Title VII of FDASIA provided FDA with numerous new authorities to protect the drug supply chain. We thought now was a good time to provide the public with a more detailed description of our work on Title VII, so we asked Howard Sklamberg, Deputy Commissioner for Global Regulatory Operations and Policy, to write a separate blog on that topic.

FDA laid out a three-year plan for implementing FDASIA and we’re on our way to achieving our stated goals. To help the public follow our progress, we set up a dedicated webpage—the FDASIA-Track. It provides useful links to each action and is updated on a regular basis.

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

A New Plan for Drug Shortages to Build on FDA’s Success

By: Capt. Valerie Jensen, R.Ph. 

I’ve led FDA’s efforts to address hundreds of drug shortages for more than 10 years. During that time, we’ve made progress. Just last year, we cut the number of new shortages by more than half. But more work needs to be done. 

In an effort to enhance FDA’s current approach to drug shortages and bring new ideas to reduce the number of patients who are affected, we provided Congress today with a strategic plan aimed at enhancing efforts to prevent and reduce drug shortages. FDA is actively working, as required by the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, to address the public health threat caused by critically needed medications being unavailable for patients. And we will continue that work and build on our progress. 

An important part of our work is understanding the impact on patients. I’ve talked with many patients and caregivers about the effects of drug shortages. It deeply saddens me to hear a mother talk about her new baby boy, born prematurely, who is struggling to survive due to the scarce supply of drugs to meet his nutritional needs. Or a husband whose wife has been battling cancer and her doctor says the hospital is running out of the medication needed to properly treat her. 

I’m often asked, “Why do drug shortages persist?” and “Why are so many lifesaving drugs in shortage?” The majority of these problems stem from quality and manufacturing problems. Therefore, the answers boil down to quality manufacturing. 

While “quality manufacturing” may sound like a simple concept, getting there is a complex process – and one in which FDA and outside stakeholders have important roles to play. 

The strategic plan includes a number of new ideas to address shortages. Many of these strategies focus on enhancing FDA’s response and communication when we become aware of quality or manufacturing issues that could lead to a shortage. Other strategies that FDA is considering include the development of new risk-based approaches to identify early warning signals for manufacturing and quality problems that could lead to production disruptions.

In addition, the strategic plan identifies some preventive measures companies can take that place a greater emphasis on manufacturing quality and stability of supply, thereby eliminating the root causes of most shortages. 

Better manufacturing quality will help eliminate drug shortages over the long-term. But when a manufacturing disruption is likely to occur, early notification by manufacturers is critical. Along with the strategic plan, therefore, FDA is today issuing a proposed regulation implementing the expanded early notification requirements included in FDASIA. This regulation would require that all manufacturers of certain medically necessary prescription drugs give FDA advance notice of a permanent discontinuance or a temporary interruption of manufacturing. It would also extend this requirement to manufacturers of biologic products. 

Advance notification of a potential shortage allows FDA to work closely with manufacturers on the underlying issues, and in many cases, we are able to prevent the shortage. 

FDA envisions all stakeholders coming together to ensure patients have access to the safe, effective, and high-quality medications they rely on and deserve, and we believe the strategic plan we presented to Congress today will make great strides in ensuring that happens.

Capt. Valerie Jensen, R.Ph., is the Associate Director of the Drug Shortages Program in FDA’s Center for Drug Evaluation and Research

 

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

Importing Drugs to Address Shortages

By: Capt. Valerie Jensen, R.Ph.

Patients deserve and expect medicines that are available when they need them. The FDA works hard to prevent shortages of the medicines patients trust and rely on, and we do all we can to mitigate them whenever necessary. 

Over the past several months, the FDA has been working to resolve the shortages of injectable drugs used to make total parenteral nutrition, or TPN. These shortages are greatly affecting children’s hospitals. They rely on this treatment for vulnerable patients who cannot get the nutrition they need through eating and must receive it intravenously to survive. 

It’s heartbreaking for us to hear that these hospitals across the country are struggling to provide the proper nutrition in the face of these shortages. As a mom, my heart goes out to the parents of these infants and children who are struggling to survive. 

When my team and I first learned that American Regent/Luitpold, the U.S. manufacturer that makes many of the TPN components, was going to voluntarily shut down to resolve its quality issues, we determined which drugs were made only by American Regent and which ones were also made by other manufacturers. For those that had other manufacturers, we reached out to those firms to see if they were able to increase their production. However, while the manufacturers were able to do so, they would not be able to meet the total supply needs. 

Shortages of these drugs – such as the trace elements injection, sodium phosphate, potassium phosphate, calcium, zinc and other IV nutrition drugs – ­are particularly challenging. To supply them to the entire country, it was clear that our best option was to ask a foreign company to dramatically increase its production. Immediately, we began working with our regulatory counterparts around the world to search for a foreign manufacturer that was willing and able to supply products. 

Once we identified the potential manufacturers who were willing and able to help with these shortages – including Fresenius Kabi USA, LLC (FK USA) – we worked to ensure that the drugs are quality products and would not pose undue risk to U.S.patients. We reviewed many aspects of the companies’ processes and operations, including: 

  • the manufacturing practices at the manufacturing facilities, as well as at the facilities where the active pharmaceutical ingredients, or APIs, are produced;
  • the history of inspections of those facilities from our own inspections or those of  our regulatory counterparts; and
  • the sterilization methods used for injectable drug products to ensure they met FDA standards. 

We then met with FK USA and the other firms to determine: 

  • a distribution and shipping plan;
  • how adverse events will be reported to FDA;
  • how an outline for a Dear Health Care Provider letter, which highlights important information for doctors and pharmacists, will be structured; and
  • product labeling. 

While this might seem like a long road to take in resolving a shortage, it is an important process to protect the health of patients during a shortage. We expect these importations to address the current supply disruption over the coming weeks and we will remain vigilant in monitoring the supplies of these drugs until patient needs are fully met.   

Capt. Valerie Jensen, R.Ph., is the Associate Director of the Drug Shortages Program in FDA’s Center for Drug Evaluation and Research

FDA is asking the public to send in ideas for combating drug shortages

By: Valerie Jensen

FDA has made progress over the last year or so in preventing and resolving shortages of important drugs — including chemotherapies, anesthetics and antibiotics. Nevertheless, the agency believes that even more can be done and is therefore turning to the American public for advice, as explained in a Federal Register notice published this week. What the public tells FDA will help inform the agency’s development of a strategic plan that will ultimately enhance FDA’s response to preventing and mitigating drug shortages.

FDA has long been tackling the problem of drug shortages, and since October 2011, has stepped up its efforts to encourage drug and biological product manufacturers to report if they know of any circumstances that could lead to a drug shortage, including temporary interruptions in manufacturing. Such early notification is the agency’s most powerful tool to address drug shortages—we can’t work to prevent, mitigate, or resolve a shortage if we don’t know about it. Along these lines, FDA supported efforts to expand the FD&C Act’s early notification requirements as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), enacted on July 9, 2012.  Happily, these efforts have been paying off.  For example:

  • The number of shortages is now less than half of what it used to be. There were 117 in 2012, down from 251 in 2011.
  • Many more shortages are now being averted. We prevented 195 in 2011. Last year, we prevented 282.

We expect the requirements in FDASIA to further enhance FDA’s efforts to work with manufacturers and other stakeholders to prevent or alleviate shortages. When notified of a potential or actual shortage, FDA can take a number of actions, as appropriate, including: expediting inspections and reviews of regulatory submissions, working with the manufacturer to solve the underlying problem contributing to the shortage, identifying alternative manufacturing sources, exercising enforcement discretion for the shipment of a critically needed drug with special instructions to healthcare providers, and using enforcement discretion for the temporary importation of non-U.S. product.

One shortage of a drug that improves or saves the life of even one patient is one shortage too many. More can be done to prevent shortages.

As required by FDASIA, FDA has also formed an internal Drug Shortages Task Force to develop a strategic plan to enhance the agency’s efforts to address and prevent drug shortages. Among other things, the strategic plan will include blueprints for enhanced coordination, communication, and decision making within FDA and with other federal agencies; and plans for effective communication in the event of a shortage, including who should be alerted about potential or actual drug shortages and what information should be shared.

FDA wants to hear from all interested stakeholders on the strategic plan. The agency published a Federal Register notice, posted Feb. 11, which provides additional information and seeks input on six targeted questions related to the Strategic Plan and to preventing and mitigating drug and biological product shortages. Comments will be accepted through Thursday, March 14, 2013.

Valerie Jensen, a pharmacist and expert on drug shortages, is associate director at FDA’s Center for Drug Evaluation and Research  

Six Month Check-Up: FDA’s Work on Drug Shortages

By Margaret Hamburg, M.D.

This week marks the six-month anniversary of President Obama signing an Executive Order to help FDA in our ongoing efforts to prevent and resolve prescription drug shortages. At FDA, we saw the Executive Order as an important step in bringing awareness to this critical public health issue and signaling the necessary tools and resources, such as early notification and additional staff, FDA must have to help address this problem. Following the Executive Order, we sent out letters to drug manufacturers asking them to voluntarily report to FDA if they saw the emerging potential for a drug shortage.

Margaret Hamburg, M.D.Six months later, I am both amazed and delighted to see the progress that’s been made. Early notification to FDA of potential disruptions in drug supply has made a huge difference in our efforts – and the numbers really tell the story. Since reaching out to industry, there has been a six-fold increase in early notifications from manufacturers. Also in that six month timeframe, we have been able to prevent 128 drug shortages, and we’re seeing fewer numbers of shortages occur – 42 new drugs in shortage reported in 2012, compared to 90 new shortages at this time last year. This data is a testament to how FDA exercises flexibility and discretion in much of our work on drug shortages and the importance of strong collaboration and constant communication with industry, health professionals, and patients.

January-October 2011 10 notifications per month and November 2011-April 2012 60 per monthBut these are simply statistics. Consider instead the impact of our work on patients, who need particular drugs to treat life-threatening diseases. For instance, supplies of methotrexate, a cancer drug used to treat childhood leukemia and osteosarcoma, are currently meeting all demand, and we do not expect any further supply issues. Also, to address the shortage of Doxil (liposomal doxorubicin), a drug used for ovarian cancer and other cancer regimens, FDA exercised enforcement discretion for the importation of Lipodox, another brand of liposomal doxorubicin, from India, meeting patient needs until Doxil is available again.

While many shortages of cancer drugs are resolving, we are still working hard to address others. Leucovorin injection, a cancer drug that is used along with methotrexate for children with a serious form of leukemia, has been in short supply for some time. We are working with the manufacturer, Teva Pharmaceuticals, to produce additional shipments in the coming weeks to help improve supplies. Mustargen (Mechlorethamine HCl) – another cancer drug used in multiple cancer regimens — has also been in shortage. FDA has worked with the manufacturer to resume production of Mustargen, and the company is planning to have product available again by August.

January 2010-October 2011 about 9, and November 2011-April 2012 about 21; 86 shortages prevented in late 2011 involved a single firmWe are equally concerned about other types of drugs in shortage. Anesthesia drugs, such as benzodiazepines and fentanyl injections, have recently been in short supply. Here again, early notification is helping. One manufacturer, Hospira, notified FDA of anticipated delays in supply of the critical anesthesia drug propofol. This advanced notice allowed FDA to work with the other manufacturer of propofol who was able to increase supplies to keep the product available for patients undergoing surgery.

Drug shortages remain a serious, complex problem, and the agency remains extremely concerned about all current and potential drug shortages, not just those that I mentioned. Our efforts require a multifaceted approach involving industry, regulators, payers, and others. And we’re working with Congress on bipartisan legislation to expand early notification of drug supply problems that could cause shortages. All of us have a responsibility to help ensure that patients have reasonable access to the drugs they need. Drug manufacturers in particular have a responsibility to manufacture quality drugs and to have a process to ensure supply continuity of critical drugs.

2005 about 60, 2006 about 55, 2007 about 85, 2008 about 110, 2009 about 160, 2010 about 180, 2011 about 445 and  about 105 prevented, 2012 about 130 and about  100 prevented; Data on Shortages prevented only available for 2011 and 2012.  Data for 2012 are projected.In a blog I wrote earlier this year, I reminded readers that “the critical issue of drug shortages isn’t about industry; it isn’t about government, or even about the drugs themselves. It is about getting people the treatments they trust, they need, and they rely on.” While that remains as true as ever, I would like to add a different kind of reminder. Today’s six-month check-up demonstrates what government and industry can accomplish when we work together. While there’s no simple solution, we are making progress. And we’ll remain vigilant – doing all we can and using every resource available – to make sure patients have access to the critical medicines they need, when they need them.

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

Hope on the Horizon

By: Margaret Hamburg, M.D.

This week we were once again reminded that the critical issue of drug shortages isn’t about industry, it isn’t about government, or even about the drugs themselves. It is about getting people the treatments they trust, they need, and they rely on. One person who understands this all too well is Sara Stuckey from Lincoln, Illinois. Sara’s son, six-year old Nate, has been on the cancer drug methatrexate since he was diagnosed with leukemia back in 2009. The drug is the preferred treatment for the disease. Unfortunately, due to the shortage, Nate’s doctor informed Sara that he only had enough of the drug for Nate’s treatment this week. 

At a briefing Tuesday hosted by the FDA for representatives from industry, health professional and patient organizations, as well as the FDA team that has been working day and night to address this problem, Sara Stuckey shared her story.
 
Watch videos from the FDA Progress on Drug Shortages briefing.
 
Sara talked about Nate, the little boy, who is the “laid-back” one in her family. She explained how the family has learned to be flexible, working around Nate’s disease, compromised immune system, and chemotherapy treatment. For this family and many others, methotrexate is a life-saving drug. So, when Sara heard about a possible shortage of the drug, she talked to Nate’s clinic. They said there was just enough supply for a week but that there were alternatives. Still, Sara was left with many questions and concerns – the same questions any parent would be asking if their child faced a life-threatening illness.
Sara Stuckey

Sara Stuckey speaks at "FDA Progress on Drug Shortages," a briefing held on February 21, 2012, about her son, six-year old Nate.

View photos from the FDA Progress on Drug Shortages briefing.
 
The good news for Sara and Nate – and many other children and families – is that the shortage has been averted.
 
  • FDA has prioritized review of and approved a preservative-free methotrexate generic drug manufactured by APP Pharmaceuticals and expects that product to become available in March and continue indefinitely.
  • At Tuesday’s briefing, the CEO of Hospira, another company that manufactures the drug, said that supplies are being ensured for months to come. Hospira expedited release of additional supplies, resulting in 31,000 vials of new product – enough for more than one month’s worth of demand – being shipped to hundreds of U.S. hospitals and treatment centers on Tuesday.
  • And FDA is actively working with other manufacturers of methotrexate who have also stepped up to increase production in order to meet patient needs, including Mylan and Sandoz Pharmaceuticals.

To remedy the critical shortage of another cancer drug Doxil (liposomal doxorubicin), the FDA took proactive steps needed to increase available supply for patients in the U.S. For Doxil, there will be temporary importation of a replacement drug, Lipodox (liposomal doxorubicin), which is expected to end the shortage and fully meet patient needs in the coming weeks.

Still, we cannot stop there. At Tuesday’s briefing, we heard from representatives of the American Cancer Society, the American Society of Clinical Oncology, the Children’s Oncology Group, and APP, as well as Hospira. All spoke forcefully for working together to prevent future shortages from affecting the lives of both children and adults. It is enough for families to cope with disease; adding real or potential shortages to their list of worries is more than unfortunate.

Members of the FDA Drug Shortages team

Members of the FDA Drug Shortages team

This event reminded us of the human impact of drug shortages – as well as what can be done when we work together. We hope this can be a model for future efforts as we move forward, working with our partners in industry, with health professionals, and with patient advocates to find answers that will work for families like Nate’s.

While there is no simple solution to resolving drug shortages, we are doing all that we can to make sure patients have access to the critical medicines they need when they need them. I’d like to give a special thanks to the FDA Drug Shortages team and all the other staff throughout our agency for their hard work and leadership on this topic.

We are making progress. Hope is on the horizon. 

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