FDA Takes Important Steps to Stem the Tide of Opioid Misuse and Abuse

By Scott Gottlieb, M.D.

 America is awash in immediate-release (IR) opioids. About 90 percent of all opioid pain medications prescribed – or 160 million prescriptions a year – are for IR formulations like hydrocodone and acetaminophen or oxycodone and acetaminophen combinations. Many people who are currently addicted to opioids became medically addicted. Their first exposure to opioids was from a legal prescription, and for many, that prescription was written for an IR formulation of these drugs. Many addicted patients may then move on to higher dose formulations or more accessible illegal street drugs.

At FDA, we believe it’s necessary to continue to take steps to address both ends of this continuum, the potential gateway to addiction that is often the IR formulations, and the higher dose, extended-release formulations, both of which carry a significant risk of overdose and mortality. We are taking several actions to address these challenges. This week, we issued letters notifying 74 manufacturers of IR opioid analgesics intended for use in the outpatient setting that their drugs will now be subject to a more stringent set of requirements under a Risk Evaluation and Mitigation Strategy (REMS). The REMS requires that training be made available to health care providers who prescribe IR opioids, including training on safe prescribing practices and consideration of non-opioid alternatives.

Dr. Scott GottliebFDA also will soon issue a final guidance document that will assist potential applicants who plan to develop, and submit to FDA, an application to seek approval of a generic version of abuse-deterrent formulations (ADFs) of opioid drugs. Most of the currently approved opioids with labeling describing abuse-deterrent properties are extended release/long-acting (ER/LA) formulations of opioids. These drugs are generally formulated to be more resistant to the sort of manipulation that would otherwise make them amenable to snorting and/or injecting. Addicted patients who start by using the IR drugs will sometimes migrate onto the ER/LA formulations, and then try to manipulate those higher-dose formulations in ways that can provide a more immediate “high” through injection or snorting. But there are currently only brand name ADF formulations. These steps that FDA is taking are aimed at addressing each end of the spectrum of abuse and addiction.

With respect to the new REMS measures to address the safer use of the IR opioid pain medications, these short-acting drugs will now be subject to the same regulatory requirements as the ER/LA opioid analgesic formulations. Since 2012, manufacturers of ER/LA opioid analgesics have been subject to a REMS, which requires, as its primary component, that training be made available to prescribers of those products. To meet this requirement, the sponsors of the ER/LA opioid analgesics have been providing unrestricted grants to accredited continuing education providers for the development of education courses for health care professionals based on content outlined by FDA, which the agency calls the “Blueprint.” FDA is now extending these REMS requirements to the IR manufacturers.

While some of the ER/LA manufacturers also make IR opioids, today’s action will greatly expand the number of products covered by the REMS. The existing REMS currently includes 64 ER/LA opioid analgesic products. Once the action is finalized, an additional 277 IR opioid analgesics will be subject to these REMS requirements.

In addition to expanding the REMS to include IR products, FDA is modifying the content of the educational “Blueprint” required under the REMS. The agency is adding content on pain management, including non-opioid alternatives. This includes principles related to the acute and chronic pain management; non-pharmacologic treatments for pain; and pharmacologic treatments for pain (both non-opioid analgesic and opioid analgesic). The revised Blueprint will also cover information about the safe use of opioids, and basic information about addiction medicine and opioid use disorders.

For the first time, this training will also be made available to other health care professionals who are involved in the management of patients with pain, including nurses and pharmacists, which is in addition to prescribers of opioid analgesics. FDA believes that all health care professionals involved in the management of patients with pain should be educated about the safe use of opioids so that when they write or dispense a prescription for an opioid analgesic, or monitor patients receiving an opioid analgesic, they can help ensure that the product is properly indicated for the patient and used under appropriate clinical care.

FDA’s new Opioid Policy Steering Committee is also considering whether there are circumstances when FDA should require some form of mandatory education for health care professionals, and how the agency would pursue such a goal. The agency’s purpose is to reduce overall exposure to opioids by making certain that prescribing doctors are properly informed about appropriate prescribing recommendations, that providers understand how to identify the risk of abuse in individual patients, and know how to get addicted patients into treatment. In fact, today, the agency issued a public notice to solicit input on a detailed series of questions related to these goals. FDA has also been scheduling meetings with provider organizations and sponsors engaged in dispensing drugs – including health systems and pharmacy chains, in an effort to solicit additional input on new strategies.

Sending out the manufacturer notification letters is the first step in extending the REMS to the IR drugs. This process could take about a year to finalize. The modified REMS will continue to include a requirement for patient Medication Guides, patient-counseling documents, and plans for assessing the effectiveness of the revised REMS. The crisis of opioid addiction is a public health tragedy of enormous proportions. By putting in place safety measures for IR opioid analgesics, and creating a more robust path to converting the high dose opioids to formulations that are more resistant to manipulation, we are addressing both ends of this crisis. Our hope is that we can help prevent new patients from becoming addicted, and keep some individuals from experiencing the serious adverse effects associated with these medications.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Making Advances Against Sickle Cell Disease

By: Patricia Oneal, M.D., and Rosanna Setse, M.D., M.P.H., Ph.D.

Patricia Oneal

Patricia Oneal, M.D., Medical Officer in the Division of Hematology Products at FDA’s Center for Drug Evaluation and Research.

The medical definition of sickle cell disease – a group of inherited red blood cell disorders caused by abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in red blood cells – does not come close to describing the condition from the patient’s perspective. Sickle cell disorders have devastating effects on patients and their families. Patients often experience recurrent episodes of excruciating pain, or sickle cell crisis, debilitating fatigue, infections, cognitive disorders, strokes, a life-threatening condition called acute chest syndrome, and damage to their vital organs, tissues, and bones. In some patients, the disease may trigger frequent and very painful sickle cell crises that require hospitalization. In others, it may cause less frequent and milder attacks. Although mortality during childhood has improved progressively, the life expectancy among individuals with sickle cell disease in the United States is on average 30 years less than the general population.

Sickle cell is a rare disease–but it’s not so rare if you are part of a certain population.  According to the Centers for Disease Control and Prevention, about 1 of every 365 African-Americans and about 1 out of every 16,300 Hispanic-Americans are born with sickle cell disease. In addition, more than 2 million people carry the sickle cell gene that enables them to possibly pass the disease on to their children. Today, bone marrow transplantation offers the only potential cure for this disorder; but finding a donor is difficult and the procedure has serious risk.

Rosana Setse

Rosanna Setse, M.D., M.P.H., Ph.D., Medical Officer in the Office of Hematology & Oncology Products at FDA’s Center for Drug Evaluation and Research.

As September — Sickle Cell Awareness Month — comes to a close, we take this opportunity to reflect on how much must be done to help patients in need and educate others on sickle cell disease — and also to recognize progress and hope for a better future.

In July, FDA approved Endari (L-glutamine oral powder) to reduce the severe complications from the blood disorder in patients age 5 years and older. Endari is only the second FDA-approved treatment for this disorder and the first since hydroxyurea was approved nearly 20 years ago. Studies showed that patients taking Endari experienced fewer trips to the emergency room and fewer hospitalizations for sickle cell pain than those given a placebo. They also had fewer occurrences of acute chest syndrome. Common side effects include constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain, and chest pain.

FDA works with all interested in improving the lives of patients with sickle cell disease. In February 2014, we held the first ever federal meeting with patients as part of our Patient Focused Drug Development program. A highlight was learning what symptoms bothered patients the most in their daily lives – the sort of information that can help inform the development and use of patient reported outcomes. And for the past several years, clinical review staff has organized meetings to facilitate drug development in sickle cell disease. During these events, academic researchers, clinicians and FDA engaged in an interactive discussion on trial design, potential endpoints, and patient reported outcomes.


Comparing a normal red blood cell and a sickle cell.

Sickle cell disease describes a group of inherited red blood cell disorders caused by abnormal hemoglobin, the protein that carries oxygen throughout the body. Normal hemoglobin moves easily through blood vessels, but sickle hemoglobin can be crescent or sickle shaped, which causes it to stick on vessel walls, blocking or stopping the flow of blood.


It is not entirely clear why progress in developing treatments for sickle cell disease has been slow. One challenge has been the multi-faceted nature of sickle cell disease as well as difficulty in defining biochemical endpoints and targets of clinical benefit in clinical trials. But there is hope.

Since 2010, we have seen a rise in the number of industry meetings, clinical trial development and investigational new drug (IND) submissions for sickle cell disease (required when companies want to conduct clinical trials of an investigational new drug), which may qualify for an expedited approval program known as Fast Track. Patient-reported outcome measures are being incorporated into clinical trials for new products. Currently 143 clinical trials (on Clinicaltrials.gov) are recruiting patients studying drug interventions, gene therapy, behavioral treatment and diagnostic testing in both adults and children.

While we at the Center for Drug Evaluation and Research work to encourage drug development, other efforts are underway to make bone marrow transplantation accessible to more patients as well as utilizing gene editing which can provide a permanent cure for sickle cell disease by correcting the sickle mutation in the stem cells.

We know there is much more work to be done, but FDA is proud to say during this Sickle Cell Awareness Month, that we are part of a dynamic team and remain committed to promoting the development of safe and effective treatments for this blood disorder.

Patricia Oneal, M.D., is a Medical Officer in the Division of Hematology Products at FDA’s Center for Drug Evaluation and Research.

Rosanna Setse, M.D., M.P.H., Ph.D., is a Medical Officer in the Office of Hematology & Oncology Products at FDA’s Center for Drug Evaluation and Research.

For more information, please visit: The FDA Encourages New Treatments for Sickle Cell Disease

How Patient Preferences Contribute to Regulatory Decisions for Medical Devices

By: Jeffrey Shuren, M.D., J.D., Anindita Saha and Martin Ho, M.S.

Jeff Shuren

Jeffrey Shuren, M.D., J.D., Director of FDA’s Center for Devices and Radiological Health

Since we launched our Patient Preference Initiative as part of our medical device regulatory decision-making process in September 2013, we’ve seen increasing evidence of the benefits of soliciting patient feedback – most recently, in giving kidney patients more therapy options and enhancing the safe use of a glucose monitor by pediatric patients with Type 1 diabetes.

In August, for the first time we cleared an expanded indication for a home hemodialysis machine so it could be used without a care partner being present, a decision based in part on asking kidney patients about their tolerance for risk.

Home dialysis may improve a patient’s quality of life, allowing them to undergo the lengthy treatments in the comfort of their home without the need to travel three times a week to a dialysis center. However, due to a risk of rare but serious events associated with performing hemodialysis alone in the home, we had previously required the presence of a care partner during the treatment.

Anindita Saha

Anindita Saha, Director of External Expertise and Partnerships at FDA’s Center for Devices and Radiological Health

During our August 2015 public workshop as part of the Kidney Health Initiative, a public-private partnership, multiple patient representatives argued that the care partner requirement effectively ruled out home treatment for those patients who lived alone or who could not afford to hire a care partner.

We told them that we were willing to reconsider this issue but needed a systematic way to evaluate risk. A medical device developer, NxStage, approached us at the meeting to propose a patient-centric approach. During the pre-submission process, we worked with NxStage to design their robust patient survey that could quantify the level of risk that patients would accept in exchange for doing hemodialysis in the home alone instead of at a dialysis center. The survey used a weighting method described in the Patient Preference Framework developed by the Medical Device Innovation Consortium (MDIC), a nonprofit that operates in partnership with FDA to improve the medical technology environment. This data helped inform the review of NxStage System One’s expanded indication that allows for home hemodialysis treatments without the presence of a care partner.

Martin Ho

Martin Ho, M.S., Associate Director for Quantitative Innovation at FDA’s Center for Devices and Radiological Health

The System One is the latest example of how we have been successfully implementing our Patient Preference Initiative, designed to identify and develop methods for assessing patient valuations of benefit and risk related to specific device types and specific illnesses and conditions that can be used to inform product review decisions.

Collecting qualitative feedback from patients is another important technique and proved helpful in enhancing the safety of the Dexcom G5 Continuous Glucose Monitoring (CGM) System and Animas Vibe System, a continuous glucose monitor with an insulin pump, for children. FDA discussed with patients, care partners, and patient groups their concerns about the safety of using an insulin pump in the young pediatric population. These conversations included how the device would be used once approved by FDA for the young pediatric population and what kind of safety considerations might be relevant.

Based on this feedback, FDA worked with the company to develop additional risk mitigation strategies that included a lockout feature to prevent unintended boluses by young children playing with the insulin pump. Patient preference information led to a safer device on the market, and parents can now have greater confidence with managing their children’s diabetes.

These are good examples of how medical device companies are leveraging different types of patient preference information to support product submissions, information which is likely to vary depending on the device, the disease, the level of risk, and its purpose in the submission.

We invite companies to start a conversation with FDA about using patient preference information to support your submission. For more information, you might want to attend our upcoming patient preference initiative meeting on December 7-8, 2017, where some of these topics will be further discussed. Patient preference is also an evolving area of regulatory science, supported in part by the nonprofit MDIC, and FDA encourages further research in this field.

Jeffrey Shuren, M.D., J.D., is Director of FDA’s Center for Devices and Radiological Health

Anindita Saha, is Director of External Expertise and Partnerships at FDA’s Center for Devices and Radiological Health

Martin Ho, M.S., is Associate Director for Quantitative Innovation at FDA’s Center for Devices and Radiological Health

Making the Case for Using Whole Genome Sequencing to Fight Foodborne Illness Globally

By: Steven Musser and Eric L. Stevens

FDA is laying the foundation for the use of whole genome sequencing (WGS) to protect consumers from foodborne illness in countries all over the world.

CODEX speaker

FDA’s Steven Musser speaks at the Codex Alimentarius Commission conference in Geneva.

We recently traveled to Geneva to join a meeting of the Codex Alimentarius Commission, an international organization that works to protect consumer health and promote fair practices in food trade. There, we participated in a panel discussion on how best to share WGS globally to fight foodborne illnesses and elicit support from the world’s governments in this effort.

There’s no time to waste. The World Health Organization (WHO) estimates that as many as 600 million people in the world fall ill every year after eating contaminated food and 420,000 of these people die.

FDA has been a leader in the use of WGS to identify the nature and source of bacteria that contaminate food and cause outbreaks of foodborne disease. By sequencing the chemical building blocks that make up the DNA of these pathogens, WGS reveals their genetic fingerprint, offering clues about their geographic source, antimicrobial resistance, and other key markers that help scientists respond more effectively to food contamination, preventing illnesses.

CODEX meeting Head table

FDA’s Steven Musser (left) and Eric Stevens (second from right) participate in an international panel on the efforts to share whole genome sequencing globally.

In the last few years, WGS has fundamentally changed the way that we detect, identify and monitor microbiological food safety hazards within the United States. This technology is rapid, precise, cost-effective, easy-to-use, and can be applied universally to all foodborne pathogens.

In 2012, FDA started the GenomeTrakr, a now-international network of laboratories sequencing microbial foodborne pathogens and uploading the data to a common public database in real time. The goal of GenomeTrakr is simple: to assemble a large, freely accessible database of genetic sequence information and accompanying metadata (e.g. geographic location and date) from food, environmental and human clinical isolates of bacterial pathogens. This information can be used by scientists on the trail of disease-causing bacteria, unmasking each contaminant’s identity and offering clues to where and how it got into the food supply.

Recently, public health institutions, including FDA, WHO and FAO (the Food and Agriculture Organization of the United Nations), have been working to raise awareness about the importance of WGS and the benefits of sharing both sequence information and metadata.

In Geneva we talked about how this technology is being utilized in some countries to support their foodborne disease surveillance system or outbreak investigation activities. We all understand that food is a global commodity, with complex shipping and distribution networks that can easily result in contaminated food being sold in more than one country. Thus, the most effective use of WGS in foodborne disease surveillance requires coordination and collaboration, and the panel emphasized the global health benefit of every country sharing their data. One approach would be sharing the data through FDA’s GenomeTrakr.

We are certain that the public health benefit of WGS will only become more evident with every foodborne pathogen’s genomic sequence that is shared. Already, GenomeTrakr has collected more than 142,000 sequenced strains, has made them freely available to anyone in the world, and continues to demonstrate how a large database of this kind is being used effectively for food safety within the United States, and throughout the world.

As the food supply becomes increasingly global, the use of WGS in a way that crosses national borders will ultimately help keep us all safe from foodborne illness.

Steven Musser, Ph.D., is the Deputy Director for Scientific Operations in FDA’s Center for Food Safety and Applied Nutrition (CFSAN).

Eric L. Stevens, Ph.D., is a Staff Fellow in FDA’s Division of Microbiology at CFSAN.

FDA is Advancing the Goals of the Orphan Drug Act

By: Scott Gottlieb, M.D.

Three months ago, I committed to fully eliminate a backlog of about 200 orphan drug designation requests that were pending review with FDA, and to implement policies that would require FDA to respond to all new designation requests within 90 days of receiving them. Moreover, the agency pledged to never allow a backlog of these designations to accumulate again.

Dr. Scott GottliebAt that same time, I said that we may pursue other policies that we believe would enable us to better advance the goals of the Orphan Drug Act (ODA). All of these commitments were part of a new Orphan Drug Modernization Plan that we announced on June 29th.

I’m pleased to update you on our progress in meeting each of these objectives.

First, owing to the dedicated efforts of the orphan drug designation team who oversee the Orphan Drug Designation Program, the first of these goals has been fully achieved. Reviews of all orphan drug designation requests older than 120 days were completed on August 28th. This was well ahead of the September 21st deadline that we had set for ourselves under our orphan drug plan. The achievement is hopeful news for those with a rare disease, defined as a disease which generally affects fewer than 200,000 people in the United States. Companies that receive orphan drug designation for their product qualify for various incentives including tax credits for clinical trial costs, relief from prescription drug user fees and the potential for seven years of marketing exclusivity after the drug is approved.


Orphan Drug Designation Requests By Year

Orphan Drug Designation Requests By Year

Note: Designations granted in a given year may include requests received from that year as well as previous years.


Second, we’re putting in place new policies to improve the efficiency of our review process to ensure that we meet our new 90-day mandate to prevent new backlogs.

Finally, we’re going to be taking new policy steps to make sure that the incentives offered by the ODA are granted by FDA in a way that’s consistent with the manner Congress intended. To that end, FDA will soon hold a public meeting to get input on complex scientific and regulatory issues such as those raised by molecularly targeted drugs and biologics and the appropriate application of orphan incentives in that paradigm. As part of this process, FDA will also be examining aspects of how the agency grants designations, to make sure they continue to reflect current science and drug development and the goals intended by Congress.

For all the success of the ODA, there’s been criticism that some sponsors are using designations as a way to sidestep other important public health goals set out by Congress. We need to make sure our policies take notice of all of these new challenges and opportunities.

FDA plans to advance certain guidance documents and other policies to address these issues. One guidance document will close a loophole that allows sponsors to avoid an obligation to study drugs in pediatric indications. This circumstance arises if sponsors received an orphan designation for a pediatric subtype of an otherwise common and non-orphaned adult disease.

The longstanding practice of allowing pediatric subpopulations of common diseases to be designated as orphan conditions was intended to promote pediatric drug development. It pre-dated the implementation of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act (PREA), two laws that were specifically aimed at promoting more pediatric studies.

Now, instead of instigating more pediatric research, the granting of the orphan designation in the pediatric subpopulation can have the opposite effect. It can allow sponsors to sidestep pediatric study requirements that are part of other laws aimed at promoting this same research.

Consider a condition like inflammatory bowel disease. A drug may be approved to treat the large population of adults with the condition. Then the same drug may be granted an orphan designation to treat the much smaller population of a subset of children suffering from the same condition.

But once a drug receives an orphan designation for a pediatric population of the adult disease, the drug then becomes statutorily exempt from the requirements of PREA. This occurs even in cases where the sponsor never goes on to develop the drug for this pediatric use. These PREA requirements could have required the sponsor to study the drug for this or other uses in children. By granting the drug a pediatric orphan designation, it means the drug never has to actually be studied for a pediatric use. It’s a loophole that is in direct opposition to what Congress intended.

Nobody envisioned this unintended conflict between the original ODA and the provisions outlined in PREA. In effect, by letting sponsors designate pediatric subpopulations of drugs intended to treat adult diseases, the drug makers receive an unintended “free pass” from having to study drugs in these or other pediatric uses. Thus, rather than ensuring more pediatric research, as Congress envisioned, we can end up with fewer pediatric studies. FDA will soon issue a draft guidance document that’s aimed at closing this inadvertent loophole.

Taking these and other steps to modernize our stewardship of the ODA is imperative. Science is giving us new opportunities to use the tools offered by the ODA to advance innovation in more areas of medicine where patients have few, if any options. At the same time, the demands on FDA’s orphan drug program continue to grow. We need to make sure the policies governing how we implement these key provisions are modern and efficient.

The number of requests received by FDA under the Orphan Drug Designation Program has steadily increased over the past five years, rising to 568 new requests in 2016. This is more than double the number of requests received in 2012.  Patients with rare disease often have limited or no treatment options. We want to maximize new opportunities for patients.

FDA will continue to make full use of tools provided by Congress to apply incentives for the efficient development of rare disease therapies, and for activating more pediatric research. These steps will help us achieve our ultimate goal: to facilitate the development of safe, effective innovations that have the potential to meaningfully impact rare diseases.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

“Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress

By: Michael Kopcha, Ph.D., R.Ph.

Today, a new and exciting technology – continuous manufacturing (CM) – can truly transform the drug manufacturing process so that it is more reliable and efficient. We discussed in a previous blog how CM enables a much faster and more reliable manufacturing process. In some cases, manufacturing that takes a month to complete with older technology — often called “batch” technology — might only take days using CM. FDA is seeking input, through a public docket open until September 21, from experts in the field about the science, technology, and best practices concerning CM.

Michael KopchaAs with any new technology, implementing CM presents challenges, such as the initial cost of investing in new equipment. However, the CM production method offers clear benefits for both patients and industry. CM can shorten production times and improve the efficiency of the manufacturing process. CM also allows for more nimble testing and control that can help reduce the likelihood of manufacturing failures. These control strategies could potentially contribute to the prevention of drug shortages. CM technology can be implemented for an entire production process, or for specific operations within the process. Manufacturers can tailor their use of CM based on their particular product and business needs.

Congress has recognized the potential benefits CM can offer for drug manufacturing as well. The 21st Century Cures Act, enacted in December 2016, authorized grants to support studying CM and recommending improvements to the process of continuous manufacturing of drugs and biological products.

FDA encourages adoption of this technology by engaging with firms interested in using CM. FDA’s Emerging Technology Team (ETT) assists companies that want to implement innovative technology, including CM, for manufacturing both new and existing drugs. We have already seen two companies that have implemented CM and benefited from early engagement with the ETT. Vertex has been using a CM process for their cystic fibrosis drug, Orkambi (lumacaftor/ivacaftor), since its approval in July 2015. In 2016, FDA approved a change in production from batch to continuous manufacturing for Janssen Products’ medication to treat HIV-1 infection, Prezista (darunavir).

With many companies now evaluating their operations for potential uses of CM, some have found specific ways to utilize CM techniques in their own production processes. As a result of these individual efforts, we now see a variety of different approaches for implementing CM technology throughout industry.

Given these emerging variations, FDA’s goal is to provide a framework of principles that clarify our expectations, while still encouraging companies to innovate and implement CM. We are talking with industry and are also helping lead this conversation on a global level by engaging our foreign regulatory counterparts regarding the development of clear regulatory standards.

To further this effort and gather more input from experts, we have opened the public docket for comment until September 21. FDA is interested in getting public feedback on published documents on this topic, including an industry-coordinated best practices document issued by the public-private consortium Center for Structured Organic Particulate Systems (C-SOPS), and white papers from a 2014 symposium published in the Journal of Pharmaceutical Sciences.

If you have experience and expertise on CM, please submit your comments, which will help us to gather and consolidate the important scientific information being developed in this area.

Assuring the availability of quality, safe and effective medications to the American public is a priority for FDA. CM, and other innovative manufacturing and control strategies, offer ways for the pharmaceutical industry to continue to help support this goal. By drawing upon the experience of FDA, industry, and academia, we will develop common guiding principles to support implementation of CM, building on the great progress made by industry to date.

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

FDA’s plan to engage the public in the agency’s new effort to strengthen and modernize FDA’s regulatory framework

By: Anna Abram

Anna AbramWe’re at a moment of extraordinary opportunity to improve the public health. New innovations are giving us fundamentally better ways to address disease. Some of the same technology is providing consumers with a broader selection of foods that can improve peoples’ diets, and products that can expand their choices. At the same time, we also face a lot of new challenges. The steps FDA takes to advance these opportunities, and address uncertainties, will directly impact the lives of families. As part of our commitment to protect and promote the public health, we’re undertaking a comprehensive review of our regulations. Our aim is to ensure that our policies and regulations keep pace with the challenges we face in protecting consumers, and the opportunities we have to improve their lives. As in all our actions, science will remain FDA’s North Star when it comes to our role in devising regulatory policy.

Over the past few months, FDA has announced a number of broad policy efforts to address public health opportunities in areas such as regenerative medicine, tobacco products, and access to affordable medicines. As with everything that we do, this work is rooted in our mission to protect and promote the public health, foster safe and effective innovation that can benefit patients, adopt regulatory approaches that enable the efficient development of new innovations, and provide for a safe, healthy and nutritious food supply. For example, we’re looking at places where FDA’s rules concerning new drugs are being used in ways that may create obstacles to the timely entry of generic competition. We want to make sure our policies aren’t being misused in ways that thwart the competition that Congress intended when it created the modern generic drug framework. We know that vigorous generic competition can help benefit patients by lowering drug costs, which improves access to medicines. It’s one example of where a closer analysis of our existing policies can help make sure our regulations are having their intended purpose.

As part of my commitment to help oversee the development and implementation of key policy issues, and to help advance these broader policy efforts, I’ve been working closely with FDA Commissioner Scott Gottlieb, M.D., and other senior agency colleagues, to explore ways to modernize our regulations in a manner that will benefit all Americans. To achieve this, we’re not only looking at what new regulations or policies we need in order to be most effective in fulfilling our public health responsibilities. We’re also taking a closer look to see if we need to revise, update, and in some cases eliminate existing regulations to help us better keep pace with scientific advancement and the people that we serve. We need policies that are as modern as the products that we’re being asked to evaluate, and a regulatory framework that uses efficient tools to achieve our vital consumer protection role.

This comprehensive review is a large undertaking given the breadth of our public health mission and the fact that FDA-regulated products account for about 20 cents of every dollar consumers spend each year. It involves the support of FDA’s senior leaders and many of our staff. FDA has long played a vital role in protecting and promoting public health, and since its founding in 1906, the scope and charge of the agency’s work has grown to include many products that Americans rely on every day. Over time, the agency has also assumed an increasingly global footprint. Along the way, we’ve taken many steps to modernize our policies and practices and evaluate our portfolio of regulations to make sure they’re keeping pace with our challenges. But our 100-plus-year history lends itself to a closer examination of the regulations that have guided our work. Some have been in place for decades, and may not reflect the most up-to-date approach to achieving our public health mission. We have a lot of ground to cover. Today, FDA’s regulations comprise more than 4,000 pages in the Code of Federal Regulations. Some regulations may not adequately reflect advances in science, technology or changes in industry practice. Others may be geared toward products and practices that have largely ceased to exist. In a world of increasing challenges and opportunities, we need to be risk-based in everything we do in order to make sure we’re using our resources efficiently. Our goal is to have regulations that reflect modern risks and opportunities, and use the full scope of our authorities to achieve our consumer protection mission.

As part of this process we’re asking ourselves and others to think about how current regulations could be reshaped to achieve our public health objectives through more efficient approaches. We are opening a number of public dockets to solicit feedback from patients, consumers, health providers, caregivers, industry, health groups, academia, as well as state, local and tribal governments, and public health partners. We’re also exploring other opportunities to solicit input from stakeholders on this effort. We believe that engaging both internal and external stakeholders are critical to focusing our attention on where our policies might need updating; to ensure FDA’s work maximizes our public health purpose.

Our approach also aligns our efforts with the Administration-wide goal for federal regulatory reform to improve how government serves the American people. At FDA we take seriously our responsibility to protect and promote the public health. This will be our guiding principle. We’ll use this opportunity to make sure our regulations reflect the new benefits that science and technology offer to advance opportunities for patients to improve their lives, and to strengthen our mandate to protect consumers. We look forward to your input and will continue to communicate our plans as we move forward on this endeavor.

Anna Abram is FDA’s Deputy Commissioner for Policy, Planning, Legislation and Analysis

For more information on how to provide input on FDA’s regulations, please visit:

Tobacco Product Master Files: What Are They and How Could They Benefit You?

By: Mitch Zeller, J.D.

In a bid to help streamline and simplify the tobacco product application process and potentially reduce the associated costs, FDA is encouraging the creation and use of tobacco product master files (TPMFs).

Mitch Zeller, J.D., Director of FDA's Center for Tobacco ProductsTPMFs are voluntary submissions to FDA that typically contain trade secrets and/or confidential commercial information about a tobacco product that the owner does not want to publicly share with others. But this information may be referenced by other parties in preparing tobacco submissions if the TPMF owner grants those other parties a right of reference.

Here’s how TPMFs are designed to work. Once a master file is submitted, anyone interested in referencing that file as part of their own submission may request a letter of authorization from the TPMF owner. If the request is granted, FDA reviewers will be able to access and review non-public information in the TPMF according to the authorization in the course of reviewing the submission, even if that information is not available to the authorized party.

For example, a flavor supplier might submit a TPMF to FDA that contains the full listing of ingredients and composition information of different flavors. The flavor supplier could then grant a customer, for example, an e-cigarette manufacturer, the right to reference the TPMF to support the customer’s premarket application for an e-cigarette that uses the supplier’s flavors. When reviewing the premarket application, FDA would also review ingredient and composition information in the TPMF, which may otherwise be confidential, without that information being shared with the customer.

TPMFs can be mutually beneficial for both file owners and parties authorized to reference the files in their own applications—ultimately resulting in potential cost savings for all parties involved. For TPMF owners, allowing FDA to keep certain information on file can reduce administrative work for the company and the need to resubmit this data for future applications, thus easing the application burden. Additionally, when a TPMF owner grants another entity access to a master file, it enables the authorized party to reference scientific data and analyses in the file that otherwise could be costly and time-consuming to obtain if the party, itself, needed to produce the information.

By filing TPMFs with FDA, owners gain the ability to expand existing customer relationships and to foster new ones while also keeping the owner’s information confidential.

Tobacco product submissions that may reference a TPMF include:

  • Premarket tobacco applications
  • Substantial equivalence reports
  • Modified risk tobacco product applications
  • Request for exemption from substantial equivalence requirements
  • Grandfathered submissions
  • Investigational tobacco product submissions
  • Ingredient listings

There are many ways TPMFs can be used in different types of applications. For instance, a lab could create a TPMF that contains protocols and methods for measuring levels of harmful and potentially harmful constituents (HPHCs) in tobacco products. An authorized manufacturer that used the lab’s services to generate HPHC data for, e.g., a substantial equivalence report could reference the lab’s TPMF in its submission to FDA, helping FDA evaluate HPHCs in its tobacco products.

FDA does not intend to conduct scientific review of a TPMF until the TPMF is referenced in a submission.

To learn more about the many benefits of becoming a TPMF owner, see “Tobacco Product Master Files: Guidance for Industry.” Contact us at ASKCTP@fda.hhs.gov or 1-877-CTP-1373 (1-877-287-1373).We will present a webinar on TPMFs soon, so stay tuned and sign up for email updates.

Mitch Zeller, J.D., is the Director of FDA’s Center for Tobacco Products

Interoperability: FDA’s Final Guidance on Smart, Safe, Medical Device Interactions

By: Bakul Patel, M.S., M.B.A.

Imagine an intensive care unit for newborns. An interface on a device called a pulse oximeter is sending data on changes in the newborns’ blood oxygen level to a hospital computer system that simultaneously gathers data from EKGs that are monitoring the electrical activity of their hearts.

Bakul PatelBy synchronizing time and information with the pulse oximeter, an EKG is able to identify important signals from the oximeter, information that will ultimately lead to smarter care. “Interoperability” is when devices talk to each other in a safe and effective way enabling smarter care.

Today’s health care providers and their patients are relying more than ever on rapid, secure interactions among different medical devices. From electrocardiograms to infusion pumps, medical devices must reliably communicate and operate in concert.

It’s not likely that medical device interoperability is a part of the everyday vocabulary of American consumers—and frankly, we hope it stays that way. At CDRH, we want patients and consumers to have confidence that medical devices work as intended without concern over how these devices operate together. But, in working with manufacturers to bring innovative medical devices to patients who need them, interoperability is an indispensable concept.

Today, FDA issued final guidance that outlines our recommendations for smart, safe, and secure interactions among medical devices and other information systems. FDA specifically recommends that all medical device manufacturers:

  • Design their devices with interoperability as an objective;
  • Conduct appropriate verification, validation and risk management activities; and,
  • Clearly specify the relevant functional, performance, and interface characteristics to the user.

Our guidance incorporates comments received from the medical device industry, designers, and the public. When premarket submission to the FDA is required, this guidance provides clarity and recommendations for what information on interoperability should be included in a manufacturer’s premarket submissions.

FDA’s first concern, of course, is safety. Errors and inadequate interoperability, such as differences in units of measure (e.g., pounds vs. kilograms) can occur in devices connected to a data exchange system. Our guidance recommends appropriate functional, performance, and interface requirements for devices with such interactions.

The guidance also encourages transparency, recommending that designers and manufacturers provide information on a product’s functional performance and interface characteristics so that those using it with other devices and systems can do so safely.

Failure to develop and provide this information to the user may lead to an inappropriate use of the device interface in a way that can lead to device malfunction, including the failure to operate, and may lead to patient injury and even death.

In many cases, the consensus standards that support interoperability specify data format, interoperability architecture design, or other aspects associated with interoperability. FDA recognizes the benefits of relying on published consensus standards in the design of medical devices. Accordingly, FDA has recognized numerous consensus standards relevant to the development and design of interoperable medical devices and encourages their use.

Manufacturers may choose to use their own design preferences for their interface (in lieu of a published consensus standard) for their medical devices. In either case, problems or misuse of interoperable medical devices can be minimized by making the functional, performance, and interface requirements openly available to all users.

Our guidance is a good step towards safer devices, and we will continue to work with all stakeholders to adapt along with the technology.

Bakul Patel, M.S., M.B.A., is Associate Director for Digital Health in FDA’s Center for Devices and Radiological Health

A Look Back: The AIDS Crisis and FDA … 30 Years Later

By: Richard M. Klein

The first patient-focused office at FDA – and very possibly the first patient engagement office in the federal government – was the Office of AIDS and Special Health Issues, established in 1994 at the height of the AIDS epidemic.

Richard M. Klein, a former entomologist in the agency’s New York Laboratory who had been working on human research protection policy at FDA’s suburban Washington, D.C., headquarters, was instrumental in setting up the new office. He recently sat down with FDA Voice to talk about his work with patient engagement during the AIDS epidemic.

Could you set the scene for us? What was it like as the AIDS epidemic grew in the years and months leading up to the creation of the Office of AIDS and Special Health Issues?

Commemorating 20 Years AIDS poster

Twenty years after the protest at FDA headquarters, the world had moved from protest to protease inhibitors, and beyond.

It was a desperate time. People lived 6 to 18 months after diagnosis. There was a pervasive sense that the government was not doing anything. One day in October 1988, the advocacy group ACTUP (AIDS Coalition to Unleash Power) functionally closed down the FDA. They surrounded the building at our Parklawn Headquarters in Rockville, Md., preventing employees from getting into the building. FDA saw other forms of protest as well. The director of the first antiviral division, created to address AIDS, received death threats. Individuals continually called up various offices of FDA complaining that no one at FDA was paying attention to AIDs. There were “fax attacks” – repeated attempts to send faxes clogging the phone lines. It was designed to disrupt “business as usual,” because they thought AIDS shouldn’t be business as usual. I was working in the New York lab at the time, and the community in New York was overwhelmed by this epidemic. People were getting sick left and right. I worked with a guy in the lab who contracted and later died from AIDS. That’s when I decided I wanted to take a more active role with AIDS and when the opportunity came up, I knew it was something I needed to do.

What did FDA do?

I mentioned the creation of the antiviral division to focus on AIDS drug development. There was also a National Commission on Aids with which we were involved. And FDA was integral to the National Task Force on AIDS Drug Development, a public/private effort brought together government, industry, academia, and patients to identify and remove barriers to successful drug development. Initially, FDA’s AIDS activities were coordinated by CBER since so many issues early on involved the blood supply, but then responsibility was shifted to the Office of the Commissioner. That’s when the new Office of AIDS and Special Health Issues was established to better communicate with the public and coordinate AIDS activities. The idea was to insulate the review division so they could do their work – and we would take the phone calls and we would get the faxes. The phone calls in the beginning were really terrible. People would say, “Murderer. Nazi. FDA is not doing anything, you are killing people,” and I wondered, what did I open myself up to?

We were the insulator, but also the conduit to the review divisions.

Tell us how you interacted with the AIDS community in those early days.

After the first meeting of the Task Force, I went down to Connecticut Avenue and had a couple beers with one of the major activists, Moises Agosto. I told him, I’m starting in this new job. What do you guys need and want? It was a really great conversation that I think opened up relationships. Later, when AIDS drug applications were filed with FDA, I would go to the advisory committee meetings and I would sit with the AIDS activists, rather than FDA staff. It gave me the opportunity to really know the community issues as we talked together about the proceedings.

Do you think that education was one of your principal roles?

Yes. I thought, if I could rationally explain to people how things work, how drugs get developed and why you can’t rush it, that you can’t expect it to turn out well if you don’t have the data, people would listen and open up to the idea that regulation has a real purpose. I would go to scientific meetings and companies with their marketing people would be there. They would hold meetings with activists and give them what I would describe as sales pitches on results involving maybe one or two patients and everybody would get very excited. But the companies would talk to the activists and say FDA is holding things up. The community would come to me and ask why is FDA is doing that. While I couldn’t talk about specific applications, I would tell them “This is how it works, any action FDA takes they send a letter to the company describing the reason(s).” I always told the activists to ask the company for the letter. They would get the letter and it would be redacted, or missing pages. “What does it say to you?” I asked them. We can’t talk about the drug and they don’t want to provide the specifics. The activists would say “Oh.”

Ultimately, patients played an important role in AIDS drug development didn’t they?

They did. People really need to understand how involved the activists were in both the policy and the science. They learned and they got into the fabric of what was going on. They were thinking outside of the box and doing a really good job at that. They would meet with NIH to learn about the basic viral and cellular research, and write White Papers about drugs in development. They pushed for the use of accelerated approval based on a surrogate endpoint – viral load. And they also pushed for expanded access, which was already on the books but wasn’t being used as much as it could have been. What’s important though, is that they recognized that policy had to move in tandem with science.

And these advocates really pioneered the patient representative program?

It all started with these guys coming in from San Francisco, all jet-lagged, to speak at the advisory committee’s open public hearing scheduled at 8:30 a.m. – before FDA and the company gave their scientific presentations. Mind you, this was before the internet and before advisory committee documents were made available 48 hours in advance. They told me “We’re coming in blind, deaf, and dumb. How can we meaningfully comment?” Some were so frustrated they would stand up during meetings and blow whistles and shout “this is an outrage.” So Lee Zwanziger, the executive director of the advisory committee, to her credit, moved the open public hearing to later in the day, after the sponsor and FDA presentations about the data. The activists also wanted to sit at the table and be part of the conversation that could so strongly affect their survival. So we worked with the review staff and with Lee to make them consultants to the committee, but they still couldn’t see the confidential background documents. So Lee said if we pay them, they can sign a contract that binds them to confidentiality. That was brilliant. This was the beginning of the patient representative program that today includes about 300 patient representatives covering more than 200 different diseases, giving patients a voice at the table.

In 1996, when protease inhibitors were approved, everything turned around. As the age of the drug cocktail evolved, AIDS patients were living longer, better lives. They could worry less about having to go to the doctor and fearing a diagnosis of new opportunistic infections and, instead, could worry about such mundane things as going to work, or paying their gas bill. This was such a success.

Interestingly, much later, when FDA was coming under fire because of its regulatory role and activities, it was AIDS activists who went to Congress and argued that FDA added necessary and important value to drug development.

Editor’s Note: The Office of AIDS and Special Health Issues took on other patient engagement responsibilities over the years and its name and its place in FDA’s organizational structure evolved. Today, it is known as the Office of Health and Constituent Affairs.

Richard M. Klein, is the Director of FDA’s Patient Liaison Program