Balancing the Prevention of Opioid Abuse and Appropriate Pain Management

By: Margaret A. Hamburg, M.D.

Earlier today I had the opportunity to address the Rx Abuse Summit in Atlanta, Georgia, an important three day conference that brings together local, state and federal agencies, business, academia, clinicians, treatment providers, counselors, educators, state and national leaders, and advocates to share ideas and strategies for reducing the growing number of tragedies resulting from prescription drug abuse.

Margaret Hamburg, M.D.For FDA, stemming the rise in prescription opioid misuse, abuse, addiction, and overdose is an issue of the highest priority. The issue is complicated by the need to balance it with another major public health priority: managing the pain that affects an estimated 100 million Americans.

This balance goes to the heart of FDA’s mission to protect and promote the public health — and to our role as drug regulators. FDA has a responsibility to demand the best science and data to uphold its high standards to ensure a proper benefit/risk profile for these drugs, and to foster discussion and research that leads to a better understanding of pain and pain drugs.

FDA shares the concerns about safe and appropriate use of all prescription opioid analgesics and the public health consequences associated with misuse and abuse of these drugs. I encourage you to read my remarks from today, in which I detail the many actions FDA has taken to address prescription opioid abuse, targeting key drivers of the problem.

Nothing can erase the tragedy that so many people have had to face as a result of the misuse, abuse and addiction of opioids. But progress to reduce and prevent our nation’s prescription drug crisis is attainable through a comprehensive and collaborative approach. For our part, FDA is committed to reducing abuse of opioids and ensuring appropriate access to pain medicines for patients in need.

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

Collaboration and Medical Countermeasures: Furthering Regulatory Science

By: Dr. Stephen Ostroff

“I hope no one ever needs these products,” isn’t something you hear too often, particularly from those developing drugs, biologics, or devices. That point of view—and a universal desire to protect the American public—is what sets biodefense professionals apart.

Stephen OstroffWithin FDA, our Medical Countermeasures initiative (MCMi) does things a little differently as well. Managed by the Office of Counterterrorism and Emerging Threats, in the Office of the Chief Scientist, MCMi thrives on collaborations. We work proactively with industry, academic and federal research centers, FDA product centers and offices, and other government entities in our mission to help protect the U.S. from chemical, biological, radiological, nuclear, and emerging infectious disease threats.

Collaborating is particularly important to advancing regulatory science: developing the tools, standards, and approaches needed to evaluate FDA-regulated products—in this case, medical countermeasures—for safety, efficacy, quality, and performance. When it comes to developing the necessary data for regulatory decisions, medical countermeasures often present unique and complex challenges since the diseases they target rarely occur naturally.

To support regulatory decision-making for medical countermeasures, FDA manages a robust research portfolio under the MCMi Regulatory Science Program. Working with other federal agencies to ensure alignment with U.S. priorities, we fund both intramural and extramural research programs to drive innovation in regulatory science.

Ongoing research projects include:

  • Developing models of radiation damage in lung, gut, and bone marrow organs-on-chips, and using these models to test candidate medical countermeasures to treat such damage;
  • Mapping immune responses to certain biothreat agents and medical countermeasures in humans and animal models to create species-specific immune function maps;
  • Assessing the feasibility of using electronic health record systems to conduct near real-time monitoring of health outcomes, including serious or unexpected adverse events associated with medical countermeasures used during public health emergencies.

For those interested in these and other medical countermeasure-related regulatory science developments, FDA will be hosting our 2014 MCMi Regulatory Science Symposium at FDA headquarters in Silver Spring, Maryland, June 2-3, 2014. The meeting is free and open to the public (pre-registration required).

We welcome poster abstract submissions until April 27, 2014, in topic areas including: animal models, biomarkers and correlates of protection, devices, diagnostics, emergency communication, new technologies, product quality, and surveillance.

I also encourage you to read more about MCMi in action in our Fiscal Year 2013 Program Update.

Stephen Ostroff, M.D., is FDA’s Acting Chief Scientist

FDA Works with China to Ensure Medical-Product Safety

By: Christopher Hickey, Ph.D.

Americans benefit greatly from medical products produced by other countries. Approximately 40 percent of finished drugs in the United States come from overseas, as well as more than 50 percent of all medical devices. About 80 percent of the manufacturers of active pharmaceutical ingredients are located outside the United States.

Christopher Hickey

Christopher Hickey, Ph.D., testifies April 3, 2014.

However, this rapid globalization of commerce presents challenges to regulators who oversee the safety and quality of medical products. Many of these challenges manifest themselves in China. As FDA’s country director for the People’s Republic of China, I testified on April 3, 2014 before the U.S.-China Economic and Security Review Commission, an advisory panel created by Congress, on our work to ensure the safety and quality of medical products produced in China and imported into the United States.

China is the source of a large and growing volume of imported foods, medical products and ingredients. In the years spanning fiscal years 2007 and 2013, the total number of shipments of FDA-regulated products from China to the United States almost quadrupled.

The challenges we see in China mirror those we see in other countries with developing regulatory systems. These issues include problems with data integrity, inadequate implementation of quality systems in manufacturing, and inconsistent regulatory oversight, among others.

As China’s role on the global stage expands, FDA has significantly increased drug and medical device inspections there, but we need to continue to strengthen our efforts. FDA is currently working to use Congressionally-appropriated funding to increase from eight to 27 the number of U.S. staff it posts in China. Visa issues that arose with the Chinese government over new FDA staff assigned there were addressed during Vice President Joe Biden’s visit to Beijing in December, and FDA continues its work to post new staff in Beijing in the coming months.

FDA recognizes that strategic engagement in China starts first and foremost with Chinese regulators. China’s Food and Drug Administration, or CFDA, is responsible for the regulation of food, drugs, and devices for domestic distribution in China, and for regulation of certain exported drugs and medical devices.

Senate Committee Hearing, April 3, 2014

Christopher Hickey, Ph.D., testifies before the U.S.-China Economic and Security Review Commission.

FDA has established a strong working relationship with CFDA. Our office has trained hundreds of Chinese inspectors in areas that include inspecting for good manufacturing practices and assessing the quality of data from sites that conduct clinical trials. Experts from FDA’s Center for Devices and Radiological Health now meet regularly with their counterparts from CFDA under the auspices of the International Medical Devices Regulatory Forum. These investments will pay long-term dividends for the American people: a stronger Chinese regulatory system can only strengthen FDA’s efforts to promote and protect U.S. public health.

Finally, in the area of inspections and enforcement, CFDA inspectors now regularly observe FDA inspections in China. And since 2012, FDA’s Office of Criminal Investigations has worked closely with CFDA to fight against Internet-based, illegal distribution into the U.S. of falsified, counterfeit and adulterated drugs.

FDA’s priorities in China match its global priorities: we work to ensure the safety and efficacy of FDA-regulated products. Manufacturers are best situated to make certain that appropriate processes are in place to ensure safety and quality in production. Regulatory bodies should hold companies accountable for lapses in the production process. Inspections and testing are important tools in that process, but they must be used as part of a larger system that emphasizes a preventive, approach to the production of safe, effective, high-quality medical products.

And in our globalized world, it’s increasingly important that regulatory partners work together to ensure the safety of products as they move through increasingly complex supply chains. Patients and consumers – whether in Beijing or Boston – deserve no less.

Christopher Hickey, Ph.D., is FDA’s Country Director for the People’s Republic of China.

For more information, please visit this Web link:

China’s Healthcare Sector, Drug Safety, and the U.S.-China Trade in Medical Products

Creating a New System to Improve the Security of the Drug Supply

By: Ilisa Bernstein, Pharm.D., J.D.

FDA is committed to protecting consumers from potentially dangerous drugs, including those that are counterfeit, stolen or tainted. We are taking steps to create a system that will help identify and trace certain prescription drugs as they are distributed within the United States.

Ilisa BernsteinThe Drug Supply Chain Security Act (DSCSA), signed into law last November, outlines the path to building this electronic tracking system. We are working now to develop standards for this new system and we can’t do it alone. Stakeholders – including drug manufacturers, wholesaler distributors, repackagers, and many dispensers (mainly retail and hospital pharmacies) – will be working with us.

The ultimate goal is to identify each individual prescription drug package in a way that will enable rapid and accurate verification of the legitimacy of the product, which will be an important tool in the fight against counterfeit drugs. If a counterfeit or other harmful drug is discovered in the supply chain, we can immediately notify patients, health care professionals, hospitals and others about the public health risk.

This system, which will include a history of the transactions involving each drug product, will also help to enable more efficient recalls to remove drugs from the market that are considered potentially dangerous.

It will be an “interoperable” system, meaning that different stakeholders in the drug supply chain will be able to communicate with each other and share information about the drug and its location.

We have posted our implementation plan at fda.gov and have opened a docket in the Federal Register with questions that we’d like these stakeholders to answer about any practices or systems they may be using to exchange information related to prescription drug transactions, in paper or electronic format. The docket is open until April 21, 2014.

We will be reviewing all information that comes into the docket as we work on establishing standards for the interoperable exchange of tracing information. On May 8 and 9, 2014, FDA is hosting a public workshop for interested parties to discuss what standards may work, what makes sense and what can be done quickly. We encourage you to participate.

Time is of the essence because the law requires FDA to issue a draft guidance document with initial standards by Nov. 27, 2014, and for many stakeholders to establish systems and processes that will enable them to comply by Jan. 1, 2015.

Experts from all over FDA are working to implement this important law. Provisions of this law will enhance FDA’s ability to help protect consumers from exposure to drugs that may be counterfeit, stolen, contaminated, or otherwise harmful through improved detection and removal of potentially dangerous drugs from the drug supply chain. U.S. consumers deserve safe, effective and high-quality medications.

Ilisa Bernstein, Pharm.D., J.D., is Deputy Director of the Office of Compliance in FDA’s Center for Drug Evaluation and Research

For more information please visit the following Web links:

Drug Supply Chain Security Act (DSCSA) Implementation Plan

Standards for the Interoperable Exchange of Information for Tracing of Human, Finished, Prescription Drugs, in Paper or Electronic Format; Establishment of a Public Docket

Public Workshop: Standards for the Interoperable Exchange of Information for Tracing of Human, Finished, Prescription Drugs, in Paper or Electronic Format

Recognizing Those Who Strive to Vanquish Alzheimer’s Disease

By: Margaret A. Hamburg, M.D.

I had the opportunity yesterday to take part in the Alzheimer’s Association’s (AA) Advocacy Forum and engage in a public discussion with the organization’s President and CEO Harry Johns about the FDA’s role in helping advance Alzheimer’s disease research and the development of new treatment options and approaches.

Margaret Hamburg and Harry Johns

Harry Johns, President and CEO of the Alzheimer’s Association, in a public conversation with FDA Commissioner Margaret Hamburg at the group’s recent Advocacy Forum in Washington, D.C.

This event recognizes the tireless efforts of a community determined to make strides in the fight against what is, in no uncertain terms, a devastating disease and world-wide crisis. Indeed, it is difficult to overstate the impact of Alzheimer’s disease on our society.

Only last month new research was published that suggests that deaths due to Alzheimer’s disease in the United States actually have been severely under-recognized. By these new estimates, Alzheimer’s disease may rank as the third leading cause of death, trailing only behind heart disease and cancer. What’s even more alarming is that it is the only cause among the top 10 without a way to meaningfully prevent, treat, or slow its progression.

Fortunately, in stark contrast to these disturbing figures, the commitment of the countless individuals entrenched in the fight against this epidemic remains resolute. The FDA shares in this determination and holds the need to facilitate the discovery of effective treatments for Alzheimer’s disease among its highest priorities.

In January 2011, President Obama signed into law the National Alzheimer’s Project Act (NAPA), which has the goal of creating a coordinated national plan to overcome the Alzheimer’s crisis. The FDA has been closely involved in the evolution of this plan and has taken several important steps toward realizing some of its stated goals.

In February 2013, the FDA published a draft guidance document responding to the shifting focus of the research community towards the earlier stages of Alzheimer’s disease. The hope is that intervening earlier in the disease process (before the onset of dementia) may provide a greater opportunity to alter the course of the condition. Given that these are uncharted waters, it is essential that we provide as much clarity as possible. Of particular note, the guidance discusses the possible use of the accelerated approval pathway as a means of approving drugs for patients in the earliest stages of the disease.

The FDA is also partnering closely with many public-private initiatives, advocacy groups and consortia in the Alzheimer’s community. As one example, the agency is a member of the recently announced NIH-led Accelerating Medicines Partnership (AMP), which is attempting to uncover biomarkers that may help predict clinical benefit in drug development. We are also working with the Coalition Against Major Disease (CAMD) to develop novel biomarkers to signal the onset of the disease and clinical-trial goals through the agency’s Drug Development Tool Qualification process, and have recently endorsed a clinical trial simulation tool they have developed. These represent just a few of our many collaborations within the Alzheimer’s disease field.

The Alzheimer’s Association used the occasion of their Advocacy Forum to honor the contributions of a number of individuals who have dedicated themselves to the vision of a world without the scourge of Alzheimer’s disease. We at FDA join in recognizing those who have made these important contributions and commitments. We also recognize and applaud the contributions of each and every member of the Alzheimer’s Association who have come to Washington this week to learn more, but also to educate policymakers through their experience, advocacy, and personal stories. Like all of them, we at FDA are committed to doing our part to meet the immense scientific and social challenges of this disease.

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

For more information please visit these Web links:

The National Alzheimer’s Project Act (NAPA)

FDA Guidance for Industry, Draft Guidance, Alzheimer’s Disease

Opioid Auto-Injector Can Help Prevent Overdose Deaths

By: Dr. Douglas C. Throckmorton

The Food and Drug Administration has today made an important advance in helping to save lives when overdoses from drugs known as opioids occur: the approval of a drug that can actually reverse that overdose.

Douglas C. Throckmorton, M.D.Opioids include legal prescription drugs, such as OxyContin (oxycodone) and Vicodin (hydrocodone with acetaminophen), used to treat pain, as well as illegal street drugs, such as heroin. In 2010, overdoses of prescription opioids were linked to 16,651 deaths and heroin was linked to 3,036 deaths in the United States.

Whether opioids are used by patients as prescribed by their health care professional or are misused or abused, these drugs have one important thing in common: They can all cause rapid and fatal overdose.

FDA, along with other organizations, has been working diligently on ways to address this major public health issue. That’s why FDA has approved a drug-device combination product that delivers the medication known as naloxone, which is the standard treatment for a drug overdose. This product is potentially easier to use than existing technology and thus could save lives.

Overcoming an Obstacle

Naloxone reverses the effects of opioids. Most significantly, it reverses the severely slowed breathing that can lead to death during an overdose. When naloxone works, the results can be dramatic: Comatose patients can wake up in minutes.

Over the years, emergency health care professionals and others with special training have saved thousands of lives by giving injections of naloxone to people suffering from opioid overdoses. Although effective, this requires expertise – to be able to draw the naloxone up from a vial and then inject it with a needle and syringe. In some cases, the injectable form is adapted so it can be administered through the nose, but there is currently no intranasal form of naloxone approved by FDA.

FDA has now approved  the first naloxone product that is given using an auto-injector, without having to use a separate needle and syringe.  Available via prescription, the product enables anyone – even the general public – to inject naloxone from a pre-filled, single-use device into a person who is overdosing. This is similar to devices used by laypeople to administer epinephrine in cases of severe allergy. In addition, the auto-injector gives recorded instructions to the user describing how to deliver the medication. The instructions also reinforce the need to seek emergency medical attention immediately because while naloxone works rapidly, it only temporarily reverses the effects of opioid overdose. The patient still needs immediate medical care.

The product’s brand name is Evzio, and information on its safe use is available by clicking this hyperlink.

This approval is the culmination of concerted efforts at FDA and throughout the Department of Health and Human Services (HHS) to spur research into alternative forms of naloxone and to expand its availability. On April 12, 2012, FDA co-sponsored a meeting that highlighted the impact of community-based naloxone distribution programs and explained to sponsors the path to FDA approval.

FDA Working on Other Fronts to Combat Opioid Misuse and Abuse

FDA has a responsibility to demand the best science and data to uphold its high standards to ensure a proper benefit/risk profile for drugs that treat pain. We also foster discussion and research that leads to a better understanding of pain and pain drugs. Because we are concerned about the public health issue, the agency has taken a number of actions to help reduce the devastating consequences of opioid misuse, abuse, and fatal overdoses. We are targeting key drivers of the problem with efforts that include:

  • Changing the labeling of certain opioids to help improve their safe use.
  • Requiring that manufacturers conduct studies of the safety of long-term use of certain prescription opioids.
  • Requiring that manufacturers  of certain opioids make training available to practitioners (physicians, dentists and others authorized to prescribe opioids) on responsible prescribing practices and assessing and addressing signs of abuse and/or dependence.
  • Strengthening our surveillance efforts to actively monitor the changing nature of prescription opioid abuse and identify emerging issues.
  • Working with the Drug Enforcement Administration on opioid controls.
  • Encouraging the development of new forms of opioids that are resistant to abuse.
  • Supporting the development of new pain treatments, especially non-addictive treatments.

While FDA plays an important role in mitigating the risks of addiction, abuse and misuse of prescription opioids, we cannot fix the problem alone. A comprehensive approach must be taken by federal and state governments, public health officials, opioid prescribers, addiction experts, researchers, industry, patient organizations, and others. That is why FDA is working closely with our HHS counterparts, including CDC, NIDA, SAMHSA, and throughout the US government.

There’s much work to be done, but today’s approval of the opioid auto-injector could save thousands of lives. FDA will continue to work to prevent the consequences of misuse and abuse of opioids, including preventing fatal overdoses.

Douglas C. Throckmorton, M.D., is Deputy Center Director for Regulatory Programs in FDA’s Center for Drug Evaluation and Research

FDA Is Seeking Ideas for a “New and Improved” Process for Regulating OTC Drugs under the OTC Drug Review

By: Janet Woodcock, M.D.

When it comes to drug approval in the United States, the focus of discussion often revolves around FDA’s efforts to approve new prescription drugs. But it’s important to remember that we also regulate over-the-counter (OTC) products, including many different drugs such as pain relievers, antacids, and cough and cold medicines.

Janet WoodcockSome OTC drugs go through the same approval process used for new prescription drugs. We use a different process known as the OTC drug review or OTC monograph process, however, to evaluate the safety and effectiveness of many other OTC drug products. Frankly, that process is outdated and does not work as quickly as FDA would like. Last week we held a two-day public meeting to gather ideas from consumers, patients, health care professionals, and the companies that manufacture OTC drugs about how we can improve the OTC drug review process.

More than 300,000 OTC drug products regulated under the OTC drug review are on the market. Each is made by following an OTC drug “monograph.” A monograph provides, in part, the necessary information for the kinds and amounts of the active ingredients, their permitted uses and what manufacturers are required to include in the written consumer information listed in the Drug Facts panel on the label. FDA does not require products that meet these requirements to obtain FDA approval before being marketed to consumers.

Some of these monographs are more than 40 years old and many need to be updated. The current process involves rulemaking, and it is slow and cumbersome. For example, the rulemaking process doesn’t allow FDA to quickly require changes to OTC drugs, or to require new warnings or other label changes to products when safety concerns arise. In addition, science is advancing quickly, and new ingredients have been developed that aren’t included in the monographs.

So our public meeting to discuss ways to make a “new and improved” version of our OTC drug review was well-timed. We heard a variety of different thoughts about how we might be able to move forward. We also heard that even though we need to improve some areas of the process, some stakeholders feel that things work and should not be changed. The meeting is over, but we still want your input. Those who could not attend can offer suggestions to our Docket No. FDA–2014–N–0202 until May 12, 2014.

We’ll consider all of this valuable feedback as we move forward. And as always, we are committed to ensuring the public has access to safe and effective drugs, both prescription and over-the-counter.

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

FDA Wants Your Perspective on Clinical Trial Demographic Data

By: Jonca Bull, M.D.

When designing clinical trials, it is essential to test the safety and effectiveness of medical products in the people they are meant to treat. Although FDA’s policies, guidances, and regulations reflect decades of agency efforts to foster the participation of diverse patient populations in clinical trials, more work is required.

Jonca Bull (2488 x 3738)FDA is seeking your comments on this important public health issue. On Tuesday, April 1, 2014, we’re holding a public hearing on the challenges of collecting and analyzing information on demographic subgroups—including sex, race, ethnicity and age—in clinical trials for FDA-regulated medical products.

We’re looking for ideas and viewpoints from our stakeholders—from clinical researchers, academia, industry, health care professionals and patient advocates. As director of FDA’s Office of Minority Health, I’m inviting you to attend this hearing in person or online, or to submit your comments before or after the hearing on issues that are vital to you.

Your perspectives will be critical as we develop our FDA action plan for improving public health across all demographic groups. The action plan will include recommendations on ways to enhance the collection and analysis of information about the sex, race, ethnicity, and age of clinical trial participants in applications that medical product developers submit for FDA review and approval. We are also seeking ideas and views about how to improve the communication of crucial information on medical products to patients, health care professionals and researchers.

Recently, in Section 907 of the Food and Drug Administration Safety and Innovation Act of 2012, Congress asked FDA to produce a report on this topic and to follow it up with an action plan. In the development of the report, FDA carefully examined 72 product applications approved in 2011.

We determined that the statutes, regulations and policies we have in place generally give drug developers a sound framework for providing information in their applications on the inclusion and analysis of these demographic groups. We also found that medical product developers generally are describing the demographic profiles of their clinical trial participants, and most applications submitted to FDA include analyses of these demographics.

However, we recognize that more can be done. So, as part of the process of developing FDA’s action plan, we’re holding this public hearing to get your views on these and related issues. We can’t do this without your help, so we hope you’ll join us at the hearing in person or online on Tuesday, April 1!

Jonca Bull, M.D., is Director of FDA’s Office of Minority Health

Rare Diseases in Children Pose Unique Challenges

By: Gayatri R. Rao, M.D., J.D.

Rare diseases – those that affect fewer than 200,000 people in the United States but collectively affect 30 million Americans – are often chronic, progressive, debilitating, and life-threatening. Because most are genetic in origin, they disproportionately affect children. The agency is strongly committed to advancing safe and effective therapies for these young patients.

Gayatri R. Rao, M.D., J.D., is Director of FDA's Office of Orphan Products DevelopmentIn recognition of International Rare Disease Day on February 28, 2014, we are focusing on pediatric rare diseases.

While developing products for any rare disease poses challenges, in part because of the small patient populations, developing products for children raises unique considerations.  Historically, pediatric care has involved the use of off-label therapies that are unstudied or under-studied in children. For example, pediatric drug dosing often involved adjusting adult doses based on a child’s decreased weight, without considering potential age-based differences in drug metabolism and toxicities. Similarly, many medical devices used in children have been adapted – in homes, clinics, and operating rooms – to solve problems quickly, with little time to consider the long term consequences of a device’s effect on a growing child’s physiology and development.

And while incentives currently exist to promote the development of products for pediatric rare diseases, development in this area continues to lag due to the compounded challenges associated with studying both a rare and pediatric population.

In recognition of these challenges, Congress directed FDA to issue a report and strategic plan focused on accelerating and encouraging the development of therapies for pediatric rare diseases. In response, FDA convened a series of public meetings from January 6 – 8, 2014 to discuss the many challenges in developing treatments for rare diseases, specifically for children with rare diseases, and how to overcome those challenges.  These meetings generated a great deal of interest in the rare disease and pediatric communities. Hundreds of people attended either in person or via webcast and represented a wide swath of these overlapping communities, including patients, academicians, researchers, clinicians, industry, and governmental agencies, many of whom were noted experts in their respective fields.

There were frank, robust and productive conversations on a wide range of topics. A few common themes emerged, especially the important role that patient advocacy groups, including parents of pediatric patients, play in furthering drug development, such as participating in the development of robust patient registries and natural history studies, and providing their perspectives on the risks and benefits of specific treatments. Another common theme was the need for strong collaborations between patients, researchers, industry, and government.

My office, the Office of Orphan Products Development (OOPD), is now coordinating a cross-agency effort with Center for Drugs Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), and the Office of Pediatric Therapeutics (OPT) to develop a report and strategic plan to encourage and accelerate the development of therapies for pediatric rare diseases. The goal of this report is to incorporate the valuable insights gained from these public meetings to inform and tailor ongoing and future agency initiatives to more effectively advance the development of such therapies.

OOPD, in collaboration with CDER, is also launching a web-based educational tool for rare disease patients, advocacy groups, researchers and industry on various FDA-related topics. Current topics include the essentials of interacting with FDA and expanded access to products under development. The goal is to continue to add to this educational resource over time. For the new educational tool, as well as additional information, visit the OOPD Educational Resources web page. In addition, FDA and the National Institutes of Health (NIH) will jointly celebrate Rare Disease Day with a one-day program at NIH Masur Auditorium highlighting various rare diseases programs, research activities, and initiatives. For more information about this event that is free and open to the public, and available via webcast, visit the OOPD web page.

The needs of rare disease patients and the pediatric population are complex and pose challenging issues. We are committed to working with the pediatric rare disease community to face those challenges head-on and to accelerate the development safe and effective therapies for these diseases.

Gayatri R. Rao, M.D., J.D., is Director of FDA’s Office of Orphan Products Development

FDA Is Committed to Determining Sex Differences in How Drugs Work

By: RADM (Ret.) Sandra L. Kweder, M.D., F.A.C.P. 

There’s a lot happening these days with regard to the personalization of medicine and how drugs work differently in people, particularly in men versus women. FDA has a long history in understanding and analyzing these effects. 

Sandra KwederWe’ve issued guidance to the pharmaceutical industry explaining in detail our expectations about analyzing clinical data for sex-related differences as well as differences according to other demographic groupings. Those assessments, depending on the drug, may start with routine animal studies, in case a difference is evident by sex, but become most important when drugs begin to be tested in humans to see if data signal potential differences that require follow-up. 

Both women and men participate in drug studies. (As early as 2001, a report from the U.S. Government Accountability Office showed women were included in all drug trials at a statistically significant level, and women were the majority of participants in trials supporting half of the applications analyzed.) We also consider separately the effects of drugs on men and women to determine whether sex differences exist and whether we need more information to assess variations, if they exist at all. 

We take action if variations are suspected or found. For instance, last year FDA updated the dosing recommendation for sleep medications, such as those containing zolpidem (Ambien and other brands), lowering the recommended starting dose for women to 5 mg (from 10 mg). We did this because women were found to be especially susceptible to zolpidem’s side effects, largely because it is cleared from the body more slowly in women than in men. Moreover, new information became available to FDA last year about how sensitive to blood levels one important side effect of zolpidem is – that of driving impairment. New methods of studying the relationship between drug levels and certain driving tests were key to this understanding. We learned that even when individuals with certain blood levels of zolpidem don’t report feeling drowsy, their driving skills can still be affected. This is true of men and women, but because of women’s slower clearance of the drug from their system they are more likely to be at risk the morning after taking zolpidem. 

This zolpidem case highlights how biologic differences can sometimes play out in individuals’ responses to medications. Some differences in how drugs affect men versus women can relate to variations in metabolism and rates of absorption, and sometimes even because a particular illness has different characteristics in men and women. So we expect our reviewers and pharmaceutical companies to routinely look for sex differences in their new drug applications. Despite looking, it is rare for us to find that drugs differ based on sex alone.

Many drug labels already comment on dose considerations or side effect profiles related to age, health problems, or sex. Some drugs are only approved for one sex. For example, Lotronex (alosetron), a drug used to treat irritable bowel syndrome (IBS), is only approved for women because clinical trial data showed the drug is not effective in men. And Giazo (balsalazide) is used to to treat mildly to moderately active ulcerative colitis in males age 18 and older because it was shown to be ineffective in female patients. 

FDA also monitors all human drugs on the market via our surveillance programs. When findings suggest safety issues we think are important, we work with companies to put that information in labeling (if it is not already present), and sometimes we require companies to do additional studies. If you, as a patient, have any concerns about your specific medication or dose, you should talk to your health care professional. A drug can act differently in people not just because of their sex, but also due to factors such as weight and other medications taken. 

Our staff, including those in our longstanding Office of Women’s Health, are dedicated to protecting and advancing women’s health through policy, science, and outreach. We’ll continue to advocate for the inclusion of women in clinical trials and for analyses of how their bodies process medications. Our recent zolpidem decision is an example of how science evolves – and shows the importance of using new information to review previous decisions when needed. This is an exciting area of science. 

Sandra L. Kweder, M.D., is the Deputy Director of the Office of New Drugs at FDA’s Center for Drug Evaluation and Research