2016: The Year of Diversity in Clinical Trials

By: Robert M. Califf, M.D.

Controlled clinical trials provide a critical base of evidence for evaluating whether a medical product is effective before the product is approved for marketing. One challenge that remains for FDA is ensuring that research participants are representative of the patients who will use the medical product.

Robert CaliffMoving from the result of a clinical trial to applying it in practice is complex. But it’s generally agreed that the composition of the population enrolled in a trial should help FDA reviewers, clinicians, or policy makers to have confidence that the trial results will apply to future practice.

Furthermore, a wide range of people should have the opportunity to participate in trials, both for access to new therapies and to have the chance to contribute to better treatment of everyone, an important altruistic goal for many Americans.

Historically, the elderly, women (in some therapeutic areas), and racial/ethnic minorities have been underrepresented in trials. A substantial body of literature has documented this under-representation in recent years, particularly for women in some cardiovascular trials and general inclusion of black/African-American and minority participants in clinical trials. In response to these concerns, Congress included Section 907 in the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, giving FDA direction to evaluate this issue and take action.

FDA has responded in multiple ways, including the creation of Drug Trials Snapshots that give the public readouts of the demographic profile of people participating in clinical trials for approved drugs. While progress has been made, we’ve learned from this program that we still have work to do. An evaluation of the Snapshots since the program began more than a year ago shows that some groups, especially ethnic and racial groups, aren’t always well represented in clinical trials.

These data are critical, because certain groups of patients may respond differently to therapies. For example, studies for a recently approved schizophrenia drug found that one side effect – the urge to move constantly – was seen more often in black/African-American patients. Two important classes of blood pressure drugs were found to work less well in black patients. And a drug for heart failure works very well in black patients but not in white patients. We also have seen labeling changes due to differences in dosing requirements between men and women, such as the recent labeling change with a sleep medication. These few examples show the importance of improving diversity in clinical trials, so medical products are safe and effective for everyone.

Increasing diversity in clinical trials is a priority for FDA. To that end, in 2016, the Agency is planning a variety of activities to push for greater inclusion, including more minority participation. For example:

  • FDA’s Office of Minority Health has developed a variety of tools to support clinical trial participation, including collaboration with the National Library of Medicine to help consumers and patients find clinical trials, educational materials on trials, as well as a multi-media campaign highlighting the importance of clinical trial participation. These materials are designed to urge those underrepresented in clinical trials to find out more information, and consider enrolling.
  • FDA’s Office of Women’s Health launched its Diverse Women in Clinical Trials initiative. Developed in collaboration with the National Institute of Health’s Office of Research on Women’s Health, this multipronged effort will raise awareness and share best practices about clinical research design, recruitment, and subpopulation analyses.
  • Our biostatisticians, trial design experts, and quantitative scientists will continue to work with the research community to develop methods to refine our approach to the conduct and analysis of trials to provide the best estimates of treatment effects for diverse populations.
  • We will continue our commitment to include patient advocacy groups to engage patients in clinical trial design, feedback and evaluation from a patient’s perspective. By engaging patients early in the trial design process, feasibility and participation may be improved.
  • Finally, our Office of External Affairs plans to publish a consumer update describing what it is like to participate in a clinical trial and encouraging the public to enroll in trials, if possible.

As mentioned above, these activities – and, indeed, the Snapshot program itself – were conceived as part of FDA’s response to Section 907 of FDASIA. This provision directed FDA to conduct an inventory of how well various population groups were being represented in clinical trials of FDA-regulated medical products and whether these data were publicly reported. Once that was done, FDA was directed to develop an action plan, which we published in August 2014. And we’ve been diligently working toward implementation and sustainability ever since.

As you heard from Barb Buch, M.D., Associate Director for Medicine at CBER, earlier this month, the public meeting at the end of next month will continue the dialogue with important stakeholders –like you – to continue this momentum.

And there’s more to come.

We want to make 2016 the year of more diversity in clinical trials. But we can’t do it alone. Stay tuned in the coming months for how we can work together to make this critical goal a reality.

Robert M. Califf, M.D., is FDA’s Deputy Commissioner for Medical Products and Tobacco

Progress and Collaboration on Clinical Trials

By: Barbara D. Buch, M.D.

There are few responsibilities at FDA more important than reviewing the design and outcomes of clinical trials. Understanding the science behind the trials — and the individuals included in them — helps us to ensure that the medical products we approve are safe and effective.

Dr. Barbara BuchLast year, FDA took important steps to support the inclusion of diverse populations in clinical trials. Following Congress’s directive in Section 907 of the Food and Drug Administration Safety and Innovation Act, FDA is looking more closely at the sex, age, and race/ethnicity data that are collected in clinical trials.

In August, FDA published an Action Plan designed to address three specific priorities: improving the quality and comprehensiveness of demographic subgroup data collection, reporting and analysis; identifying and eliminating barriers for increased participation in clinical trials; and improving the transparency of subgroup data.

We’ve come far in achieving this plan. As we begin 2016, I want to outline our progress in preparation for the next important milestone: a public meeting on this topic on February 29.

Priority 1 – Quality

  • FDA updated and/or finalized relevant guidance on demographic subgroup data, as illustrated by these two examples of FDA staff training and/or outreach to external stakeholders:
  • The Office of Minority Health (OMH) developed a plan that supports specific research projects and leads to better understanding of medical product clinical outcomes in racial/ethnic demographic subgroups.
  • The Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Center for Biologics Evaluation and Research (CBER) modified their clinical review templates:
    • CDER developed a review process that encourages reviewers to watch for inappropriate clinical trial exclusion and inclusion criteria; accompanying training emphasizes the need to include broad population diversity in clinical trials.
    • CDRH and CBER modified statistical reviewer templates to include analysis of demographic subgroup information.
  • CBER and CDER incorporated discussions on diverse inclusion and subgroup participation and analysis into pre-application submission meetings with industry.
  • FDA updated its MedWatch forms to standardize collection of demographic information on possible adverse events that occur after medical products are broadly available on the U.S. market.
  • And a few days ago, the Office of Women’s Health (OWH) posted their Research Roadmap and its strategic plan for women’s health research. OWH also funded two research projects:
    • Methods to improve data quality in demographic subgroups
    • Examination of sex-specific outcomes with cardiac resynchronization therapy.

Priority 2 – Participation

  • FDA is making demographic information from clinical trials more easily available to consumers through its easy-to-read online Drug Trials Snapshots webpage and a corresponding article for consumers.
  • The Office of Minority Health and the Institute of Medicine convened a Public Meeting to discuss minority health disparities and clinically meaningful differences.
  • FDA and The Johns Hopkins University co-sponsored a clinical trials workshop, Assessing Safety and Efficacy for a Diverse Population.

Priority 3 — Transparency

  • FDA established a Language Access Plan Working Group designed to implement communication strategies sensitive to the needs of under-represented subpopulations, focusing on language access and health literacy.
  • CBER launched a transparency pilot program to make demographic information available to physicians and the public for original Biologics License Applications.
  • CDRH modified templates for certain documents that are posted to the FDA website upon approval of certain medical devices to ensure that demographic information is consistently included.

We’ve certainly made progress, and will continue the forward momentum in the years to come. And we will need the continued investment of our stakeholders and partners.

We look forward to continuing this important and productive conversation with you next month at the public meeting.

Barbara D. Buch, M.D., is the Chair of the 907 Steering committee and the Associate Director for Medicine in FDA’s Center for Biologics Evaluation and Research

FDA 2015: A Look Back (and Ahead) – Part 3: Food, Tobacco, and Antimicrobial Resistance

By: Stephen M. Ostroff, M.D.

In my third and final post reflecting on FDA’s work to protect and promote public health in 2015, we’ll take a look at our achievements in food, antimicrobial resistance, and tobacco product regulation.

Acting FDA Commissioner, Stephen Ostroff, M.D.Modernizing Food Safety

In a groundbreaking development, in 2015 FDA took several major steps to prevent foodborne illness by finalizing five rules that will implement the landmark FDA Food Safety Modernization Act (FSMA).

In September, we issued the first two final FSMA rules mandating modern, preventive practices in both human and animal food facilities. They will help establish a food safety system in which industry systematically implements measures we know are effective in preventing contamination.

In November, we took another step toward modernizing our food-safety system by issuing the final produce safety rule and two import safety rules. For the first time, these new rules establish enforceable science-based safety standards for the growing and harvesting of produce and make importers accountable for conducting risk-based verification to determine that imported food meets U.S. safety standards. In addition, through this rulemaking we established a program for the accreditation of third-party certification bodies to conduct food safety audits of foreign food facilities.

Together, these rules are designed to reduce the burden of foodborne illness in the United States. They support the broad goal of the law to proactively prevent problems across the entire food system, and to strengthen food safety coordination with other nations that produce the foods that Americans consume.

Strengthening Nutrition, Protecting Health

2015 also saw important progress in the area of nutrition. We finalized our determination that partially hydrogenated oils, the primary dietary source of artificial trans fat in processed foods, are not generally recognized as safe (GRAS) for use in human food, a decision that will make an enormously positive difference in the health of Americans. We also are continuing to work to develop sodium reduction targets, which have the potential for major public health gains and cost savings to the health care system.

And late in 2014, we finalized two new rules requiring caloric information on restaurant menus and menu boards and on vending machines. These rules are designed to provide consumers with more information so they can make informed choices for themselves and their families, without placing an undue burden on small businesses or individual food establishments. We are working with industry to support implementation.

We also proposed additional changes to the familiar “Nutrition Facts” label on packaged foods which, when finalized, will give Americans updated nutrition information, reflecting the most current nutrition science, to help them make healthy choices when purchasing packaged foods. This includes a revision that would establish a Daily Reference Value for added sugars and require the percent Daily Value on the label. There is strong evidence healthy dietary patterns of intake associated with a decreased risk of cardiovascular disease are characterized, in part, by lower intakes of sugar-sweetened foods and beverages.

Combating Antibiotic Resistance

Another area in which we saw great progress in 2015, thanks to collaborative efforts across our government and with our international partners, was in combating antibiotic resistance. If left unchecked, this growing problem threatens to turn back the clock on decades of progress in infectious disease control and medical discoveries, drive health care costs higher, and increase human disease and death.

Early in 2015, the White House released the National Action Plan for Combating Antibiotic-resistant Bacteria, a plan that that recognizes that humans and animals share the same environment – and the same microbes – and so we must address the use of antibiotics in both.

One of the central principles for slowing the development of resistance – in both humans and animals – is the judicious use of antibiotics. For decades medically-important antibiotics have been used not only to treat sick animals, but to promote growth in healthy ones. The FDA has already made significant progress developing policies to promote appropriate use of antibiotics in animal health. For instance, we issued the Veterinary Feed Directive (VFD) final rule, an important part of our overall strategy because it promotes judicious use of medically important antimicrobials in feed for food-producing animals by bringing the use of these drugs under veterinary supervision.

But a critical part of combating resistance is to know the changing patterns and use of antibiotics in farming and how these changes impact resistance patterns among foodborne pathogens associated with farm animals. We are strengthening our data collection under the National Antimicrobial Resistance Monitoring Program in several ways, and in September we held a Public Meeting with several other federal agencies on data collection on farms. This and other work will help us to develop a more comprehensive and science-based understanding of antimicrobial drug use and resistance in animal agriculture and help us to measure the impact of our regulatory actions.

While the problem of antimicrobial resistance is finally getting the attention it warrants, it will require an ongoing and sustained effort to overcome the decades of neglect that led to the current situation.

Regulating Tobacco Products

Our newest area of regulatory oversight is one of our busiest. It’s hard to believe it was more than 50 years ago that the Surgeon General issued the first Report on Smoking and Health. But it’s been just six years since Congress passed the Tobacco Control Act, which gave FDA the authority to oversee the manufacture, marketing, distribution, and sale of regulated tobacco products and protect the public from their dangers.

We’ve already built a great deal on that foundation, creating our Center for Tobacco Products and establishing a framework for industry registration, product listing and submission of information on ingredients in tobacco products; implementing and enforcing a statutory ban on cigarettes with certain characterizing flavors; and restricting access and marketing of cigarettes and smokeless tobacco products to youth. We’ve also already begun to build a robust regulatory science program to conduct and fund science and research programs designed to help us better understand the risks associated with tobacco use.

After an extraordinary amount of study and research, and review of tens of thousands of public comments, FDA is preparing to publish the final rule to extend the agency’s authority over additional, unregulated tobacco products, such as e-cigarettes, cigars, hookah tobacco, and pipe tobacco. Like everything we do at FDA, this policy will be based on a thorough scientific evaluation of how individual products in each category may affect public health.

And in 2015, we unveiled a dynamic public education campaign designed to prevent and reduce tobacco use among at-risk African Americans, Hispanics, and Asian American/Pacific Islander youth age 12 to 17. This promising effort flows from our “Real Cost” campaign launched in 2014, which I’m pleased to note, won a gold “Effie Award” for effectiveness in advertising in the Disease Awareness and Education category.

It’s been a fruitful and productive year at the FDA. I am proud of all we have accomplished in 2015 and look forward to our continued progress.

Stephen M. Ostroff, M.D., is Acting Commissioner of Food and Drugs

FDA 2015: A Look Back (and Ahead) – Part 2: Medical Product Safety and Oversight

By: Stephen M. Ostroff, M.D.

In my first look back on FDA’s 2015 accomplishments, I focused on our achievements in medical product innovation and our constant drive to make safe, effective and innovative products available. Because FDA’s responsibility covers the entire life cycle of products, in this second year-end blog post, I will review FDA’s impact on medical product safety and oversight.

Acting FDA Commissioner, Stephen Ostroff, M.D.Responding to Ebola

In a world where disease knows no borders FDA’s response to the Ebola epidemic in West Africa demonstrates how we use our scientific expertise and regulatory authorities to the fullest extent possible to address a tragic public health crisis of global impact. Our response involved collaborating with partners across government, pharmaceutical and diagnostic companies, international organizations like the World Health Organization, and our international regulatory counterparts. We played a key role in expediting the availability of diagnostic tests and investigational therapeutics and vaccines, as well as investigating fraudulent products marketed to diagnose, prevent and treat Ebola. And many FDA commissioned corps officers of the U.S. Public Health Service served on the front lines, deployed in a humanitarian mission to provide care to patients at the Monrovia Medical Unit in Liberia, one of the West African nations that were hard hit by the outbreak.

Addressing Transmission of Infections from Duodenoscopes

This year we took steps to help protect the public from the risk of transmitted infections, including antibiotic-resistant infections, from duodenoscopes. Duodenoscopes are complex devices used during endoscopic retrograde cholangiopancreatography (ERCP), a potentially life-saving procedure to diagnose and treat blockages in the pancreas and bile ducts. In the United States, duodenoscopes are used in more than 500,000 ERCP procedures each year.

Last February, the FDA issued a safety communication to raise awareness about the risk of transmitted infections from duodenoscopes, after it determined that the design of these devices may impede effective reprocessing, even when the manufacturer’s reprocessing instructions are followed correctly. Reports also indicated that some healthcare facilities may not have adequately followed the manufacturer’s reprocessing instructions. To address these concerns, the FDA has been working with the device manufacturers to ensure that the reprocessing instructions for their duodenoscopes are put through the most rigorous testing. The Agency held a public advisory committee meeting in May to discuss the scientific challenges, and it incorporated recommendations for enhancing the safety margin of reprocessing duodenoscopes into a safety communication in August. Also in August, FDA issued Warning Letters to all three duodenoscope manufacturers citing violations found during recent inspections. In October, the FDA ordered the manufacturers to develop postmarket surveillance studies of how the devices are reprocessed in real-world clinical settings.

Our foremost concern is protecting patients, and we are committed to taking steps to assure that duodenoscopes – and all reprocessed medical devices — are safe to use.

Compounding

We continue to respond effectively to the 2012 outbreak of fungal meningitis linked to contaminated compounded drugs. We are implementing the Drug Quality and Security Act and continuing our inspection and enforcement efforts at compounding facilities nationwide. To that end we have issued numerous policy documents regarding compounding and related activities to provide guidance to industry as we implement the new law. We’ve also held meetings with stakeholders, including pharmacy, physician, and consumer groups, and we have continued our active and successful collaborations with state governments.

Addressing the Opioid Abuse Crisis

Over the last year, we’ve been very focused on the growing epidemic of opioid abuse and addiction and its devastating impact on public health. This focus has required us to strike a delicate balance: ensuring medical treatments are available for patients who are in pain, while addressing the often tragic consequences of abuse and misuse, which all too often overwhelm individuals, families, friends and communities. Our approach is multi-pronged, from encouraging scientific investigation to improving the training of practitioners who prescribe these powerful medicines.

We believe it is vitally important to encourage the development of abuse-deterrent formulations of opioids and to support options for medication-assisted treatment of opioid-dependence. Final guidance for industry regarding the development of abuse-deterrent formulations was issued in April and several abuse-deterrent products have been approved. We are also making strides to treat the consequences of overdoses. In November, FDA approved the first nasal spray version of naloxone hydrochloride, to provide a route of delivery in addition to injection for this life-saving medication that can stop or reverse an opioid overdose. And we are working with our federal partners to improve access to naloxone.

While we cannot solve this complex problem alone, we remain committed to making the best use of our regulatory authorities and working with our partners both in and outside government to reduce the risks associated with opioids. To continue to achieve that, we have been engaging in a comprehensive review of our many current activities related to opioids and identifying which measures can and should be strengthened and what further measures are needed to address this crisis during 2016.

Ensuring the safety of the medical products we regulate requires us to manage a wide-range of issues across multiple scientific disciplines; and to employ scientists with the knowledge to solve today’s complex regulatory challenges. The last year brought many challenges, and just as many solutions.

In my final post, I will address some of our accomplishments in the area of food, tobacco product regulation, and antimicrobial resistance.

Stephen M. Ostroff, M.D., is Acting Commissioner of Food and Drugs

FDA 2015: A Look Back (and Ahead) – Part 1: Medical Product Innovation

By: Stephen M. Ostroff, M.D.

As the year draws to a close, I want to reflect on FDA’s many accomplishments in these previous 12 months, the last nine of which it has been my pleasure to serve as Acting Commissioner. FDA has broad responsibilities – indeed, we are tasked with overseeing products that account for about 20 cents of the consumer dollar — so we work on a wide range of topics in any given year. In this and two additional blog posts over the coming days I’ll cover some of our key accomplishments in 2015. Each blog will examine a different area of FDA’s work. This first post will focus on medical product innovation – our role in making safe, effective and innovative products available to patients who need them.

Acting FDA Commissioner, Stephen Ostroff, M.D.Scientific advances and unprecedented innovation in the sectors we regulate make it an exciting time to work at and lead FDA. To protect and promote the public health our regulatory decision-making must be nimble and current, adapted to the forward march of science.

One measure of our success is revealed in a study released in September by FDA’s independent Science Board. Mission Possible: How FDA Can Move at the Speed of Science documents the Agency’s progress and transformation over the last eight years, dating from a time when FDA had been increasingly unable to meet its scientific responsibilities due to chronic underfunding, a loss of scientific expertise, and the need to implement new legislative mandates without the resources to do so. In stark contrast, today FDA’s regulatory science enterprise is much stronger, which better allows us to effectively fulfill our commitment to protect the public health. The report also provides recommendations for future investments in regulatory science to assure FDA keeps pace with emerging trends in science and technology.

Medical Product Approvals

For many years now, we’ve strived to modernize and streamline the regulatory process along the entire development, review, and product oversight continuum.

The success of these changes is shown by the large number and wide variety of medical products we’ve approved across our medical product centers. So far this year, we have approved more than 40 novel drugs, including four new treatments for patients with multiple myeloma, two new drugs for patients with heart failure, and another robust year of approvals of drugs for rare or “orphan” diseases. We’ve approved several important vaccines, including one for serogroup B meningococcal disease, the first seasonal influenza vaccine to contain an adjuvant (intended for people 65 years and older), and a new indication for anthrax vaccine to prevent disease following exposure to anthrax – the first vaccine to receive an approved indication based on the Animal Rule (which provides for testing certain products on animals alone). And we saw the approval of several innovative devices that will make a positive difference in the lives of patients, including a device that extends the survival time of patients with brain cancer, and a transcatheter pulmonary valve that can be placed in certain patients with congenital heart disease, without requiring open heart surgery.

Our success is also measured in our speed and efficiency of approvals. The U.S. continues to lead the world in approving novel drugs first. And we’ve seen important progress in our device review program. Our average time to reach decisions on PMAs has dropped 36 percent since 2009. And not since 2001 FDA has approved as many medical devices under the original premarket approval pathway and the panel track supplement pathway (for significant changes to a PMA device) as we did this year – 58 as of December 14th.

The number of approvals, and the agency’s ability to review products efficiently, continue to be buoyed by FDA’s expedited development and review programs. When we talk to drug and device makers at the early stages of development, and apply better regulatory science to our ultimate review of their applications, products that are likely to fail are weeded out, allowing manufacturers to focus on those more likely to attain approval.

Most importantly, enhanced flexibility and an efficient approval process have come without lowering our gold standard of safety and efficacy. At the end of the day, innovative therapies are only helpful to patients if they work and are demonstrated to be safe. So it is imperative that we ensure the right balances among patient access, sound science, and safe and effective products.

Amplifying the Patient Voice

Enhancing the patient’s voice in the medical product approval and evaluation process is an important emerging area of product development, which we have embraced in a number of ways.

Those living with a disease are in a unique position to provide essential insights about life with their condition, its severity, and the adequacy of treatment options. We also recognize patients and caregivers have their own perspectives on benefits and risks of medical products, and we believe this input should be considered during regulatory decision-making.

Our Patient-Focused Drug Development initiative is a five-year effort that includes holding at least 20 public meetings in different disease areas. Seventeen of those meetings have occurred and seven more are being scheduled. After receiving patient input during each meeting and in the agency docket, FDA develops a Voice of the Patient report that is then posted on our website. In a complementary effort, our medical device program launched the Patient Preference Initiative. It includes studies to evaluate patient preferences in medical devices, and publishing of a draft guidance that describes how patient tolerance for risk and perspective on benefit, in addition to clinical data and other information, may be considered in FDA’s benefit-risk assessments for certain medical devices. This year FDA approved a weight loss device treatment, and our decision was informed in part by data from a patient preference study funded and co-designed by the Agency.

In September 2015, FDA announced our first-ever Patient Engagement Advisory Committee, which will provide advice on complex issues related to the regulation of medical devices and their use by patients. This Advisory Committee will help ensure the needs, experiences, and perspectives of patients are considered in our work and incorporated in our decision-making.

Biosimilars

Five years ago Congress authorized an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. The intent was to create greater competition in the medical marketplace that would not only increase treatment options for patients, but also lead to less expensive alternatives to comparable products. FDA has been developing its biosimilar program since then, an effort which led to the approval of the first biosimilar in March. And there are more applications in the pipeline. To prepare, FDA has produced a variety of guidances in this area, including the recent draft guidance on how these biosimilars should be named.

Advancing the Development of Next Generation Sequencing Tests and Strengthening Clinical Trials

Our strengthened focus on regulatory science is helping to drive innovation. One illuminating example is our growing ability to apply the sophisticated technologies of next generation sequencing and precision medicine.

FDA today is better prepared and more engaged than ever in facilitating the development of these new technologies (as well as new uses for older technologies), while assuring they are safe and effective. These efforts help to achieve more precise diagnosis or treatment, through the development and review of state of the art diagnostics that use genetic information to make therapies more targeted.

We continue to move forward on the White House’s Precision Medicine Initiative to advance biomedical understanding by leveraging genomic advances, health information technologies, and new methods of analyzing large volumes of data. Just this month, we launched FDA’s precisionFDA web platform, a cloud-based portal that will allow scientists from industry, academia, government and other partners to come together to foster innovation and develop the science behind next-generation sequencing and help us design treatments tailored to a person’s individual genetic blueprint.

And we also are working to refine clinical trial design and statistical methods of analysis to create more efficient studies with smaller patient populations, more focused therapies, and better outcomes. For instance, we continue to support collaborative efforts in clinical trials, such as the I-SPY trials (for breast cancer) and the Lung-MAP protocol (for lung cancer).

It’s impossible to capture in one blog post the many ways that FDA’s focus on regulatory science is helping drive innovation and speed the discovery, development, and delivery of medical products to prevent and cure disease and improve health. We are immeasurably proud of these accomplishments, which provide a strong foundation for continuing success.

Stephen M. Ostroff, M.D., is Acting Commissioner of Food and Drugs

What We Mean When We Talk About Data

By: Robert M. Califf, M.D. and Rachel Sherman, M.D., M.P.H.

Robert Califf

Robert M. Califf, M.D., FDA’s Deputy Commissioner for Medical Products and Tobacco

Medical care and biomedical research are in the midst of a data revolution. Networked systems, electronic health records, electronic insurance claims databases, social media, patient registries, and smartphones and other personal devices together comprise an immense new set of sources for data about health and healthcare. In addition, these “real-world” sources can provide data about patients in the setting of their environments—whether at home or at work—and in the social context of their lives. Many researchers are eager to tap into these streams in order to provide more accurate and nuanced answers to questions about patient health and the safety and effectiveness of medical products—and to do so quickly, efficiently, and at a lower cost than has previously been possible.

But before we can realize the dramatic potential of the healthcare data revolution, a number of practical, logistical, and scientific challenges must be overcome. And one of the first that must be tackled is the issue of terminology.

Defining Terms

Although “data,” “information,” and “evidence” are often used as if they were interchangeable terms, they are not. Data are best understood as raw measurements of some thing or process. By themselves they are meaningless; only when we add critical context about what is being measured and how do they become information. That information can then be analyzed and combined to yield evidence, which in turn, can be used to guide decision-making. In other words, it’s not enough merely to have data, even very large amounts of it. What we need, ultimately, is evidence that can be applied to answering scientific and clinical questions.

So far, so good. But what do we mean when we talk about “real-world data” or “real-world evidence”?

Rachel Sherman

Rachel Sherman, M.D., M.P.H., FDA’s Associate Deputy Commissioner for Medical Products and Tobacco.

Clinical research often takes place in highly controlled settings that may not reflect the day-to-day realities of typical patient care or the life of a patient outside of the medical care system. Further, those who enroll in clinical trials are carefully selected according to criteria that may exclude many patients, especially those who have other diseases, are taking other drugs, or cannot travel to the investigation site. In other words, the data gathered from such studies may not actually depict the “real world” that many patients and care providers will experience—and this could lead to important limitations in our understanding of the effectiveness and safety of medical treatments. Clinicians and patients must be able to relate the results of clinical trials—studies that are done in controlled environments with certain patient populations excluded and which may therefore be challenging to generalize—to their own professional and personal experiences. It seems straightforward, then, to think that studies including a much fuller and more diverse range of individuals and clinical circumstances could ultimately lead to better scientific evidence for application to decisions about use of medical products and healthcare decisions.

But “real-world evidence” has its own issues that must be understood and dealt with carefully. First of all, the vague term “real-world” may imply a closer relationship with the truth—that the real-world measurement is preferable to one taken in a controlled environment. For example, is “real-world” blood pressure data gathered from an individual’s personal device or health app better (e.g., more reliable and accurate) than a blood pressure measurement from a doctor’s office? It could be, because a patient’s blood pressure might be uncharacteristically elevated during a visit to the physician. But at the same time, do we know enough about the data gathered from the patient’s personal device—how accurate is it? Is the patient taking their own blood pressure correctly? What other factors might be affecting it?—to use it for generating evidence? Already we are being reminded of the complexities of potentially relying on data that were gathered for purposes other than the ones for which they were originally intended.

In most cases “real-world evidence” is thought of as reflecting data already collected, i.e., epidemiologic or cohort data that researchers review and analyze retrospectively. Also of interest is whether randomized trials can be conducted in these “real-world” environments. In considering comparisons of treatments, one must always consider the possibility that the treatments were not assigned randomly, but reflected some relevant patient characteristic. This is, of course, the reason for doing randomized clinical trials.

Better Terms for Complex Subjects

There is little doubt that the new sources of data now being opened to researchers, clinicians, and patients hold enormous potential for improving the quality, safety, and efficiency of medical care. But as we work to understand both the promise and pitfalls of far-reaching technological changes, we need a more functional vocabulary for talking about these complex subjects, one that allows us to think about data, information, and evidence in ways that capture multiple dimensions of quality and fitness for purpose (e.g., for appropriate use in regulatory decision making). The incorporation of “real-world evidence”—that is, evidence derived from data gathered from actual patient experiences, in all their diversity— in many ways represents an important step toward a fundamentally better understanding of states of disease and health. As we begin to adapt “real-world data” into our processes for creating scientific evidence, and as we begin to recognize and effectively address their challenges, we are likely to find that the quality of the answers we receive will depend in large part on whether we can frame the questions in a meaningful way.

Robert M. Califf, M.D., is FDA’s Deputy Commissioner for Medical Products and Tobacco.

Rachel Sherman, M.D., M.P.H., is FDA’s Associate Deputy Commissioner for Medical Products and Tobacco.

The Merging of Medical Products: Enhancing review of therapeutic and diagnostic combination products

By: Robert M. Califf, M.D. and Jill Hartzler Warner, J.D.

Combination products – medical products that do not fit into the traditional categories of drugs, devices, or biological products – are a growing and important category of therapeutic and diagnostic products under FDA’s regulatory authority.

Robert Califf

Robert M. Califf, M.D., FDA’s Deputy Commissioner for Medical Products and Tobacco.

These products, that combine drugs, devices, and/or biological product (“constituent parts”) with one another, come in three configurations. The constituent parts may be physically or chemically combined, co-packaged, or separately distributed with specific labeling for their combined use.

Products in this category range from familiar products such as prefilled syringes and surgical kits to novel and innovative products, which target and enhance therapies. Examples of groundbreaking combination products include antibodies combined with drugs for targeted cancer therapy and products that mimic or replace organs, such as an artificial pancreas.

Combination products pose unique challenges – both because they may involve new, complex technologies – and because their review at FDA often involves the expertise of more than one Center.

While review of such products falls to a cross-center team of experts, it is led by the medical product Center responsible for the constituent part that provides the product’s primary mode of action, which, in the case of a syringe prefilled with a drug, for example, would be FDA’s Center for Drug Evaluation and Research.

Effective coordination among FDA staff, and between FDA and the company, is essential – and depends on identifying the proper experts across Centers, supporting processes for communication, and implementing systems for efficient data access and sharing.

Jill Warner

Jill Hartzler Warner, J.D., FDA’s Associate Commissioner for Special Medical Programs.

FDA’s Office of Combination Products (OCP), within the Office of Special Medical Programs, oversees and coordinates FDA’s regulation of combination products. This includes helping to resolve differences of opinion between Centers or with sponsors, developing guidance and regulations, and working with the medical product Centers to develop processes and policies..

Congress has expressed interest in FDA’s regulation of combination products as part of the 21st Century Cures legislative initiative, with one major theme being the assurance that the premarket review process runs smoothly.

While we already have policies and processes in place to address such issues, we know we can do more. To that end, we’ve recently conducted a focus group study with reviewers from the different Centers based on input from industry to assess how we’re doing. The report confirmed that differences in communication, policies, practices, systems and application types can be challenging when the Centers work together on a review of a combination product. The report also recommended actions to take, confirming the value of efforts already underway. Consistent with these findings, we’re taking a number of steps to clarify regulatory requirements and improve our internal processes and IT systems. It may sound a bit mundane, but doing this work could help us work more efficiently and avoid unnecessary surprises for sponsors. These steps include:

  • Issuing more guidance for review of combination products (e.g., our pending draft guidance document on human factors);
  • Enhancing and simplifying data access and sharing for internal staff;
  • Making it easier for staff to request and monitor inter-center consults;
  • Updating and maintaining our internal contact directory for experts to review a combination product; and
  • Improving our internal standard operating procedures for premarket reviews and compliance activities.

Some improvements are already in place and others will be coming this year and next. We continue to want to hear your ideas for enhancing how we work with you on combination products. We are listening — and excited to do our part by evaluating innovative combination products and helping to improve the well-being of patients by approving new safe and effective therapies.

Robert M. Califf, M.D., is FDA’s Deputy Commissioner for Medical Products and Tobacco.

Jill Hartzler Warner, J.D., is FDA’s Associate Commissioner for Special Medical Programs.

FDA Invests in Innovative Ways to Communicate to Hispanics

By: Gloria Sánchez-Contreras, M.A.

En Español

National Hispanic Heritage Month–celebrated annually from September 15 to October 15—gives Americans a great opportunity to celebrate the histories, cultures, and contributions of Hispanic Americans whose roots are in Spain, Mexico, the Caribbean, and Central and South America.

Gloria Sanchez-ContrerasAt FDA, we join in this celebration as we continue to use innovative ways to reach Hispanics as part of our mission to protect the public health. To achieve this goal, FDA uses media strategies that are culturally and linguistically tailored to Hispanics, who, according to research, are avid users of online and social media.

There are 54 million people of Hispanic origin in the United States, making them the nation’s largest ethnic or racial minority group, with 17 percent of the nation’s total population, according to the U.S. Census Bureau. The United States has the second-largest population of Spanish-speaking residents in the world, ahead of Colombia and Spain, and second to Mexico, a recent study by the Instituto Cervantes shows.

These statistics cannot go unnoticed. FDA recognizes the importance of connecting with this growing and diverse segment of our population. Consequently, we have increased our online consumer information in Spanish and developed a variety of bilingual communications strategies to reach and engage all Hispanics.

One of the most important strategies we use is to make sure that messages created for Hispanics speak to them effectively. We consider Hispanics’ informational needs, lifestyles, and cultural health beliefs both when creating new messaging and when translating messaging from English to Spanish.

For example, we know Hispanics respond better when communications are in their primary language – which can be English or Spanish – and when communications use images that relate to them. We do this by employing a bilingual and bicultural team that reviews messaging for cultural competence and adapts translations to ensure they are culturally sensitive and in plain language.

In addition to our English-language communications, we have developed strategies to reach out to Spanish-speaking Hispanics online. Our Consumer Updates and drug safety communications are regularly translated into Spanish. We share Spanish-language information through our social media channels, including Twitter, Facebook, Pinterest, and YouTube.

In addition, we also have a complete Web section in Spanish for consumers (www.FDA.gov/ArticulosConsumidor), a press room (“Comunicados de Prensa”), and a central page (www.FDA.gov/Espanol) that links to a variety of Spanish-language content developed across the Agency’s product centers and offices.

These are exciting times, and it is a privilege to lead some of these efforts for our agency. The Office of External Affairs works diligently across FDA to share important and timely public health news with Latino consumers, stakeholders, media, and community organizations. And during Hispanic Heritage Month—and all the months of the year–we want Hispanics to know that FDA is a trusted source of consumer information.

Gloria Sanchez-Contreras, M.A., is a Bilingual Public Affairs Specialist and the Spanish-Language Communications Lead in FDA’s Office of Media Affairs.

A Quarter Century of Groundbreaking Science: The Forensic Chemistry Center

By: Stephen M. Ostroff, M.D.

This month marks the 25th anniversary of our Forensic Chemistry Center (FCC) in Cincinnati, Ohio. I recently joined former and current administrators and staff of this lab—one of FDA’s many incredible field laboratories—at an event celebrating this milestone.

Acting FDA Commissioner, Stephen Ostroff, M.D.One thing is clear: The last quarter-century has been a period of tremendous success at the FCC. FCC scientists use their scientific analysis and original research to investigate the physical and chemical characteristics and effects of adulterants on products regulated by the Agency, including chemical fingerprinting of poisons, glass, pharmaceuticals, food products and product packaging materials. By analyzing physical samples they can identify counterfeits, trace the origin of a pathogen or solve a crime.

In short, they are the CSI of FDA.

The commitment, expertise, and curiosity of FCC scientists have helped FDA overcome many scientific challenges, and made an extraordinary difference in the lives and safety of millions of Americans. Time and again the sophisticated analyses of puzzling substances by our scientists—often using innovative, esoteric methods, and groundbreaking research, along with the development of new processes and procedures—have made a critical difference in FDA’s ability to investigate and enforce–and protect the American public.

FCC Anniversary group photo

Former and current administrators and staff of the Forensic Chemistry Center (FCC) in Cincinnati, Ohio, at an event celebrating the 25th Anniversary. From left to right: Paul Norris, Director, Office of Regulatory Science; Steve Solomon, Deputy Associate Commissioner for Regulatory Affairs; Dr. Ostroff, Acting Commissioner of Food and Drugs; Phil Walsky, Deputy Director, Office of Criminal Investigations; Fred Fricke, former Director of FCC; and, Duane Satzger, Director of FCC.

FCC’s work has paved the way for passage of important laws, legal prosecutions, and consumer protection activities like recalls. And it has helped strengthen international relationships and advance international cooperation to ensure product quality and consumer safety.

Just a few highlights of FCC’s important efforts include:

  • In the 1990s, the lab supported some of FDA’s early work evaluating nicotine, which was recently cited in the proposed rule to deem additional tobacco products subject to the agency’s tobacco product authorities;
  • In 2001, after 22 people died in the Croatian Republic after receiving dialysis using certain devices, FCC’s analysis identified the presence of a toxic performance fluid in those devices that resulted in their recall by the manufacturers;
  • FCC investigated numerous illnesses and deaths of cats and dogs during 2007-8, which led to the determination that the pet food was adulterated with melamine and related compounds;
  • FCC’s investigation and analysis following the death of cattle in Washington State helped the FBI rule out the possibility that it was caused by terrorism;
  • Following the deaths of a number of infants in India who had been given the measles vaccine, FCC investigated the vaccine’s manufacturing process and discovered that the cause was not, as initially feared, a vaccine of poor quality. Instead the children had received pancuronium bromide, a muscle relaxant, which had been packaged in vials with similar size and shape to the vaccine, rather than the vaccine itself. This discovery was communicated to the Indian government, leading to a critical change in their immunization practices; and,
  • FCC developed a method for examining the sea animals impacted by the Deepwater Horizon oil spill, which helped determine when the seafood would be safe to consume.

It is an extraordinary record. And it’s meant so much to FDA—and the nation—over the past 25 years. But the anniversary and success of this one lab also underscores the remarkable work done by all of FDA’s laboratories across the country. These labs and the districts in which they are located are the critical front line eyes and ears of FDA. And they are the springboard for excellent science.

Good science is fundamental to the mission of FDA. We need it to make good regulatory decisions. It’s what the public expects and deserves. By being able to handle and apply the science of today and anticipate the science of tomorrow we can be more flexible and adaptive, and support innovation.

Having seen the impressive and important work our labs are doing, I’m more committed than ever of the need to invest in better facilities and the best support. We must maintain state-of-the-art laboratories and research facilities, and attract, hire, and retain the best scientists to work in them. First-rate regulatory science requires first-rate scientists working in first-rate facilities.

It’s why I’ve made this a priority for FDA. And why we will put it high on our list of subjects for discussion with Congress as they shape future budgets for the Agency.

The scientists in FDA’s field laboratories are among the unsung heroes of FDA’s work to protect the public health. So let me congratulate and thank those at the FCC and across FDA on the milestone occasion of the 25th anniversary of the Forensic Chemistry Center.

Stephen M. Ostroff, M.D., is Acting Commissioner of the U.S. Food and Drug Administration

Why Partnerships are Key to the Science of Patient Input

By: Nina L. Hunter and Robert M. Califf, M.D.

We recently announced the first FDA Patient Engagement Advisory Committee (PEAC), supported by the Center of Devices and Radiological Health (CDRH). The Committee will provide advice to the FDA Commissioner on complex issues relating to medical devices, the regulation of devices, and their use by patients. The PEAC will bring patients, patient advocacy groups, and experts together for a broader discussion of important patient-related issues, to increase integration of patient perspectives into the regulatory process, and to help drive more patient-centric medical device innovation, development, evaluation, and access.

Nina Hunter

Nina L. Hunter, Ph.D., a Regulatory Scientist in FDA’s Center for Devices and Radiological Health, currently on detail as a Special Assistant for Medical Policy to the Office of Medical Products and Tobacco.

With the PEAC offering an important avenue for patient views to be incorporated in the assessment of new medical devices, complementary programs in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are continuing to explore multiple approaches to patient involvement in development programs for drugs and biologic products, respectively. The Patient-Focused Drug Development (PFDD) Program, led by Dr. Theresa Mullin, provides a way for scientists from across the Agency to obtain patients’ input on specific disease areas, including their perspectives on their condition, its impact on daily life, and available therapies. As part of this program, FDA is holding a series of public meetings, each focused on a specific disease area. Outcomes of these meetings include detailed descriptions of patient perspectives on the most significant symptoms and treatments.

While FDA continues our work on patient engagement through our newly formed advisory committee and the PFDD Program, public-private partnerships (PPPs) are key to empowering patients across the spectrum of medical product development and evaluation. Here we will describe three such important partnerships.

FDA is a founding member of the Medical Device Innovation Consortium (MDIC), a PPP created with the objective of advancing medical device regulatory science. MDIC recently issued a catalog of available methods that can be used for collecting data on patient preferences, along with a framework for considering how to incorporate patient preferences across the total lifecycle of a device. The ultimate goal is to use these data to guide the development, assessment, and delivery of medical devices that better meet patients’ needs. As the scientific evidence and methodological approaches in this area mature, FDA will continue to collaborate with others on efforts to collect and use patient preference data for regulatory purposes.

Robert Califf

Robert M. Califf, M.D., FDA’s Deputy Commissioner for Medical Products and Tobacco.

Like the MDIC, the Kidney Health Initiative (KHI) is a PPP that includes representatives from the FDA, healthcare professional societies, patient groups, and the medical products industry. Recently, KHI convened a workshop under the leadership of Dr. Frank Hurst and Ms. Carolyn Neuland, with patients, care partners, scientists, doctors, nurses, technicians, companies, and FDA, to hear discussions about the issues that patients with kidney diseases consider most important. More than 80 patients attended this workshop; many of these were not members of an organized patient advocacy group, but instead individuals truly driven to improve the plight of all patients with kidney disease. CDRH and CDER are working with the KHI to advance scientific understanding of the implications for patient health and safety posed by new and existing medical products, as well as fostering development of new therapies for kidney diseases. This PPP creates a transparent infrastructure and processes that facilitate collaboration and communication among the greater Nephrology community and FDA.

FDA has also held several meetings with the National Institutes of Health (NIH) throughout the PROMIS initiative, including the Patient Reported Outcome Consortium. PROMIS aims to provide clinicians and researchers access to efficient, precise, valid, and responsive patient-reported measures of health and well-being. PROMIS measures can be used as primary or secondary endpoints in clinical studies of the effectiveness of treatment, and PROMIS tools can be used across a wide variety of chronic diseases and conditions and in the general population. These tools pertain to all medical products, and they can be used to understand the burden of their disease and impacts of treatment on how patients feel and function in their daily lives, so that appropriate patient-centered outcome assessments can be developed and integrated into clinical trials to produce meaningful data to guide treatment decisions. Specifically at CDRH, the use of patient-reported outcome measures (PROMs) in regulatory submissions has increased significantly, with approximately 20 submissions per year citing PROMs prior to FDA’s guidance on the topic, to over 120 last year alone. This jump indicates significant interest by industry and clinical researchers in generating patient-centered evidence from studies done for regulatory purposes.

FDA is ready to advance the science of patient input and work with a wider community of patients, clinicians, and social science researchers in a collaborative way. We expect the number of partnerships with patients and their caregivers to grow, and the effort to become more effective as the underlying science and cultural understanding continues to develop.

Nina L. Hunter, Ph.D., is a Regulatory Scientist in the Center of Devices and Radiological Health, currently on detail as a Special Assistant for Medical Policy to the Office of Medical Products and Tobacco.

Robert M. Califf, M.D., is FDA’s Deputy Commissioner for Medical Products and Tobacco.