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 M. Califf, M.D., MACC, FDA's Commissioner of Food and DrugsMoving 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., previously FDA’s Deputy Commissioner for Medical Products and Tobacco, became FDA’s Commissioner of Food and Drugs on Feb. 25, 2016

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 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 M. Califf, M.D., MACC, FDA's Commissioner of Food and Drugs

Robert M. Califf, M.D., Commissioner of the U.S. Food and Drug Administration

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., previously FDA’s Deputy Commissioner for Medical Products and Tobacco, became FDA’s Commissioner of Food and Drugs on Feb. 25, 2016.

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

Why FDA Should Oversee Laboratory Developed Tests

By: Peter Lurie, M.D., M.P.H.

Today FDA is issuing a report that illustrates the real and potential harms to patients and to public health from certain laboratory developed tests (LDTs) – tests that are designed, manufactured and used in a single laboratory.

Dr. Peter LurieWhen FDA first began regulating medical devices under the Medical Device Amendments in the 1970s, we chose not to enforce applicable regulatory requirements for LDTs because they were relatively simple tests generally confined to local labs, and often used for rare conditions.

But times have changed. LDTs have increased in complexity and availability and are now frequently used to diagnose common, serious medical conditions, including cancer and heart disease, with potentially greater impact on patients. And yet, LDTs are still under a general policy of enforcement discretion. That means they have rarely undergone FDA review to determine whether they are accurate, reliable, and provide clinically meaningful results. It also means that FDA’s own adverse event reporting databases rarely capture problems associated with a faulty LDT. Nevertheless, the Agency was able to pull together 20 case studies based on information available in the public domain that show how lack of LDT oversight may be causing or is causing significant harm to patients.

Some LDTs provide positive results even though the patient doesn’t have the disease. For example, a patient can receive a false positive result from a test that is supposed to determine whether someone has been infected with the bacteria that cause Lyme Disease. Patients may then undergo unnecessary treatments and potentially delay diagnosis of their true condition. Such false positives can be even more detrimental when the test is for ovarian cancer, which could prompt women to remove their ovaries.

The report cites other tests that may produce the opposite problem: false negatives. These tests may suggest that a patient doesn’t have a disease or condition, when in fact they do. That’s the case for a test for the gene mutation that makes an excess of human epidermal growth factor receptor 2 (HER2), which promotes the growth of breast cancer cells. Patients who express HER2 typically take drugs that target HER2, in addition to standard chemotherapy. The majority of tests used to detect HER2 protein or gene amplification are LDTs, but, at least in the past, approximately 20 percent of tests may have been inaccurate. That means that some breast cancer patients may not receive the best treatment when the test fails to detect high HER2 levels.

Noninvasive Prenatal Testing to detect a range of fetal chromosomal abnormalities is an example of testing that may result in either false negatives or false positives. Women with false-positive results may abort a normal pregnancy; women with false-negative results may deliver a child with an unanticipated genetic syndrome. The report also lists tests that have no clear relevance to the disease being tested and others that are based on disproven scientific concepts.

And the costs of this lack of oversight are staggering. We were able to derive an estimate of the public health cost for five of the 20 cited tests. For the CARE Clinical Autism Biomarkers Test alone (one of those cited in the report), FDA economists estimated a total public health cost of $66.1 million.

FDA has proposed to step up our oversight of LDTs. We issued a draft guidance last year which we’re currently working to finalize, that proposes to phase in enforcement of premarket review requirements for LDTs. FDA oversight would help ensure that tests are supported by rigorous evidence, that patients and health care providers can have confidence in the test results, and that LDTs have more scientifically accurate product labeling.

As this report demonstrates, strengthening FDA’s oversight over LDTs is critical to protect both patients and the public health.

Peter Lurie, M.D., M.P.H., is FDA’s Associate Commissioner for Public Health Strategy and Analysis

The Case for Quality: Working with Stakeholders to Improve the Safety of Medical Devices for Patients

By: Howard Sklamberg, J.D., Jeffrey Shuren, M.D., J.D., and Melinda K. Plaisier, M.S.W.

Howard Sklamberg

Howard Sklamberg, FDA’s Deputy Commissioner for Global Regulatory Operations and Policy

Across FDA, we are devoting tremendous effort, in collaboration with a variety of stakeholders, toward activities that drive–and increase–product and manufacturing quality. We believe quality can be quantified through close attention to data and consistent review and analysis of that data, which in turn can promote the practice and culture of quality within firms.

The metrics and assessment tools being developed are key parts of the Case for Quality (CfQ). We are working with a wide variety of stakeholders–including the medical device industry, patients, other governmental and academic colleagues, and payer/provider counterparts–to identify and promote practices that will result in higher quality devices.

The CfQ was launched in October 2011 following an in-depth review of device quality data and feedback from both FDA and industry stakeholders. FDA’s analysis flagged manufacturing quality risks and showed tremendous benefits for firms that drive quality organization-wide. They receive fewer complaints and internal investigations per batch of devices manufactured, often house smaller quality staffs, and have lower quality-related costs, compared with competitors.

Jeffrey Shuren

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

In the four years since the conclusion of the analysis, FDA has continued to observe that the percentage of inspections calling for official action by FDA has remained static, with the same issues recurring frequently year after year. Given this observation, in addition to FDA inspecting device firms on a regular basis, we are thinking about other ways to support quality beyond inspections and traditional regulatory approaches.

FDA introduced the CfQ in an effort to help device manufacturers elevate their focus from the baseline requirements of compliance with regulations alone, and instead focus on predictive and proactive measures they can take independently to improve quality. CfQ also provides FDA the opportunity to change our approach to focus more on what matters most in assuring product and manufacturing quality and safety for patients.

The CfQ has three priorities for addressing the barriers that were identified:

  1. Focus on Quality. FDA and CfQ stakeholders consider compliance to be a baseline, and have shifted our focus increasingly to characteristics and practices that, when present in day-to-day device design and production, correlate to higher-quality outcomes. Through the CfQ, we are collaborating with internal and external customers to identify characteristics that are critical to the quality of a particular device. This will result in a shared understanding of product features and manufacturing processes most important to patient safety.
  2. Stakeholder engagement. FDA works closely with the device industry and a broad group of customers to collaborate on CfQ and solicit feedback. This effort recognizes the extraordinary impact that engagement and agreement among regulators, industry, patients, providers, and payers can have on device quality.
  3. Data transparency. FDA receives a broad array of quality-related data, including information from recalls and adverse event reports. To support device quality, FDA has made device data (except certain information that we are prevented by federal law and regulations from disclosing) available on open.fda.gov.
Melinda Plaisier

Melinda K. Plaisier, FDA’s Associate Commissioner for Regulatory Affairs

The outcomes of the CfQ will allow stakeholders to focus resources on activities with the greatest impact on assuring that patients and users receive high-quality devices. This effort brings together metrics, successful quality practices, and our partnerships with stakeholders to promote quality and excellence in the medical device industry. It reflects our commitment to ensuring that devices perform as intended, meeting FDA’s mission of protecting and promoting public health.

For more on the Case for Quality initiative, visit http://www.fda.gov/medicaldevices/deviceregulationandguidance/medicaldevicequalityandcompliance/ucm378185.htm.

 

Howard Sklamberg, J.D., is FDA’s Deputy Commissioner for Global Regulatory Operations and Policy.

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

Melinda K. Plaisier, M.S.W., is FDA’s Associate Commissioner for Regulatory Affairs.

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 M. Califf, M.D., MACC, FDA's Commissioner of Food and Drugs

Robert M. Califf, M.D., Commissioner of the U.S. Food and Drug Administration

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., previously FDA’s Deputy Commissioner for Medical Products and Tobacco, became FDA’s Commissioner of Food and Drugs on Feb. 25, 2016.

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