FDA Offers Free, Continuing Education Course to Help Health Care Providers Understand ‘Biosimilars’

By: Leah Christl, Ph.D.

You may have heard about a new category of products called “biosimilars.” What are biosimilars and how do they relate to biological products already widely in use?

Leah ChristlBiological products derived from living organisms can treat patients with cancer, chronic kidney disease, rheumatoid arthritis, inflammatory bowel disease, and other serious conditions. Biological products that are “biosimilar” to, or “interchangeable” with, an already-approved FDA biological product (an FDA-licensed reference product) are one way to improve access and increase treatment options at potentially lower cost for our nation’s health care system.

These products are licensed through a new pathway created in the United States in 2009. FDA is well aware that health care professionals–including prescribers, the nurses who will administer them, and the pharmacists who will dispense them–need to understand how these drugs work and how they are intended to be used.

To that end, FDA has developed a free, Continuing Education Course for health care professionals – titled, FDA Overview of Biosimilar Products – to help them strengthen their knowledge and understanding of biosimilars and interchangeable products. Biosimilars and interchangeable products, for instance, are not generic products, and this education course will help health care professionals fully appreciate the distinction.

There’s a growing interest in biosimilars and interchangeable products in the pharmaceutical industry. The first biosimilar in the U.S. was approved in 2015. It boosts the production of white blood cells and helps to ward off infection in patients receiving strong chemotherapy for some tumors. FDA is reviewing several other marketing applications for proposed biosimilar products.

This course also will help health care professionals understand how a biosimilar can be prescribed and dispensed, and how and when an interchangeable product can be substituted for another biological product.

The program will inform healthcare professionals about the development process and approval pathway for biosimilars and interchangeable products. It also includes information about FDA’s general review process for these products that will help attendees gain a better understanding of the relationships between biosimilars and interchangeable products.

The course is available to health professionals on FDA’s CDERLearn Website, and can be completed on a tablet for those on the go and not at their desktop computer.

Leah Christl, Ph.D., is the Associate Director for Therapeutic Biologics in the Office of New Drugs, at the Center for Drug Evaluation and Research at FDA

CBER’s Laboratory Quality System Management Helps Keep Biological Product Standards High

By: Peter Marks, M.D., Ph.D.

Part of the vision of the Center for Biologics Evaluation and Research (CBER) is to strengthen the Center as the preeminent regulatory organization for biologics. One way CBER is achieving this: Through the work of the Office of Compliance and Biologics Quality (OCBQ) and the Office of Vaccines Research and Review (OVRR).

Peter MarksThese offices play a major role in helping to ensure the safety and quality of products regulated by CBER. Their work shows that CBER isn’t just talking the talk about its vision, it’s also walking the walk to demonstrate the expertise needed to fulfill that vision.

That walk leads directly to OCBQ’s Division of Biological Standards and Quality Control (DBSQC), OVRR’s Laboratory of Immunobiochemistry (LIB), and the Center’s Laboratory Quality System (LQS) Program.

LQS is the coordinated structure, procedures, processes, and resources that the Center uses to evaluate and test CBER-regulated biological products. LQS product testing supports biological product licensing, Lot release and surveillance of licensed biological products, and other Center actions. The LQS program also is critical to the development and evaluation of reference materials, standards, and manufacturers’ assays. This extensive responsibility makes LQS an important link in the chain of regulatory actions that support CBER’s mission to help ensure the safety, purity, and potency of biological products.

CBER is authorized by law to create regulations that authorize OCBQ and OVRR to oversee facilities that manufacture CBER-regulated biological products and the biological products they make. CBER leaders wanted to go further in demonstrating the Center’s commitment to quality systems, and decided to voluntarily submit the LQS program to accreditation by an unbiased, non-governmental, nonprofit third party: the International Organization for Standardization (ISO).

ISO sets laboratory accreditation standards for academic and industrial organizations worldwide. Laboratories that receive ISO accreditation can rightly state their test results are precise and reproducible. OCBQ and OVRR accepted the challenge to ensure that their work meets high, internationally recognized standards.

The particular standards CBER sought to meet, called ISO/IEC 17025:2005, are used by testing and calibration laboratories. In the United States, industry laboratories can get accredited to ISO standards by one of many accrediting bodies. CBER turned to the American Association for Laboratory Accreditation (A2LA).

In 2010, CBER received accreditation from A2LA for six methods to test influenza vaccines, including those for sterility and potency, and seven methods for evaluating blood donor screening kits that detect the presence of HIV, HBV, HCV, HTLV-I/II, Trypanosoma cruzi, and West Nile virus.

Additional methods have been accredited since then. CBER’s recent accreditation renewal in October 2015, demonstrated the Center’s competence in 32 test methods previously accredited and added a new laboratory test: evaluating a cELISA allergen test used by CBER for cat hair, ragweed, and dust mites in the newly accredited Laboratory of Immunobiochemistry.

These laboratory accreditations signify that this program is an international leader in biological product regulation based on demonstrated expertise in these laboratory techniques. And they offer more evidence that CBER’s goal of being a preeminent regulatory organization isn’t just a vision, it’s a reality that CBER and FDA, can be proud of.

Peter Marks, M.D., Ph.D., is Director of FDA’s Center for Biologics Evaluation and Research

What is FDA Doing to Improve the Health of African-Americans?

By: Jovonni Spinner, M.P.H., C.H.E.S.

Every February, we celebrate Black History Month – a time to reflect, celebrate, and honor the contributions of African-Americans to our society. We know that achieving and maintaining good health is a long-standing issue for this group, many of whom may experience worse health outcomes in critical areas like heart disease and diabetes. But, we want to focus on the positive and provide consumers with health education materials to support healthy behavior changes!

Jovonni SpinnerIt’s true that the health equity gap has narrowed over time, but there is still significant room for improvement. Here are few things that the FDA and the Office of Minority Health (OMH) have done over the past year to reduce health disparities.

Public Engagement: More than 29.2 million blacks/African-Americans are on social media — and we want to meet consumers where they are. So we’re using Facebook, Twitter, and other social media platforms and electronic communications (e.g. our newsletter and e-blasts) to educate African- Americans on issues such as heart disease, diabetes, and sickle cell disease among others, and also provide tangible solutions to help manage these chronic conditions.

For example, to mark American Heart Month in February, we developed a social media toolkit to help our stakeholders engage with their members and partnered with the Association of Black Cardiologists to spearhead an #ILoveMyHeart social media campaign.

Stakeholder Engagement: We have cultivated relationships with a core set of partners to better understand their health needs, aligned our priorities to meet those needs, and worked together to leverage each other’s resources for the common good. By doing so, we’ve increased our stakeholder’s capacity to communicate with the agency on regulatory issues. For example, multicultural stakeholders are now better able to make their voice heard in FDA-sponsored public meetings and on open dockets.

Minority Health Research: We worked with academia to fund African-American-based research projects (e.g. HIV/AIDs and triple negative breast cancer) and research fellows working on topics like genomics and digital communications. This allows us to increase the knowledge base on these issues and ensure a diverse workforce is in place to solve these complex health problems.

Resources: We have taken care to tailor our health education resources, such as infographics and fact sheets, to African Americans. Our website has valuable information on sickle cell disease and lupus, both of which affect African Americans more than any other racial/ethnic group.

Clinical Trial Diversity: Did you know that sometimes minority populations may respond differently to medical products? One example is an FDA-approved heart failure medication that reduces the risk of death and hospitalization in people with certain types of long-lasting/chronic heart failure.

During clinical trials, it was found there was an increased risk of an allergic reaction called angioedema in blacks. In this trial, only 5% of the participants were black, even though blacks represent 13% of the U.S. population and experience heart failure at rates higher than the rest of the population. This is why we continue to work toward increasing clinical trial diversity, to ensure that medical products are safe and effective for everyone!

President Obama has said, “If you’re walking down the right path and you’re willing to keep walking, eventually you’ll make progress.” OMH will continue walking down the path to improving health equity and we want you to join us, because this work cannot be done alone.

Visit FDA’s OMH at: www.fda.gov/minorityhealth

Follow us on Twitter @FDAOMH

Jovonni R. Spinner, M.P.H., C.H.E.S., is a Public Health Advisor in FDA’s Office of Minority Health

Clarifying What We Mean When We Talk About Biomarkers: An NIH/FDA Joint Leadership Council Success

By: Melissa A. Robb, B.S.N., M.S. (RegSci), and Robert M. Califf, M.D.

What if there was a more uniform way to convey key technical terms to help advance scientific progress? Thanks to the Biomarkers, Endpoints, and other Tools (BEST) Resource, we’re one step closer to that goal.

Melissa Robb

Melissa A. Robb, B.S.N., M.S. (RegSci), FDA’s Associate Director for Regulatory Affairs, Office of Medical Policy, Center for Drug Evaluation and Research

Now available on the National Center for Biotechnology Information’s Bookshelf, the BEST Resource was developed through a collaboration of the Food and Drug Administration (FDA) and the National Institutes of Health (NIH). It includes a glossary of terms and definitions that will ensure the consistency and clarity needed to drive progress in biomedical research and clinical care.

Why is this textbook so important? In the spring of 2015, the FDA-NIH Joint Leadership Council identified a problem: Confusion about the definitions and inconsistent use of key terms–including biomarkers, surrogates, and clinical outcome assessments. This can deter progress in developing medical products and thereby potentially compromise efficiency in achieving public health benefits.

Accordingly, the council identified a high priority: harmonizing terms—or making sure that everyone is “speaking the same language”–that describe and categorize types of endpoints.

Members from multiple FDA Centers and NIH institutes formed a working group to focus on creating a glossary. This was the first step to a publicly available and open access textbook that could be continuously updated and expanded.

Robert M. Califf, MD, MACC; Commissioner, U.S. Food and Drug Administration

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

As the basis of their work, the group considered existing terminology and definitions. Those include FDA guidance documents and other literature, especially a seminal FDA-sponsored Institute of Medicine study.

The use of biomarkers has recently expanded widely to include fields such as mechanistic biomedical research, clinical trials, drug discovery, medical product development, clinical care, and regulatory science. Recognizing this broad influence and the accepted vernacular of these varied fields, the group sought to first reach consensus around biomarker taxonomy.

For example, there’s misunderstanding about the various types of biomarkers and the distinction between biomarkers and surrogate endpoints. One challenge was to settle upon definitions that were broad enough to be used by diverse communities, including biomedical scientists, translational researchers, clinical researchers, medical product developers, and clinicians, and also across diverse types of products.

Where possible, to provide more context and insight into important terms, examples are given alongside many definitions in the BEST Resource. NIH and FDA intend to use the definitions included in this glossary when communicating on topics related to its contents (e.g., biomarkers) to ensure a consistent use of the terms and therefore, a common understanding of the issues. FDA’s Biomarker Working Group, with representation from all of our Centers, contributed to developing these definitions.

Now we need your help. We need your feedback and comments on the glossary. You can provide them at the BEST (Biomarkers, EndpointS, and other Tools) Resource.

In the meantime, we’ll continue to work on adding context to terms related to regulatory science, clinical trials, and laboratory science.

Effective, unambiguous communication is essential for efficient translation of promising scientific discoveries into approved medical products. Once we are all speaking the same language, we can tackle other challenges to bring the promises of biomedical research and clinical care to fruition.

The FDA-NIH Biomarker Working Group members include: from FDA – Shashi Amur, Robert L. Becker, Robert Califf, Aloka G. Chakravarty, David S. Cho, Nina L. Hunter, Ilan Irony, Christopher Leptak, Kathryn M. O’Callaghan, Michael A. Pacanowski, Elektra J. Papadopoulos, Vasum Peiris, Melissa Robb, Hobart L. Rogers, Rachel E. Sherman, Robert J. Temple, Ann Marie Trentacosti, and Sue Jane Wang; and from the NIH – Holli Hamilton, Pamela McInnes, Lisa M. McShane, and Monica R. Shah.

Melissa A. Robb, B.S.N., M.S. (RegSci), is FDA’s Associate Director for Regulatory Affairs, Office of Medical Policy, Center for Drug Evaluation and Research

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

Building a Case for Medical Device Interoperability: FDA’s Call to Action

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

As Yoda might say: build a case for interoperability, we must. While we may not have yet realized the technological accomplishments of Yoda’s advanced world, today connectivity shows great promise for the future.

From blood pressure to brain scans, today’s health care allows for the rapid transfer and use of information between and among different medical devices. This concept—called interoperability—is less about basic communication and more about the smart and safe interaction among medical devices and information systems.

Seamless interoperability among medical devices can improve patient care, reduce errors and adverse events, and lower costs. In fact, interoperability is one of the key factors for safety that can drive innovation in care delivery.

Think of a scenario in which devices collect a patient’s vitals during surgery. Then think about staff having to manually enter those vitals into a health care record because the format of the data generated by operating room devices isn’t compatible with the format necessary for the health care record, which by the way, only operates in one format. In this situation, the lack of interoperability can lead to errors during the manual entry process, and possible inefficiencies in patient care.

Now think about another scenario in which a patient is connected to a ventilator that can alert a caregiver—or automatically adjust its function—by monitoring an oximeter that measures blood’s oxygen saturation levels. In this situation, the interoperability between the ventilator and oximeter better coordinates their interaction and may reduce nuisance alarms, allowing clinicians to focus on true clinically significant alarms.

FDA has been collaborating with hospitals, health care providers, manufacturers, standards-development organizations, and other interested parties to promote medical device interoperability because it helps patients.

Some key activities in pursuit of this goal include the following:

In addition, we recently released draft guidance, Design Considerations and Pre-market Submission Recommendations for Interoperable Medical Devices, which outlines our ideas on design considerations for manufacturers developing interoperable devices. It contains our recommendations for information manufacturers should include in their pre-market submissions and ultimate product labeling. It also encourages manufacturers to make all necessary and relevant functional, performance, and interface characteristics openly available, enabling users to safely use medical devices with other devices or systems.

This draft guidance is intended to promote and facilitate development of safe and effective interoperable devices, thereby strengthening the much needed “case” for interoperable medical devices. We intend to work with stakeholders toward a future where interoperable devices increase care efficiency and reduce care costs, while keeping patient safety in the forefront.

We’re encouraging all stakeholders to share comments on this draft guidance with us.

We believe now is the time for all stakeholders—including medical device manufacturers, health care organizations, researchers, and information systems firms—to come together and continue to build this case to accelerate the development and availability of safe interoperable medical devices.

In Yoda’s words…may the force of interoperability be with us!

Bakul Patel, M.S., M.B.A., is associate director for digital health in FDA’s Center for Devices and Radiological Health

Using Social Media to Teach Consumers About Heart Health

By: Jonca Bull, M.D.

Jonca BullFebruary is American Heart Month. Heart disease remains a significant problem in the United States – it’s the leading cause of death, disproportionately affecting minorities. In particular, minorities have higher rates of hypertension, diabetes, and smoking, which are risk factors that can cause heart disease. This month, we’ll be working with the Centers for Disease Control and Prevention and the National Institutes of Health to help raise awareness.

Our social media platforms will be key to engaging the multicultural population. And they have a proven reach: 65% of Hispanics and 56% of African Americans use social media. In 2014, on average 40% of all cell phone owners used a social media site, with blacks and Hispanics leading the trend at 48% and 49%, respectively.

So, how will FDA’s Office of Minority Health use social media to reach key populations? Here are just a few things we have in store for February:

  • Sharing culturally relevant messages for Twitter and Facebook. We want to stimulate dialogue on two key areas: (1) knowing your risk factors and (2) using our resources to help manage them. This month, our outreach will provide information and resources on the following:
    • Heart Disease: Who does it affect and what are the risk factors?
    • Smoking: Smoking is a risk factor for developing heart disease. FDA has resources to help you quit.
    • Healthy Eating and Living: FDA has materials to help consumers make heart healthy decisions (e.g. how to read the food label), manage their risk factors through FDA-approved medications, and tips for preparing healthy meals.
  • Working with stakeholders to use social media as an engagement tool. We have developed a social media toolkit to guide stakeholders in communicating with their members. The toolkit will contain drafted social media messages, infographics, and links for consumers on heart disease and risk factor management. Email omh@fda.hhs.gov to receive the toolkit.
  • Hosting a bilingual Twitter chat with our partner, @SaludToday on Tuesday, Feb. 16th from 1 p.m. – 2 p.m., EST. We’ll chat about risk factors for heart disease and provide tips to lead a heart healthy lifestyle. We hope you can join us and provide your insights on this important topic.
  • Spearheading an #ILoveMyHeart social media campaign with our partners @SaludToday and @ABCardio1 asking you to show us how much you love your heart! Participants will upload pictures with the #ILoveMyHeart hashtag describing their heart healthy activities. Be sure to post your picture and tag @FDAOMH!

We know that social media is becoming a valuable health education tool to reach minorities. And, we will continue to use it to engage with our audience. Please follow us and share heart-healthy messages all month.

For more information about FDA’s OMH visit us at: www.fda.gov/minorityhealth

Follow us on Twitter @FDAOMH

Jonca Bull, M.D., is FDA’s Assistant Commissioner for Minority Health

Changing course: A new approach to opioid pain medication at FDA

By: Robert M. Califf, M.D.

As a doctor, I have a first-hand understanding of the important and legitimate need for powerful medication to help people deal with chronic or severe pain. If you have had a family member or loved one touched by a serious illness or injury, you understand it too. You know how tough it can be to see them try to endure pain that can’t be touched by anything you can get over the counter.

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

But as all of you know, more Americans now die every year from drug overdoses than they do in motor vehicle crashes. Opioids were involved in 28,648 deaths in 2014, according to the CDC.

The FDA is deeply concerned about this growing epidemic, and I am personally disturbed by the toll it has taken in communities across the country. It’s an issue I’ve been involved with for years as an academic, having overseen the NIH’s National Institute on Drug Abuse Clinical Trial Network, which was involved in some of the early medication assisted treatment studies.

After seeing the dependence and mortality numbers continue to rise and hearing from voices who care about this issue, I asked our folks to take a hard look at whether we’re doing everything we can to ensure that we’re appropriately taking into account the public health crisis that confronts us in the context of the role we play in ensuring the safety and efficacy of drugs.

The conclusion of that comprehensive assessment was that we can do more.

So we are announcing a change in course in how our agency approaches opioids – their approval, their labeling and their prescribing. We are going to fundamentally re-examine the risk-benefit paradigm for opioids and ensure that we consider their wider public health effects.

To that end, we have developed a comprehensive action plan to take concrete steps toward reducing the impact of opioid abuse on American families and communities.

There are four main pillars to the plan.

First, we’re going to be more transparent and open in the approval process for this category of drugs. Starting today, the FDA will convene an expert advisory committee before approving any new drug application for an opioid that is not in an abuse-deterrent formulation (ADF).

Additionally, we’re going to engage the Pediatric Advisory Committee to make recommendations on pediatric opioid labeling before any new labeling is approved.

Importantly, the advisory committee process is going to provide opportunity for public input, which is going to help us better understand and answer the concerns people have about these drugs.

We have also engaged the National Academies of Sciences, Engineering, and Medicine on how to take into account our evolving understanding of the risks of opioids, not only to the patient but also the risks of misuse by other persons who obtain them. The goal is to formally incorporate the broader public health impact of opioid abuse in approval decisions. And in March, we will seek advice from the Agency’s Science Board to reassess the risk-benefit approval framework for opioid use. The results of these efforts will be made public.

Second, we’re going to improve our communication with the medical community about these drugs. That starts with enhancing safety labeling. Our goal is to provide better information to doctors about the risks of these drugs and how to safely prescribe them. We’re developing changes to immediate release opioid labeling that will bring it more in line with the extended-release/long-acting labeling that occurred in 2013.

After reviewing the existing requirements and hearing recommendations from an advisory committee, we’re also going to update our Risk Evaluation and Mitigation Strategy (REMS) program requirements for opioids. We need to increase the number of prescribers who receive training on pain management and improve the safe prescribing of opioids to decrease inappropriate prescribing.

That effort will complement work being done at the Department level and at the CDC to help ensure that opioids are prescribed appropriately. We believe that this is a key component of ending this public health crisis. The more than 250 million prescriptions for these types of pain killers in 2012 – enough for every adult in the U.S. to have a bottle of pills – is clear evidence of the work ahead of us.

Third, we’re going to work to improve the information that’s available about opioid use. We’re going to require drugmakers to strengthen post-market analysis of these drugs. Today, that information, especially about long-term use, is lacking. We need more and better evidence on the risks of misuse and abuse associated with long-term opioid use and to better understand predictors of addiction, among other issues.

Finally, we’re going to focus efforts on approving drugs that have the potential to help mitigate the crisis. That means spurring the development of promising generics with abuse deterrent formulations. The FDA will issue draft guidance with its recommendations for the approval standards for generic abuse-deterrent formulations. We believe the availability of less costly generic products should accelerate prescribers’ update of abuse deterrent formulations.

And we’re going to work to improve access to naloxone, which is effective at treating overdoses. The FDA is reviewing options, including over-the-counter availability, to make naloxone more accessible. That work builds on FDA’s recent approval of intranasal naloxone.

What I’ve just described is a change in course – a framework for how FDA can better do its part to confront the opioids epidemic. In the coming weeks and months, we’re going to further develop these plans and continue to fill in the details for each initiative I’ve described.

But it’s time for us to act – to take the first steps toward changing how we do business and addressing this problem.

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

Building a Modern Generic Drug Review Process

By: Stephen Ostroff, M.D.

Recent hearings on Capitol Hill highlighted an issue of growing importance for patients and for public health: access to quality, affordable medicines, in particular generic drugs. FDA’s generic drug program promotes access to quality affordable medicines by reviewing Abbreviated New Drug Applications (ANDAs), the pathway that allows generic drugs to come to market.

Acting FDA Commissioner, Stephen Ostroff, M.D.The generic drug sector has been enormously successful, growing from about 40 percent of drugs dispensed about 20 years ago to 88 percent today. And the cost savings have been enormous – approximately $1.68 trillion from 2005 to 2014 alone.

As my colleague Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER) at FDA, said in Congressional testimony, FDA is currently working to efficiently process and approve generic drug applications, at record or near-record levels, so when drug patents expire, less expensive generic options are available.

What’s helping FDA keep up that pace of approvals is the added resources that FDA and industry agreed to several years ago in the Generic Drug User Fee Amendments (GDUFA), part of the law passed by Congress known as the Food and Drug Administration Safety and Innovation Act of 2012. With this funding, we were able to hire and train over 1,000 new employees, develop an updated informatics platform to support our review program, and reorganize our generic drug office. Now, after several years of building a modern generic drug review process, FDA is on track to achieve the kind of success this legislation envisioned.

Today FDA is achieving – and in some instances surpassing – important GDUFA goals, including our approval of the ‘first generic” versions of an innovator drug.

generic drug chart

Generic Substitutions & Annual Savings

Although potential first generics constitute only a small percentage of our overall workload, they are very important for the market. Over the past three years, we have approved hundreds of first generics for over 200 new drug products. How? We made substantial program improvements. We solicited nationwide technical input from outside experts and organizations; issued a public-facing, transparent prioritization policy; formed a team to expedite the review of first generics; trained review staff; and enhanced our computer systems to streamline the process.

We’ve also eliminated our filing backlog of ANDAs. In August 2014, there were more than 1,100 applications that had not been reviewed for an initial filing decision. Today there is no backlog.

The cumulative result of our efforts is a huge increase in the productivity of the generics program. We ended 2015 at a new monthly high of 99 generic drug approvals and tentative approvals in December.

Finally, FDA is undertaking major changes in quality regulation so the public can be confident that we’re holding generic drugs to the same standards as brand drugs, no matter where in the world they are manufactured or tested.

All of us at FDA are extremely proud of what we’ve accomplished in implementing GDUFA. In the first two years of the program, we substantially enhanced our ANDA review program. Now we’re cranking it up. There will be up months and down months, but the overall trend will be one of continuing increases in output. More approved generics, if marketed, can further expand patient access to quality, affordable medicines.

We are currently engaged in discussions with industry and the public regarding the development of the second generation of GDUFA, which we call GDUFA II. GDUFA II is scheduled to begin in 2017. We welcome the opportunity which GDUFA II offers to build on our success, and make significant program improvements. Our goal is to bring safe, effective, high quality, affordable generics onto the market. This will benefit the health of every American.

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

Modernizing Pharmaceutical Manufacturing to Improve Drug Quality: Ensuring a Safe and Adequate Supply of Drugs

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

FDA is working with drug makers in a new way to help the industry adopt scientifically sound, novel technologies to produce quality medicines that are consistently safe and effective — with an eye toward avoiding drug shortages.

Michael KopchaWhen manufacturing problems arise in drug manufacturing facilities, drug shortages may follow. In fact, 65 percent of all drug shortages are caused by manufacturing and quality issues. This underscores the need for a safe and reliable drug supply chain.

In recent years, hundreds of drug shortages have been reported to FDA. We’ve done much to minimize their impact and prevent future drug shortages. For example, we’ve expedited the review of new applications for generic drugs when potential shortage issues arise with approved drugs.

Unfortunately, a significant number of these shortages have affected patients with serious conditions, including cancer, life-threatening infections, and severe malnutrition. These shortages can delay or prevent care to patients and can lead practitioners with no other option but to prescribe less effective therapies.

Other industries (such as electronics, chemicals, and automobile) have embraced the use of advanced manufacturing technologies and demonstrated improved quality, increased efficiency, and a reduced number of product failures. These lessons learned could be replicated. Working to modernize pharmaceutical manufacturing technology is key to our new approach to help the industry reduce and prevent drug quality and shortage problems.

By adopting similar technological advances as other industries, the pharmaceutical industry can create a more robust drug manufacturing process with fewer interruptions. This will minimize product failures and provide greater assurance that the product will consistently deliver the expected clinical performance.

FDA strives to support the modernization of pharmaceutical manufacturing by providing guidance to drug companies that are pursuing new technologies. One example is the recent approval of the first ever 3D printed pill which was for Spritam (levetiracetam), a medication to treat epilepsy. In this case, FDA worked closely with the manufacturer to make 3D printing technology a reality.

By adopting this novel technology, the drug maker is able to produce pills that can disintegrate more rapidly in a patient’s mouth, greatly aiding those who have trouble swallowing. This approval is a strong example to FDA’s efforts to put emerging technology to work for the health of Americans.

FDA is taking further measures to improve drug quality. To further help advancements in pharmaceutical manufacturing, FDA established the Emerging Technology Team (ETT). This specialized group—which includes representation from the Agency’s Office of Pharmaceutical Quality and the Office of Regulatory Affairs—works directly with industry to help identify and resolve scientific issues for new technologies. What makes this approach novel is that this dialogue can occur during early technology development prior to the submission of a drug application to the FDA. Such early engagement enables the FDA to proactively identify and address potential roadblocks and helps eliminate potential delay in the adoption of promising new technologies.

To clarify the mission and scope of the ETT, we’ve recently issued a draft guidance titled, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base. It provides recommendations to pharmaceutical companies on effective ways to work with the ETT. The document explains the ETT and provides specific recommendations to drug manufacturers for obtaining important early feedback from the FDA regarding their efforts to develop novel manufacturing technologies.

We’ve received much positive feedback and look forward to continuing productive interactions with industry. Expanding this program will not only help to prevent drug shortages, it will help reinvigorate our country’s pharmaceutical manufacturing sector while fulfilling a critical part of FDA’s mission: ensuring that safe and effective drugs are consistently available to the American public.

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

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