This is Not a Test: RMAT Designation Goes Live

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

The field of regenerative medicine encompasses a wide scope of innovative products including cell therapies, therapeutic tissue engineering products, human cell and tissue products, and certain combination products using such therapies. Examples include genetically-modified cellular therapies, such as chimeric antigen receptor T-cells (CAR-T cells) and human tissues grown on scaffolds for subsequent use. These products hold great promise in addressing serious unmet medical needs. For example, data from a number of different published studies indicate the potential for CAR-T cells to treat certain relapsed or refractory blood cancers.

Peter MarksRecognizing the importance of this field, Congress included several provisions related to regenerative medicine in the 21st Century Cures Act, signed into law on Dec. 13, 2016. Building on the FDA’s existing expedited programs available to regenerative medicine products, one of these provisions established a new program to help foster the development and approval of these products: Regenerative Medicine Advanced Therapy (RMAT) Designation.

Sponsors of certain cell therapies, therapeutic tissue engineering products, human cell and tissue products, and certain combination products may obtain the RMAT designation for their drug product if the drug is intended to treat serious or life-threatening diseases or conditions and if there is preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for that disease or condition. Sponsors may make such a request with or after submission of an investigational new drug application and the agency then will take action on the requests within 60 calendar days of receipt.

Sponsors of RMAT-designated products are eligible for increased and earlier interactions with the FDA, similar to those interactions available to sponsors of breakthrough-designated therapies. In addition, they may be eligible for priority review and accelerated approval. The meetings with sponsors of RMAT-designated products may include discussions of whether accelerated approval would be appropriate based on surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites.

Once approved, when appropriate, the FDA can permit fulfillment of post-approval requirements under accelerated approval through the submission of clinical evidence, clinical studies, patient registries, or other sources of real world evidence such as electronic health records; through the collection of larger confirmatory datasets; or through post-approval monitoring of all patients treated with the therapy prior to approval.

The FDA’s Center for Biologics Evaluation and Research is committed to helping make regenerative medicine advanced therapies that are shown to be safe and effective available as soon as possible, particularly for patients with serious or life-threatening diseases or conditions lacking other treatment options.

We have started receiving RMAT designation requests and expect that, as with Breakthrough Therapy Designation, early and frequent communication facilitated by the RMAT designation will help reduce overall product development times. We very much look forward to continuing to work with sponsors of these products and other stakeholders to help make these exciting new therapies available to those in need.

Peter Marks, M.D., Ph.D., is the director of the Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration.

FDA-Patented Invention Earns 2016 Patents for Humanity Award for Impact on Global Public Health

By: Carolyn A. Wilson, Ph.D., and Alice Welch, Ph.D. 

In 2003, two scientists in FDA’s Office of Vaccines Research and Review within the Center for Biologics Evaluation and Research (CBER) developed a pivotal step in the manufacture of a vaccine now called MenAfriVac. This vaccine has since protected more than 235 million lives against recurring meningitis outbreaks in sub-Saharan Africa. The patented chemical method devised by these two researchers, Dr. Robert Lee and Dr. Carl E. Frasch, enabled the production of the inexpensive and highly effective MenAfriVac vaccine, earning FDA a 2016 Patents for Humanity Award from the U.S. Patent and Trademark Office.

Carolyn A. Wilson

Carolyn A. Wilson, Ph.D., Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

FDA’s scientific research doesn’t often grab headlines. But FDA’s research program is a critical part of the work we do to protect public health and speed innovations that make safe and effective medicines available. And sometimes FDA scientists make significant discoveries that are patentable inventions. When they do, FDA’s Technology Transfer program facilitates the transfer of such technologies to the private sector so they can become useful solutions to public health challenges. The MenAfriVac vaccine is a stellar example of such an FDA invention.

So it was with particular pride and satisfaction that we joined Drs. Lee and Frasch this past November as the U.S. Patent and Trademark Office honored them with a Patents for Humanity Award, in recognition of the critical contribution the patented technique made to the development of the MenAfriVac vaccine.

The story began in late 2003, when Dr. Lee devised a set of chemical reactions for a technique called “conjugation.” It is a method for efficiently linking one ingredient of a potential vaccine with a molecule that supercharges that ingredient’s ability to stimulate the immune system. That chemical joining, along with the collaboration with Dr. Frasch, became the basis of the FDA patent.

At the time, it was just another quiet development in the quest to make the production of certain types of vaccines more efficient. Little did the two researchers know that this patent would later help the Bill & Melinda Gates Foundation-supported non-profit PATH save tens of thousands of lives in the African meningitis belt.

Alice Welch

Alice Welch, Ph.D., Director of FDA’s Technology Transfer Program.

Just a couple of years earlier in 2001, the Meningitis Vaccine Project (MVP), a World Health Organization (WHO) and PATH partnership, had received Gates Foundation funding. Their goal was to produce an inexpensive, safe, and effective vaccine so that the affected countries could afford mass group A meningitis vaccination programs.

But MVP lacked access to a technique that was simple, efficient, and produced meningitis vaccines inexpensively. Thanks to the scientific accomplishment of these two scientists, CBER was able to provide its new technique to MVP via PATH, through a technology transfer agreement made with help from the National Institutes of Health. CBER also developed reagents to evaluate the performance and safety of the vaccine as well as methods to monitor the manufacturing process. And in December 2003, scientists from the Serum Institute of India Limited came to CBER to learn how to use the technique to make the vaccine on MVP’s behalf. The resulting vaccine didn’t need to be refrigerated, which greatly simplified deployment of this product in sub-Saharan Africa.

Awards Ceremony

Alice Welch holds the 2016 Patent for Humanity Award from the US Patent and Trademark Office.
Also in attendance for the ceremony were (left to right) Carolyn Wilson, Carl Frasch, and Robert Lee.

Early in December 2010, MVP initiated its vaccination campaign using MenAfriVac, first in Burkina Faso, then Mali, and then Niger. A year later, MVP extended the campaign to Cameroon, Chad, and Nigeria.

WHO is now helping countries transition from mass campaigns to routine immunization to establish sustainable disease control in the region. By 2020 the vaccine is expected to have protected more than 400 million people, preventing 100 million cases of meningitis A, 150,000 deaths, and 250,000 cases of severe disability.

In an era when established and emerging infectious disease outbreaks affect the lives of more people worldwide than ever before, the American public and the global community will increasingly depend on FDA to provide the kind of scientific research and expertise that have led to the successful development of medical countermeasures and vaccines like MenAfriVac.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

Alice Welch, Ph.D., is Director of FDA’s Technology Transfer Program.

21st Century Cures Act: Making Progress on Shared Goals for Patients

By: Robert M. Califf, M.D.

Today, President Obama signed into law the 21st Century Cures Act, which, I am pleased to report, builds on FDA’s ongoing efforts to advance medical product innovation and ensure that patients get access to treatments as quickly as possible, with continued assurance from high quality evidence that they are safe and effective.

Robert CaliffCures will greatly improve FDA’s ability to hire and retain scientific experts. One of our ongoing challenges has been recruiting and retaining the experts we need in specialized areas to allow us to get our work done and meet our growing responsibilities. This is an especially important need given the tremendous advances in biological sciences, engineering, information technology and data science. Preventive, diagnostic and therapeutic strategies will become more complex with much greater potential for benefit and in some cases greater risk if used without adequate evidence to exclude risks that exceed potential benefits.

This new law rightly recognizes that patients should play an essential role in the development of drugs and devices to diagnose and treat their disease, since patients are in a unique position to provide essential insights about what it is like to live with and fight their disease. That’s been our perspective as well, and it’s why FDA has continued to advance the science of patient input through our patient-focused drug development program and our partner with patients program for medical devices. As it is, Cures will enhance these ongoing efforts to better incorporate the patient’s voice into FDA’s decision-making.

Cures will also support our efforts to modernize and improve efficiency in clinical trial design. This has been an important FDA priority for decades, but exciting new approaches are now available, and we need to develop a common understanding of which designs should be used for which clinical issues. In cancer, for example, we’re already weighing the use of common control trials, which share a control arm, involve multiple different drugs for the same indication, and may even involve different companies. One of the benefits of using a common control arm is that the overall number of patients who need to be recruited and enrolled decreases, thereby optimizing clinical trial resources and potentially shortening the time it takes to get a new study off the ground

Even without the benefit of Cures, patients have been well-served by FDA’s program efficiencies, emphasis on early meetings, and use of expedited pathway programs to speed approval and delivery of new drugs and devices to patients. Rather than passively processing product applications, FDA works to advise companies and inventors from the earliest stages of the development process on the kinds of medical products needed, how to do the necessary research, and how to viably and effectively translate from concept to product. This not only means that important new products will be developed as efficiently as possible but also that medicines and devices with no chance of success are identified much earlier so that money isn’t wasted on futile development. These programs have been embraced by developers of medical products in this country, and they are making a real and positive difference.

In the United States, the FDA uses expedited programs (fast track, priority review, accelerated approval, and breakthrough therapy) for drugs and biologics more than comparable drug and biologic regulators in other countries use theirs and as a result FDA is the first to approve a majority of novel drugs compared to our foreign counterparts.

For devices, this past year was the first full year of operation for FDA’s expedited access pathway (EAP) program, which helps speed the development and availability of certain medical devices that demonstrate the potential to address unmet medical needs for life-threatening or irreversibly-debilitating diseases or conditions. So far, we have granted 24 devices access to this program. Cures builds on EAP by creating the breakthrough device pathway.

The law establishes other new programs as well. For instance, the Limited Population pathway will help streamline the development programs for certain antibacterials and antifungals intended to treat targeted groups of patients suffering from serious or life-threatening infections where unmet need exists due to lack of available therapies. Approvals of these antimicrobials are expected to rely on data primarily targeting these limited populations. The statement “Limited Population” will appear prominently next to the drug’s name in labeling, which will provide notice to healthcare providers that the drug is indicated for use in a limited and specific population of patients. The limited population statement, additional labeling statements describing the data, and FDA review of promotional materials, will help assure these drugs are used narrowly to treat these serious and life-threatening infections while additional evidence is generated to assess safety and effectiveness for broader use.

Cures also creates a new program for  the development of regenerative medicine products, an important and exciting new field that deserves this special focus. The program designates drugs as regenerative advanced therapies and takes appropriate actions to improve the efficiency of development and to enhance the exchange of information among FDA, researchers and developers. An especially important element of this program is the creation of a research network and a public-private partnership to assist developers in generating definitive evidence about whether their proposed therapies indeed provide clinical benefits that are hoped for.

Looking ahead, much still needs to be done to spur product development. There have yet to be successful therapies identified for certain diseases, such as Alzheimer’s disease, where underlying scientific knowledge is still lacking.  In addition, we are only at the early stage in building a national evidence generation system based on registries, claims data, and electronic health records that will be a rich source of post-market data and an avenue for conducting more efficient research. Last week we published a consensus of FDA leadership on the use of real world evidence in the New England Journal of Medicine, focusing on the misperception that randomized trials and real world data are incompatible.  In fact, the use of randomization within the context of clinical practice will constitute a major advance in evidence generation and we are actively encouraging proposals with this combination of randomized trials conducted in real world practice. Cures provides support for continued exploration of the use of real world evidence in the regulatory context.

The law also addresses drug firms providing healthcare economic information to payers and formulary committees. This complex area will require careful delineation of principles to guide information exchange to enable these entities to appropriately assess the value of drugs.

With Cures, great progress has been made towards our shared goal of advancing regulatory science so that we can continue to speed the discovery, development, and delivery of medical products to prevent and cure disease and improve health while sustaining the evidence framework that enables assurance to the public of the safety and effectiveness of medical products. We are excited about the major advances in NIH funding, and welcome the increasing focus on rigorous translational science and data sharing reflected in the bill. Furthermore the funding of opioid addiction treatment and mental health services is a major positive element for our country and consistent with tremendous needs that we recognize.

FDA now stands ready to work with Congress, our sister federal agencies and the medical products ecosystem to implement these important provisions as we continue to work on behalf of all Americans to protect and promote public health and promote innovation in this exciting time.

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

The Mutual Reliance Initiative: A New Path for Pharmaceutical Inspections in Europe and Beyond

By: Dara Corrigan, J.D.

Dara CorriganFor FDA professionals focused on drug quality and safety, the rapid increase in imported drugs from nations where we devote limited inspection resources is of great concern. One way to address this concern would be to create an expanded inspectorate, one where investigators and inspectors from FDA and trusted partners, such as those in the European Union, would work together, rely on each other’s inspections, avoid duplicating inspections, and conduct more inspections in areas where the increase in drug manufacturing has greatly increased, like in China and India.

To meet this challenge, FDA has responded with the Mutual Reliance Initiative (MRI). The concept is simple. EU country inspectors inspect in their respective countries, FDA inspects the manufacturing facilities in the U.S., and the EU and FDA would rely upon each other. This would avoid duplication, lower costs, and enable the regulators to devote more resources to other parts of the world where there is greater risk. The savings would be considerable – over the last 5 years, about 40 percent of FDA’s drug inspections were performed in the EU.

The Mutual Reliance Initiative

There is a history to U.S.-EU collaboration. In 1998, in an annex to a U.S.-EU trade agreement, the U.S. and the EU agreed to recognize each other’s good manufacturing practice drug inspections. However, the agreement was never fully implemented.

Since 1998, FDA has expanded its reach beyond U.S. borders by opening foreign offices in China, Europe, India, and Latin America. We conduct more foreign inspections now and have gathered more than 15 years of experience in collaborating with the EU.

Equally important was the 2012 passage of the Food and Drug Administration Safety and Innovation Act. Congress recognized that FDA cannot and should not monitor the world’s drug inventory by itself and authorized FDA to accept the findings of a foreign inspector when its drug inspectorate is capable of conducting inspections that meet U.S. standards.

Working With The EU Inspectorates

The MRI was launched in May 2014. As part of MRI, FDA and EU assembled dedicated teams to assess the risk and benefits of entering into a mutual recognition agreement. FDA was invited to observe the EU’s Joint Audit Programme, in which two EU nations audit the inspectorate – the regulatory authority – of another member. FDA first observed the audit of Sweden’s inspectorate by auditors from the United Kingdom and Norway. Since then, FDA has observed an additional 12 audits of drug inspectorates across the EU with more audit observations planned through 2017.

This unprecedented access allows FDA observers to gather firsthand knowledge of the laws that govern EU GMP drug inspections and how inspectorates manage the drug inventory within their respective borders. Also, interacting with auditors across the EU provides a unique opportunity to understand the regulatory framework in the EU. With 28 member states (27 after Britain leaves the EU), there can be differences FDA must understand.

And to clarify, the so-called “Brexit” has no impact on FDA’s relationship with our United Kingdom counterparts at this time. Once the UK finalizes its departure from the EU, FDA and the UK will reexamine existing commitments and, if necessary, renegotiate any existing agreements. According to reports, it is likely going to take the UK and EU two years to finalize the terms of the Brexit.

MRI is one of the key components of the pharmaceutical sector covered in the Transatlantic Trade and Investment Partnerships (T-TIP) but could also take another path if the initiative progresses more quickly than the trade negotiations.

The observation and analysis of the drug inspectorates in the EU has only been possible because of the extraordinary devotion and collaboration across FDA. Observers of the audits have included subject matter experts, management, and investigators from the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, the Office of Regulatory Affairs and the Office of Global Regulatory Operations and Policy. These same FDA employees, and others, guided FDA successfully through the EU’s audit of FDA in September 2015 when the EU visited three district offices, the main campus, and a drug laboratory as part of its assessment. The EU team applied the same criteria that it applies within the EU when it audits its own member states.

Looking Forward

What is next? We hope to sign an agreement with the EU soon and are working to complete assessments of the capability of the drug manufacturing inspectorates of two to four countries within the EU.

These first steps with the EU will lead toward our goal of an expanded inspectorate, containing investigators and inspectors from FDA and from across the EU. These collaborations will enhance our ability to evaluate risk, produce better data, and minimize public health risk globally. Indeed, the need to engage globally in different ways is imperative. With MRI, we are moving boldly forward in that direction.

Dara Corrigan, J.D., is FDA’s Associate Commissioner for Global Regulatory Policy

Combination Products Review Program: Progress and Potential

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

Nina Hunter

Nina L. Hunter, Ph.D., FDA’s Associate Director for Science Policy in the Office of Medical Products and Tobacco

About a year ago, we shared with you our Combination Product Review, Intercenter Consult Process Study Report, which was developed by FDA’s Office of Planning. The report’s findings were derived from focus group studies with reviewers from FDA’s different Centers and included input from industry. Since then, we have built on foundational policies and processes to address many of the issues identified in the report.

The team has made tremendous progress toward the goal of modernizing the combination products review program by improving coordination, ensuring consistency, enhancing clarity, and providing transparency within the Agency as well as with all stakeholders. We are excited to share our progress with you now. The table below summarizes some key achievements from the past year, including publication of draft guidances, a variety of new processes, and a look at future goals.

Robert Califf

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

As technologies advance across multiple fields, the distinctions that previously allowed combination products to be neatly categorized by FDA’s medical product centers are blurring or even vanishing.

Combination products account for a growing proportion of products submitted for review, and FDA will continue to pursue new approaches to collaboration that ensure safe, effective and innovative medical products are made available to patients as quickly as possible. Continued collaboration with you, our stakeholders, will be critical as together we continue to make progress in this important area.

We are still listening and have much more work to do!

Combination Products Review Table

This table summarizes key Combination Product Review Program achievements from the past year. Click on table for PDF version.

The PDF version of the table is also located here: combination-products-review-program

Nina L. Hunter, Ph.D., is FDA’s Associate Director for Science Policy in the Office of Medical Products and Tobacco

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

Trade Alert: FDA Issues New Import Data Requirements

By: Howard Sklamberg, J.D.

One of FDA’s many responsibilities is to review imported products regulated by the agency to determine admissibility. This job has become increasingly challenging with growing volumes of imports of FDA-regulated products each year — from six million import entries in 2002 to 35 million in 2015.

Howard SklambergTo help meet that challenge in a way that benefits both government and the trade community, import entries of products regulated by FDA are submitted through an electronic system called the Automated Commercial Environment (ACE). A final rule published on November 29 in the Federal Register specifies certain data that must be submitted in ACE when an FDA-regulated product is offered for import into the United States. The effective date of the rule is December 29, 2016, 30 days from the date of publication.

The trade community helped us pilot ACE, which is operated by U.S. Customs and Border Protection (CBP), from August 2015 to May 2016. In July 2016, ACE became the sole CBP-authorized system for electronic submissions of entries that contain FDA-regulated products.

The rule also includes technical revisions to certain sections of FDA regulations:

  • The owner or consignee of an FDA-regulated product is now defined as the importer of record. This brings FDA regulations up to date with previous revisions to customs laws. (21 CFR 1.83 and 21 CFR 1005.2)
  • FDA will now directly provide a notice that an FDA-regulated product is to be sampled, rather than having to go through CBP to provide that notice. (21 CFR 1.90)
  • FDA may now provide written notices electronically to the importer of record about FDA actions to refuse FDA-regulated products and/or subject certain drug products to administrative destruction. (21 CFR 1.94)
  • The rule clarifies that FDA can reject an entry for failure to provide through ACE the complete and accurate information required by the rule.

As a result of the more streamlined import process for FDA-regulated products provided by ACE, the rule is expected to lead to an efficient use of FDA and importer resources, and more effective enforcement of laws and regulations enforced by FDA.

FDA will continue to provide assistance to filers working to properly submit the required data. Some of the measures we have instituted:

  • We are offering telephone meetings with importers, customs brokers, and other stakeholders, in real-time, while they are filing entries in ACE. Request a meeting by emailing ACE_Support@fda.hhs.gov.
  • An ACE Support Center is staffed 24/7. Reach FDA staff by email at ACE_Support@fda.hhs.gov or by phone at a domestic toll-free line (877-345-1101) or a local/international line (571-620-7320).
  • Upon request, FDA will assist in a filer’s first ACE submission, or for filers who import various commodities, FDA will assist with every first submission of a particular commodity.
  • Additional assistance for general import operations and policy questions, including FDA product codes and entry requirements, is available via email at FDAImportsInquiry@fda.hhs.gov or by calling 301-796-0356.

ACE replaces the Automated Commercial System, an older electronic submission system. Additionally, ACE provides an efficient single window for importers. Prior to the development of ACE, importers of products regulated by multiple government agencies could in some cases be required to submit information more than once.

ACE has already shown promise in accomplishing the dual goal of protecting public health while also serving the needs of the trade community by facilitating a more efficient review for admissibility of compliant products. FDA processing times for both automated and manual review have already been substantially reduced, by approximately 75% and 93% respectively, compared with the agency’s processing times in the previous system.

The ACE system serves to protect public health by allowing FDA to focus its limited resources on those FDA-regulated products being offered for import that may be associated with a greater public health risk.

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

New FDA/EMA rare diseases and patient engagement clusters underway

By: Jonathan Goldsmith, M.D., FACP, and Sandy Kweder, M.D., RADM (Ret.) US Public Health Service

Drug development and approval happens across the globe and we at FDA strive to collaborate with other countries and international regulatory agencies to ensure public health. One of our most valuable collaborators is the European Medicines Agency (EMA) — our counterpart agency for drug regulation in Europe that coordinates a network of 4,500 scientists and evaluates and supervises medicines for more than 500 million people in 31 countries.

Dr. Jonathan Goldsmith

Jonathan C. Goldsmith, M.D., FACP, FDA’s Associate Director Rare Diseases Program, Center for Drug Evaluation and Research, Office of New Drugs

For more than a decade, FDA and EMA scientists have collaborated to help solve some of our biggest challenges. We work with them in groups called “clusters.” The first cluster was initiated in 2004. Since then clusters have been formed to focus on treatments for children; establish effective measures for the development and use of biosimilar medications as cost effective alternatives to brand name biologic drugs; evaluate new treatments for patients with cancer; set standards to help develop medicines personalized to a patient’s genetic makeup, and much more. Both agencies have benefited from this joint work. The EMA summarizes these and our other clusters on its website.

We are excited about the initiation of our most recent cluster activity with our EMA colleagues. Just last month we established a cluster that will work to advance treatments for patients with rare diseases. This cluster’s primary goal is for FDA and EMA scientists to share valuable information about their work and to collaborate on certain review aspects of rare disease drug development programs. FDA’s core members of the cluster include experts from FDA’s Center for Drug Evaluation and Research’s Rare Diseases Program, the Office of Pediatric Therapeutics, the Center for Biologics Evaluation and Research’s director’s office, and the Office of Orphan Products Development, but other experts will be engaged on specific topic areas as the cluster evolves. Among many other important activities, our agencies will collaborate on:

  • Identification and validation of trial end points;
  • Potential trial designs when only small populations of patients are available for testing the safety and effectiveness of prospective new therapies;
  • Ways to apply flexibility in evaluation of drug development programs;
  • Expediting the review and approval of drugs to treat rare diseases to bring new drugs to patients in need as soon as possible.
Sandra Kweder

Sandra Kweder, M.D., Rear Admiral (Ret.) US Public Health Service, FDA’s Deputy Director, Europe Office, and Liaison to European Medicines Agency

Our work also builds on another exciting and recent development — a patient engagement cluster formed in June 2016 to incorporate the patient’s involvement and viewpoint in the drug development process. FDA and EMA are interested in understanding patient’s experiences and gaining input on their tolerance for risk and uncertainty, on current therapy and its benefits or shortcomings and on the benefits that patients seek. This cluster, among other valuable efforts, will:

  • Help each agency learn how the other involves patients in their work, and to develop common goals of expanding future engagement activities with patients;
  • Discuss ways for finding patients that can serve as spokespersons for their community;
  • Explore ideas to help train selected patients and advocates to effectively participate in agency activities, and;
  • Develop strategies for reporting the significant impact of patient involvement.

Given the focus of both of these new clusters, we expect they will address new areas of interest and also draw on expertise from all of the other clusters, such as oncology, pediatrics, and orphan diseases, contributing to more advanced and robust collaborations across both of our organizations.

Focusing on patients with rare diseases and working to advance patient input enhances the value of our cluster activities. With our colleagues at the EMA we look forward to accomplishing more than what we can individually.

Jonathan C. Goldsmith, M.D., FACP, FDA’s Associate Director, Rare Diseases Program, Center for Drug Evaluation and Research, Office of New Drugs

Sandra Kweder, M.D., Rear Admiral (Ret.) US Public Health Service, FDA’s Deputy Director, Europe Office, and Liaison to European Medicines Agency

Where We Are/What We Have Done – Two Years After Releasing Our FDASIA 907 Action Plan

By: Janice Soreth, M.D.

Since it’s been more than two years since FDA unveiled its Action Plan to advance the inclusion of diverse populations in clinical trials, we’d like to update you on how much we have accomplished, and acknowledge that continued commitment is critical in order to build on this foundation.

Janice SorethThe Congressional mandate under Section 907 of the FDA Safety and Innovation Act of 2012 required FDA to develop a report examining the extent to which various demographic groups were included in clinical trials and their outcomes reported in labeling for medical products for which applications were submitted to FDA. The legislation also required FDA to develop an Action Plan based on the report findings and input from stakeholders, issued in August 2014. The Action Plan identified 27 discrete actions for FDA to take within the three priority areas: improving data quality, encouraging greater clinical trial participation, and ensuring more data transparency.

As we discussed at our public meeting on February 29th, we have made progress on nearly every one of our action items and we continue to make strides.

In June 2016, FDA issued the draft guidance, “Evaluation and Reporting of Race and Ethnicity Data in Medical Device Clinical Studies.” We are also updating the 2005 “Guidance for Industry Collection of Race and Ethnicity Data in Clinical Trials.”

Our popular Drug Trials Snapshots, providing information about who participated in clinical trials supporting FDA-approved drugs and biologics, have now been posted on some 75 products. This innovative program developed by our Center for Drugs Evaluation and Research also highlights whether there were any differences in the benefits and side effects among sex, race, and age groups

We have significantly advanced efforts to raise clinical trials awareness. FDA’s Office of Women’s Health instituted a new initiative on “Diverse Women in Clinical Trials” that is disseminating consumer resources in English and Spanish and tools for clinical researchers in partnership with NIH’s Office of Research on Women’s Health. Our Office of Minority Health developed a tool kit and posted several public service announcements on FDA’s YouTube channel aimed at engaging patient participation. And we are currently reviewing the public comments from a range of organizations that we received to the public docket that was opened at the time of the public meeting.

Finally, I want to announce that I recently took over the chairmanship of the steering committee charged with implementing this plan. I am currently the Acting Associate Commissioner for Special Medical Programs, which has oversight of our advisory committee programs, combination products, and pediatric and orphan products programs among other responsibilities. Since joining FDA as a primary medical reviewer 25 years ago, I have served as CDER’s director of the division of Anti-Infectives and Ophthalmology and most recently spent five years in London as Deputy Director of the FDA Europe Office and Liaison to European Medicines Agency.

As we look back at our accomplishments, we believe that transparency in reporting about clinical trial inclusion will make a difference in encouraging broader demographic diversity and want to thank the former chair, Barbara Buch, M.D., of CBER, for her accomplishments. Going forward, I encourage you and all of our key stakeholders – patient and disease advocates, health professionals, and industry to continue partnering with us to advance this important work in ensuring demographic diversity and representation.

Janice Soreth, M.D., is Chair of the FDA Safety and Innovation Act Section 907 Steering Committee and the Acting Associate Commissioner for Special Medical Programs

Making Continuous Improvements in the Combination Products Program: The Pre-RFD Process

By: Thinh Nguyen and Rachel E. Sherman, M.D., M.P.H.

One question that sponsors often ask FDA is whether their medical product will be regulated as a drug, a device, a biologic, or as a combination product, and in the case of the latter, which FDA component will regulate it.

Thinh Nguyen

Thinh Nguyen, FDA’s Director, Office of Combination Products

One way sponsors may determine how their product will be classified is to submit a Request for Designation (RFD) to the Office of Combination Products (OCP). This request requires FDA to provide a written determination of product classification and/or which agency component will regulate the product if it is a combination product. Sponsors have also been able to obtain less formal feedback regarding product classification through communications with OCP.

We are pleased to announce that the Agency is making some changes to our internal procedures for responding to communications from sponsors regarding preliminary product classification assessments from OCP. The Pre-Request for Designation (Pre-RFD) process is the result of cooperative efforts by OCP, the Office of Medical Products and Tobacco, and CDER Lean, including a formal internal evaluation that incorporates current state process mapping and identifies and integrates process improvements.

Rachel Sherman

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

The Pre-RFD process shares some similarities with the RFD process. In both cases, FDA’s assessment depends on sponsors providing a complete, clear, and detailed product description, which includes the product’s indication for use, its composition/ingredients, and an explanation of how it works. In most instances, both processes also require input from the product jurisdiction officers in the relevant Centers and, if necessary, legal perspectives from the Office of Chief Counsel.

Once OCP has received the necessary input, the Office makes its assessment of the classification and/or Center assignment for the product. OCP’s goal for Pre-RFDs is to respond to sponsors within 60 days following receipt of all information needed to initiate the review—the same timeline for responding to RFDs. During this review period the office will communicate with the sponsors as needed.

When may this Pre-RFD process be useful?

The Pre-RFD process can be used at any point during medical product development. It may be preferable to the more formal RFD process when a sponsor would like to engage FDA using a more interactive approach—a course that may be especially helpful when a medical product is at an early stage in its development, or when a sponsor is contemplating whether to develop a specific product, or what configuration of that product to pursue. In such cases, sponsors may find the Pre-RFD process beneficial for the following reasons:

(1) Sponsors are not required to provide a recommendation for classification and assignment of their product along with a corresponding rationale (e.g., bench studies; clinical studies) for that recommendation;

(2) Sponsors are not required to discuss the classification of currently marketed products that they believe to be similar to their product; and,

(3) Sponsors can receive preliminary feedback and information from the Agency that is derived from a structured and efficient process. The feedback will ultimately help lead to better decision-making and development of products for the sponsors.

Pre-RFD flow chart

FDA’s Pre-RFD Process Flow: To view, click on the image.

Because our feedback will be based on the information submitted, sponsors should bear in mind that the speed and quality of any review, whether Pre-RFD or formal RFD, is highly dependent on the quality of the submitted data.

The Agency is developing a draft guidance about the Pre-RFD process, which provides details about information sponsors should include in a Pre-RFD and describes the procedure for FDA’s review. In addition, the Agency plans to publish a list of product classifications for various types of products. We believe this list will offer additional transparency and clarity to sponsors that will ultimately foster innovation and promote better health for patients. We welcome your feedback regarding the Pre-RFD and RFD Programs, as well any other thoughts regarding the jurisdictional assessment of products.

A sponsor who wishes to submit a Pre-RFD or an RFD for a product can find detailed information at the OCP website or contact OCP at combination@fda.gov for further assistance.

Thinh Nguyen is FDA’s Director, Office of Combination Products

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

Piloting an Improved Intercenter Consult Process

By: Michael Rappel, Ph.D., and Rachel E. Sherman, M.D., M.P.H.

Over the last few months, we’ve shared what FDA is doing to improve the review of combination products, including establishing the Combination Product Council and identifying necessary process improvements through lean mapping of the combination product review process. We are pleased to update you on the proposed intercenter consult request (ICCR) process that will be piloted across the Agency today.

Michael Rappel

Michael Rappel, Ph.D., Senior Science Advisor in FDA’s Center for Drug Evaluation and Research and member of the Lean Management Team.

Combination products—those that combine drugs, devices, and/or biological products—present both policy and review challenges in large part because they include constituent parts that fall into more than one regulatory category (e.g., drug and device; drug and biologic) covered by more than one FDA product center. As such, close intercenter collaboration and communication are important to facilitate timely, appropriately-tailored and well-informed submission review. A combination product will generally have a lead center which may seek consults from the other centers that oversee one of the product’s constituent parts. Timely and consistent consults are critical, yet achieving this has been challenging due to different policies, practices, and timelines for consults across centers and insufficient communications between centers and sponsors.

Our new process addresses these issues with four important improvements:

  • Establishing timelines, specific to center and submission type, for identifying products as combination products and issuing and completing consults needed to support the review;
  • Developing  a tiered consult approach that streamlines interactions across centers and identifies a clear process for identifying the right experts for a consult;
  • Defining clear roles and responsibilities for the Lead Center, the Consulted Center(s), the Office of Combination Products (OCP), and the Combination Product Council for review of a combination product submission; and,
  • Creating a standard, semi-automated, user-friendly ICCR form that is managed electronically to ensure 1) users always have the most updated version and 2) all forms, and thus all intercenter combination product consults, are tracked through a single system.
Rachel Sherman

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

FDA will begin piloting this new ICCR process today in select offices within our three medical product centers, focusing on those offices or divisions that routinely receive combination product submissions that require cross center consults. The pilot will be comprised of three phases, with phase 1 planned to last for two months. Additional offices in each center will be rolled into the pilot in subsequent phases with the goal of achieving implementation across all Offices by the end of 2Q 2017 (targeted).

During each phase of implementation, we will collect quantitative and qualitative data to evaluate success. What we learn at each stage will allow us to refine processes, procedures, and training for subsequent phases. In particular, data from phases 1 and 2 will be used largely to refine the initial steps of the ICCR process (e.g., consult request, ICCR form, reviewer assignment) though some limited consult completion data (e.g., consult quality and timeliness) available for Investigational Device Exemptions/Investigational New Drugs may provide initial insights on consult closeout. Consult completion data for other submission types will also be collected but may not be available for several months due to the longer submission review timelines.

This iterative approach will ensure implementation of a robust ICCR process that enables efficient, effective collaboration on the review of combination products. Further, auditing regarding combination product designation and consult tier assignment completed by each center will verify effective knowledge transfer or highlight gaps to focus on in subsequent improvement efforts.

This current effort has been driven by a cross-Agency ICCR working group and builds on the important work of many others across the Agency.

We hope this overarching approach to cross-center activity will, if successful, serve as a flagship model for other cross-Agency initiatives requiring close collaboration. We believe that this kind of nimble, adaptive cooperation reflects the future of medical product development and review in an increasingly complex and nuanced arena. Stay tuned—we plan to keep you updated on our progress along the way. Meanwhile, if you have any feedback or input, please feel free to contact us at: combinationproductICCRpilot@fda.hhs.gov.

Michael Rappel, Ph.D., is Senior Science Advisor in FDA’s Center for Drug Evaluation and Research and is a member of the Lean Management Team

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