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

FDA’s Sunscreen Guidance outlines safety and effectiveness data recommended for additional active ingredients

Editor’s Note: This blog has been updated since its original posting from 9:00AM EST, November 22, 2016.

By: Theresa M. Michele, M.D.

American consumers rely extensively on over-the-counter (OTC) sunscreens to help prevent sunburn. Certain sunscreens are also used, along with other protective measures, to reduce the risks of skin cancer and early skin aging caused by the sun.

Theresa Michele, M.D.The vast majority of sunscreens available in the United States are marketed under a regulatory framework called the OTC Monograph System. FDA reviews the active ingredients in these products to determine whether the ingredients are generally recognized as safe and effective (GRASE) for OTC sunscreen use.

The Sunscreen Innovation Act (SIA) of 2014 established an alternative process for the review of safety and effectiveness of additional active ingredients for use in sunscreens, and set deadlines for reviewing the ingredients and taking certain other actions. But SIA did not eliminate the need for a GRASE determination for new sunscreen active ingredients before reaching the market without an approved marketing application, and it did not relax the scientific standards for these products. Further, FDA’s review deadlines are only triggered after the data have been submitted to the agency.

Since the SIA was passed, FDA has met all of the deadlines for implementing this complex legislation. That includes inviting public comment on our actions, holding requested meetings with industry, issuing draft and final guidances, issuing proposed and final rulemaking required to date, and issuing a report to Congress on our progress.

When the SIA was enacted, eight sunscreen active ingredients were already under evaluation. The FDA has issued proposed sunscreen orders identifying data we believe is necessary for the agency to make a positive GRASE determination on those within the SIA-required time frame, but has yet to receive the additional data we requested.

Today, as required by the SIA, we released a final guidance document that details the Agency’s current thinking on the specific information we believe we need from sunscreen manufacturers or other interested parties before we can determine that a sunscreen active ingredient is GRASE for use in OTC sunscreens. This guidance will also help clarify FDA’s outstanding requests for additional safety and effectiveness data on the eight active ingredients, including the importance of human absorption data.

Sunscreens are intended to be used on a regular basis in liberal amounts and over large portions of the body surface whenever consumers are exposed to the sun. And yet some sunscreen active ingredients may be absorbed through the skin into the body, making it important to complete studies in humans to determine whether, and to what extent, consumers’ use of sunscreen products as directed may result in unintended, chronic, systemic exposure to these ingredients.

The guidance recommends that industry provide data from a Maximal Usage Trial or MUsT, to help determine if the ingredient is absorbed into the blood and at what level. This type of study is designed to capture the effect of maximal use on absorption into the blood. It is the same standard used by FDA for all topically applied drugs, and especially for drugs that are used routinely over the course of one’s life.

Sunscreens are a valuable tool for sun safety and public health, but of course, are not the only tool. Seeking shade at peak sunlight hours and wearing protective clothing, hats, and sunglasses are key to every sun protection plan. The sunscreen page on FDA’s website provides useful information for sun safety.  

FDA is committed to helping to ensure that sunscreens are safe and effective for U.S. consumers, but we need data to move forward.

We hope the final guidance encourages industry to provide the FDA with the data we need, so that together we can help bring a wider assortment of safe and effective sunscreen products to the American public.

Theresa M. Michele, M.D., is the Director of the Division of Nonprescription Drug Products, Office of New Drugs, at FDA’s Center for Drug Evaluation and Research

The Race to bring Penicillin to the Troops in WWII

By: John P. Swann, Ph.D.

John SwannThis Veterans Day we remember that nearly 75 years ago dozens of American academic, commercial, nonprofit, and governmental institutions – including FDA – joined together in a race to provide a promising but complex and unstable medicine to troops fighting in World War II — penicillin. Knowing that infection is the major killer in wars, not battle injuries, their goal was to help turn a British discovery into a crucial wartime medical contribution and what would become an indispensable therapeutic agent long after that conflict ended.

Many people are familiar with the story of Alexander Fleming’s 1928 discovery of a Penicillium mold that had contaminated — and surprisingly destroyed — his cultures of pathogenic organisms.

The strain of Penicillium notatum that Fleming discovered at St. Mary’s Hospital in London

The strain of Penicillium notatum that Fleming discovered at St. Mary’s Hospital in London.

Though Fleming and several others in the next decade studied the mold filtrate, known as penicillin, it was Howard Florey and his colleagues at Oxford who uncovered the drug’s chemotherapeutic potential. Their work began with studies in mice in May 1940 and transitioned to a handful of clinical cases nine months later. However, the drug was difficult to purify. Also, it presented an immense challenge to produce in sufficient quantities for study, and with Britain under siege firms there were too involved in other aspects of the war effort to offer much assistance. So Florey and a colleague came to the U. S. in the summer of 1941 for help.

Northern Regional Research Lab

A meeting of NRRL staff in the 1940s (courtesy of the American Institute of the History of Pharmacy).

Among the first sites they visited was the Department of Agriculture’s Northern Regional Research Laboratory (NRRL) in Illinois, which had extensive experience in fermentation work, and from there they contacted several drug and chemical companies to drum up support.  Americans quickly combined forces to tackle the challenge. The federal Office of Scientific Research and Development (OSRD), the federal entity that organized and facilitated investigations to support the war effort, arranged to act as a clearing-house for the latest research on chemical and other studies of penicillin, exchanging data with dozens of organizations in the U.S. and Britain. NRRL developed several production modifications that increased the yield of penicillin by 100 fold.

Penicillin Moisture Testing

An FDA analyst in the 1950s carries out part of the procedure in testing penicillin for moisture content.

FDA’s first experience with the potential wonder drug was around September 1942, when the NRRL Director approached FDA about testing the antibacterial effectiveness of a small quantity of penicillin. A year later, enough of the drug had been produced to confirm in 200 patients what the early results at Oxford had suggested, and penicillin was ready to enter the war. First, however, OSRD asked that FDA certify every lot produced by the half-dozen or so manufacturers, a task the agency also performed for insulin under statutory authority that began in 1941. Six FDA technicians certified samples for potency, absence of fever-producing contaminants, toxicity, sterility, and optimum moisture, which can affect the drug’s stability. So scarce was penicillin that companies always reconditioned the occasional rejected lot rather than destroying it.

By the end of the war, some of the participating firms had increased purity of the drug from the Oxford group’s one percent to about 85 percent. Penicillin was not only more potent, it was also more abundant, its production having increased by a factor of 500 from 1943 to 1945. In fact, by 1945 the output of penicillin, formerly under severe restriction outside of military and scientific use, was now available for most civilian needs as well. In a few years the cost of producing penicillin had decreased so much that the glass used to store ampules of the drug cost more than the drug itself. FDA’s wartime work was codified in the Penicillin Amendment of 1945, which mandated FDA’s certification of penicillin and, through subsequent laws, most other antibiotics — a responsibility that continued for nearly four decades, when the need for government testing no longer existed based on industry’s record of production.

But it all started with an international effort to provide a lifesaving drug to the armed forces, bringing together all sorts of scientific and medical institutions, including FDA. Like so many others participating in this collaboration on a scale unseen up to that point, FDA played a small but critical role to support our troops at this time of global crisis.

John P. Swann, Ph.D., is an FDA Historian

Key Facts about “Abuse-Deterrent” Opioids

By: Douglas C. Throckmorton, M.D.

Here at FDA, we work diligently to be part of our nation’s solution to the opioid abuse epidemic. While there is no single solution to this complex problem, we continue to encourage efforts to develop new opioid formulations with abuse-deterrent properties that make it harder to abuse these powerful medications.

Douglas C. Throckmorton, M.D.Knowing there are some 100 million Americans with significant pain each year, we need to help ensure that patients in need continue to have appropriate access to pain medications, including opioids. At the same time we must work to ensure that these powerful medications are used as safely as possible.

To date, FDA has approved seven opioid formulations with abuse-deterrent properties consistent with FDA guidance, and there are more in the development pipeline.

What does it mean to be abuse-deterrent? Opioids with abuse-deterrent properties are tablets or capsules that are designed to deter abusers from crushing them into a powder for swallowing, snorting or injecting to create a faster, more intense high.

Each manufacturer has its own proprietary technology for deterring abuse. Some abuse-deterrent formulations consist of tablets with a hardened surface that is difficult to crush and some turn the crushed medicine into a gooey substance that is difficult to inject.  Other current approaches combine the opioid with naloxone or naltrexone, drugs that block the effects of the opioid in the body that are activated when the opioid is crushed.  Additional approaches are currently under development.

The manufacturers of the seven FDA-approved opioids with abuse-deterrent properties to date have all submitted study data demonstrating that the products are expected to deter abuse. This work was guided by the 2015 final guidance for industry, Abuse-Deterrent Opioids — Evaluation and Labeling. As a result of FDA’s review, FDA-approved product “labeling” (prescribing information) for these medications clearly states the product’s abuse-deterrent properties. Other manufacturers have chosen to add what they may intend as abuse-deterrent properties to their product, but FDA has not seen sufficient evidence that these properties are effective and therefore the FDA-approved labeling for these products does not identify them as having abuse-deterrent properties. Prescribers and patients can look to our web site for the list of FDA-approved products with abuse-deterrent properties in their labeling.

It’s important to recognize that FDA refers to these drugs as “abuse-deterrent” not abuse-proof. There will always be some potential for abuse of these products. For instance, a patient can orally ingest a quantity beyond what is prescribed. It’s also true that people intent on abusing an opioid may find ways to overcome the abuse-deterrent properties of the drug that were not identified during premarketing research. With this in mind, FDA requires that any drug approved as having abuse-deterrent properties be further evaluated by its manufacturer after it is marketed. The manufacturer is required to conduct studies to evaluate the impact of the product on abuse in the community. If necessary, we may approve updated product labeling that describes the drug’s abuse deterrent features after approval.

Still, abuse deterrent technology certainly helps. That’s why FDA is looking at ways to encourage the development of abuse-deterrent generic versions of an opioid since none currently exist. We released draft guidance for industry in March and we’re looking forward to an interesting public discussion of the topic next Monday and Tuesday.

The FDA opioid action plan we issued in February involves a multi-faceted approach to reducing opioid misuse and abuse. And we continue to look for ways to make a difference. We recently announced we would help fund the development of assessment tools to evaluate packaging, storage, delivery, and disposal solutions, as well as product formulations, designed to prevent or deter misuse and abuse of opioid analgesics.

Support for abuse deterrent formulations is one important part of a strategy to help prescribers and patients make the best possible choices about how to use these powerful drugs. Our goal is to find the balance between appropriate access to opioids for patients in pain and the need to reduce abuse and misuse of these medications.

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

FDA’s Opioids Action Plan: A Midyear Checkup

By: Robert M. Califf, M.D.

As FDA works to address the opioid epidemic of abuse, misuse and addiction, it’s valuable to see firsthand some of the ways the crisis is affecting our communities.

This summer, I toured areas hard-hit by the opioid crisis in Tennessee, West Virginia, and Kentucky, visiting  with survivors of opioid addiction and overdose as well as community activists, government officials, and health care providers, all of whom are working diligently and creatively to address and overcome this crisis.

Robert Califf

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

My visit to the nationally-recognized neonatal intensive care unit at East Tennessee Children’s Hospital was deeply moving and set the stage for the rest of my tour and underscored the urgency of fighting this epidemic. More than a third of the babies admitted to the NICU have neonatal opioid withdrawal syndrome (NOWS), a condition which can be life-threatening if not recognized and treated

Watching a nurse treat a fretful baby suffering from NOWS underscored the complexity of the opioid problem.  Many women taking opioids haven’t planned their pregnancy, don’t immediately know they are pregnant and may not be aware of the risk that opioids pose to their unborn child. This includes those women who are taking medication as part of medication-assisted treatment (MAT) which also includes counseling and behavioral therapies. For women on MAT, the risk of NOWS must be balanced against the additional dangers of untreated opioid addiction during pregnancy.

How best to prevent NOWS and treat opioids use disorder was a continued theme of my trip, and among the issues we grappled with during a roundtable at the University of Tennessee’s Medical Center hosted by Surgeon General Vivek Murthy, who is traveling the country to discuss solutions to opioid abuse as part of his TurnTheTideRx campaign. I’m pleased that expanding access to and the use of evidence-based MAT is a key focus area for the Administration, is a part of the HHS-wide opioid initiative, and is an approach supported by a recent FDA advisory committee.

In Charleston, WV, I met with several patients who are reclaiming their lives with the use of MAT including “Dave.” Like so many others, Dave became addicted to opioid pain medication after being treated for an injury. As a result of his addiction, his marriage failed and he lost contact with his children. But with treatment, he has reunited with his family and next spring will graduate from college and hopes to taper off of his treatment.

Throughout my tour, I heard that opioid education – including training during medical school and residency and greater public awareness far and wide – is a key component in fighting the opioid epidemic. At a roundtable in Charleston, Gov. Earl Ray Tomblin and U.S. Sen. Joe Manchin singled out their state’s model mandatory education program for prescribers and they told me the state is leading an effort to implement the CDC’s Guideline for Prescribing Opioids for Chronic Pain as a best practice for their state-run Medicaid program.

At a firehouse in the town of Williamson, WV, I met with those on the frontlines of the opioid epidemic – the firefighters and first responders who carry life-saving naloxone to help reverse an overdose. They told me more education about naloxone was needed and told me that they appreciate our efforts to help make naloxone more available to the general public.

My last stop this summer was to Kentucky where I toured the emergency room at the Pikeville Medical Center and participated in a roundtable with physicians, pharmacists, and state policy and community leaders brought together with the help of the regional organization Operation UNITE. UNITE coordinates treatment for those with substance use disorder as well as support for their families and friends, and educates the public about the dangers of drug use. These measures, combined with a recent state law requiring prescribers to register with a prescription drug monitoring program are working, we were told.

Throughout my travels, I listened and learned more about how FDA can help end this crisis. I also had the chance to share what FDA has been doing this year to implement a multipart plan to address the opioid epidemic.

Our milestones so far include:

  • Developing warning and safety information for immediate release opioids and requiring that prescription opioid analgesics and opioid-containing cough product labels include strengthened warnings about the risk of using benzodiazepines at the same time.
  • Working to better understand the long-term safety of using extended release/long acting opioids. Sponsors must now conduct a number of studies to generate postmarket data on these products.
  • Issuing draft guidance for industry to support the development of generic versions of approved opioids with abuse-deterrent formulations.
  • Seeking advice from the National Academy of Science Engineering and Medicine on how to balance both the needs of patients with pain and the need to address opioid misuse and abuse.
  • Supporting increased access to naloxone; for instance, by awarding a contract to conduct consumer behavior studies based on model product labeling for a potential OTC version of the antidote and by launching a competition to create a mobile app that could help find the closest available naloxone treatment in an emergency.
  • Approving the first implantable treatment for the maintenance treatment of opioid dependence.

The community-based successes I observed on my three-state tour reinforced my view that we are making important progress in addressing this crisis.  But continued hard work, creative ideas, and collaboration — across government, with the medical profession, health care providers, industry, and, most importantly, patients and their families, is still required.

We at FDA will continue to work with all of these groups, using all the resources at our disposal, to improve the judicious and responsible use of opioids and to help bring an end to this epidemic.

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

 

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

Our 20th Patient-Focused Drug Development meeting: Enhancing the patient’s voice in FDA’s approach to drug review and development

By: Theresa M. Mullin, Ph.D.

Since the launch of the Patient Focused Drug Development program as part of the fifth authorization of the Prescription Drug User Fee Act (PDUFA V), we have worked intensively to explore ways to enhance the patient’s voice in drug development. Recently we reached a particularly gratifying milestone in this important work — our 20th Patient-Focused Drug Development (PFDD) public meeting.

Theresa MullinThe PDUFA program provides much needed funding from the pharmaceutical industry to support FDA’s premarket review activities and the agency’s work to encourage drug development. Under PDUFA V, FDA committed to obtain patients’ views in at least 20 disease areas over the course of the program’s five year period, which ends in September, 2017. That means conducting a public meeting for each disease area to obtain patient perspectives on the impact of the condition on daily life and current treatment approaches. Our 20th PFDD meeting, with patients who have received organ transplants, took place on September 27th. With that meeting completed, we fulfilled our commitment — one year ahead of schedule.

The PFDD meetings have given us the opportunity to strengthen our understanding of the targeted disease areas and hear directly from patients, their families, and caregivers about the symptoms that matter most to them; the impact of the disease on daily life, and their experiences with currently available treatments. Having this kind of input is extremely valuable for us because hearing what patients care about can help us determine how best to facilitate drug development for a particular disease area. Hearing the patients’ perspectives also helps us understand how patients view the benefits, risks, and burdens of treatments for their condition.

While FDA plays a critical role in drug development, we are only one of the players in the process; other stakeholders, including healthcare providers and industry sponsors, who have attended the PFDD meetings to hear from patients, are also gaining valuable information. The  PFDD meetings have also helped  identify areas of unmet need within the patient population (e.g., the psoriasis meeting highlighted the need for treatments for the pediatric population living with psoriasis) and helped raise awareness and focus engagement within the patient community itself (e.g., in preparation for the narcolepsy meeting patient groups collaborated to form a coalition called Unite Narcolepsy). We’ve chronicled this and more in our Voice of the Patient reports, which provide a detailed account of the valuable input we’ve heard at each meeting.

The Voice of the Patient reports are intended to be useful to both our FDA colleagues conducting reviews and the broader community. These reports summarize what FDA heard through patient speaker panels, audience participation, the webcast, and submissions to the public docket. Each report faithfully captures this information as a valuable resource for the FDA review divisions and is distributed internally to the relevant review divisions for reference when advising sponsors on their drug development programs and when assessing products under review in that disease area.

As drug development advances in the 21st Century, sponsors are using increasingly sophisticated and vital forms of technology to generate the medicines of the future. But there is a critical part of drug development — gaining ever increasing importance in the process — that has little to do with advanced technology. Instead, it has to do with listening to patients and their personal experiences living with their disease and its treatment, and determining the best ways to reliably capture this perspective so that it can be better integrated into decision making.

We believe that the long-term impact of PFDD will be better, more informed FDA decisions and oversight both during drug development and during our review of a marketing application. We are extremely grateful to all of the hundreds of patients and their loved ones who have so generously and, in some cases, courageously, participated in our meetings and have shared their personal stories, experiences, and perspectives.

We may have met the letter of our PDUFA commitment, but we are not finished. Patient-Focused Drug Development is a priority for FDA. Beyond the 20 meetings we have already held, we plan to hold four more PFDD meetings by the end of FY2017. Additionally, we recognize that there are many more disease areas to address. To help expand the benefits of FDA’s PFDD initiative, FDA welcomes similar patient-focused meetings organized by the patient groups themselves. For this parallel effort to FDA’s PFDD initiative, interested patient groups can submit a letter of intent. More information is outlined on FDA’s website.

One of the most valuable things we can do as regulators at FDA is simply to listen. I’m reminded of that each time we hold a PFDD public meeting. FDA will continue to listen — and learn — and we look forward to continuing to gain the additional insights that only patients, their families, and caregivers can provide.

Theresa M. Mullin, Ph.D., is Director of FDA’s Office of Strategic Programs in the Center for Drug Evaluation and Research