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

The Unique Voices of Our Patient Representatives

By: Robert M. Califf, M.D., and Heidi C. Marchand, Pharm.D.

We recently met with 21 inspirational patients and patient caregivers who have made the extraordinary commitment to become FDA patient representatives. These volunteers were in Washington to participate in our two-day Patient Representative Workshop so they can receive training that will allow them to help FDA meet its critical responsibility of guiding the development and evaluation of safe and effective medical products.

Robert Califf

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

The patient representative program has existed since 1999 and is integral to fulfilling FDA’s strong commitment to ensure that the needs and choices of patients – as well as their families, caregivers, and advocates – are incorporated in ever greater ways in the work we do.

Patients add context and content to the cutting-edge science and other empirical evidence that is so important in our regulatory decision-making.  Including their perspectives and voices in our work along the entire medical product continuum, from development to review and evaluation to post-market surveillance, offers opportunities to enhance our knowledge of the benefits and risks of medical products. It’s not only smart science; it just makes good sense. We know, for instance, that patients who live with a chronic disease are experts in the tangible effects of that disease and its treatments.

The training that patient representatives receive helps prepare them to serve on FDA advisory committees, meetings and workshops, where they are knowledgeable about what it is like to cope with their disease – including such topics as side effects from treatments and important lifestyle issues. They also provide valuable contributions as consultants to our review staff.

Heidi Marchand

Heidi C. Marchand, Pharm.D., Assistant Commissioner in FDA’s Office of Health and Constituent Affairs

To give you an idea of the unique set of skills and experiences patient representatives bring to their work, consider the stories and experiences we heard at the workshop.

One was an elite world class athlete, who initially thought her pain was muscular in nature before it was diagnosed as a serious blood clot. She has been on a series of different products since then and is now intimately familiar with what it is like to be on anticoagulants – reflecting on both the benefits and risks of taking these medications.

Two of our patient representatives are caregivers who have a personal experience with a rare disease, Batten’s Disease, a fatal, inherited disorder of the nervous system. Sadly, each lost a young son to the disease. But in the face of this tragedy, these two mothers have advocated tirelessly to find a cure for this disease and worked to educate other parents.

Another mother related the story of her daughter who, at age 16, survived two craniotomies to remove a lemon-sized brain tumor. The daughter went on to receive of 48 weeks of chemotherapy and 8 weeks of brain and spine radiation. The daughter is now 33 years old and doing well. And the mother told us how critical it was for her daughter to take an opioid to relieve her pain. This kind of input, from those who have experienced it first hand, is critical to our future decisions.

2016 FDA Patient Representative Group photo

FDA Patient Representatives at the 12th Annual FDA Patient Representative Workshop, hosted by FDA’s Office of Health and Constituent Affairs

The stories that these patient representatives tell are moving. But even more moving – and indeed inspirational – is their commitment to the future. That’s why they were selected – because of their individual involvement with their respective patient communities, their analytical skills, and their ability to maintain an open mind and consider options.

While we will help train them about the nuts and bolts of FDA – such as the various pathways that products take to get to market – it is their personal experience and their ability to understand and to articulate the perspectives, concerns, and experiences of patients – that makes them truly special.

As we continue to evaluate potential treatments and cures for different diseases, we must make sure that patients are more than simply statistics in this equation. They are real people, with names, faces, and, thanks to these patient representatives, important voices who represent an essential piece of the puzzle to be solved.

FDA is committed to looking for new and better ways to integrate the patient voice. Our patient representatives are an important piece of this commitment. They have an extraordinary impact. We thank them for their service and commitment, and look forward to working with them.

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

Heidi C. Marchand, Pharm.D., is Assistant Commissioner in FDA’s Office of Health and Constituent Affairs

The Rise in Orphan Drug Designations: Meeting the Growing Demand

By: Gayatri Rao, M.D., J.D.

Developing drugs for rare diseases, once considered a rare phenomenon itself, has fast become a mainstay for many companies’ drug development pipelines. This is exciting news for the 30 million Americans with rare diseases and their families.

Dr. Gayatri RaoCongress played no small role in making this a reality when it passed the Orphan Drug Act in 1983.  One of the key features of this Act was the creation of the Orphan Drug Designation Program, which provides important financial incentives to encourage companies to develop drugs and biologics for rare diseases. This legislation includes major tax credits to defray the cost of conducting clinical trials, as well as eligibility for seven years of market exclusivity. As a result of later amendments to the Act, no user fee is required for orphan drug product submissions, except when an application includes an indication for a non-rare disease or condition.

The number of requests for orphan drug designation received by FDA’s Office of Orphan Products Development (OOPD) has grown dramatically in recent years and is prompting FDA to adjust its timeframes for reviewing orphan drug designations in order to meet the demand. In 2014, we saw a 30% increase over the prior year’s record number. Yet, that record was broken the very next year when we received close to 470 requests. And the pace does not seem to be slowing. In fact, comparing the number of new requests received so far in 2016 with the corresponding date in 2015, there appears to be yet another 30% increase.

We strive to review these requests in an efficient and timely manner because we understand how critical designation can be for companies to move forward with their drug development plans. At the same time, we endeavor to safeguard the intent of the Orphan Drug Act by conducting a thorough review to ensure that the drugs we designate fully satisfy the criteria for designation and the financial incentives associated with designation.

While there is no statutory or regulatory review deadline, it has been our internal goal to review 75% of designation requests within 90 days of receipt. By streamlining our programs, modifying work priorities, and restructuring workloads, we have generally been able to meet or exceed that internal goal. However, the sustained increase in designation requests over the last three years, coupled with the increasing number of incentive programs and competing workload priorities, have forced us to reconsider our internal review target. Reviewing these applications in an efficient and timely manner continues to be a top priority, but to ensure we continue to conduct these reviews with the appropriate level of care and consideration, our current goal is to review on average 75% of designation requests within 120 days of receipt.

We will continue to evaluate workload in relation to resources, and may need to further adjust review timelines in the future.

Companies can play a critical role in ensuring that the new review timeframe does not translate into a delay in obtaining orphan drug designation by doing their part to reduce the number of review cycles needed (i.e., when OOPD needs additional information from the sponsor prior to determining the outcome of an orphan drug designation request).

On average, a request for designation today goes through two such review cycles. Sponsors can shorten this process by ensuring that designation requests are complete and fully address all requirements. We recommend sponsors review the information at www.fda.gov/orphan for helpful hints and FAQs when developing their requests.

The rise in the number of requests for orphan drug designation holds promise for the future of rare disease drug development. We remain committed to the timely and effective administration of the Orphan Drug Designation Program with the shared hope of bringing safe and effective products quickly to the patients who need them most.

Gayatri Rao, M.D., J.D., is FDA’s Director for The Office of Orphan Products Development

FDA Takes Action against Zika Virus

By: Robert M. Califf, M.D., and Luciana Borio, M.D.

Zika virus was first identified in 1947 in Uganda and for decades only sporadic cases and a few outbreaks were recognized in a number of locations, including parts of Africa, Asia, and the Pacific. Since 2015, the situation has changed dramatically, with 48 countries and territories reporting a first outbreak of Zika virus as of July 2016. In the United States, cases of Zika virus disease acquired by the bite of an infected mosquito have only been reported in U.S. territories; to date, cases of Zika virus infection reported in the continental United States have involved travelers and in some instances their sexual contacts. However, given the number of Zika cases among travelers visiting or returning to the United States and the increased mosquito activity in the summer months, we expect that imported cases could result in local spread of the virus in some areas of the United States.

Robert Califf

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

The FDA is taking important steps to rapidly respond to the Zika virus outbreak. We are engaged with our partners across the U.S. Government, the private sector, and the international community—including the World Health Organization and ANVISA (the Brazilian Health Regulatory Agency)—to help minimize the impact of this outbreak.

Protecting Tissues and the Blood Supply

One of the FDA’s first actions was to take important steps to help protect the safety of the blood supply. The FDA issued guidance in February 2016 recommending the deferral of individuals from donating blood if they have been to areas with active Zika virus transmission, were potentially exposed to the virus, or have had a confirmed infection. The guidance also recommends that areas with active Zika virus transmission, like Puerto Rico, obtain whole blood and blood components from areas of the United States without active virus transmission unless a blood donor screening test for Zika virus is used. Because there were no blood donor screening tests available for Zika virus at the time, HHS arranged for and funded shipments of blood products from the continental U.S. to Puerto Rico to ensure an adequate supply of safe blood for residents until a blood donor screening test became available. The FDA worked closely with developers in a highly accelerated time frame to make available an investigational test for blood screening in March 2016. The availability of this investigational test, which has been in use in Puerto Rico since early April, has allowed blood establishments to safely collect blood in areas with active Zika virus transmission. A second investigational blood screening test was made available in June 2016. Together, these tests have also enabled blood donor screening to be put in place in areas of the United States where local virus transmission is anticipated, but not yet detected, helping to maintain the safety of the blood supply.

Dr. Lu Borio

Luciana Borio, M.D., is FDA’s Acting Chief Scientist

Zika virus also poses a risk for transmission by human cells, tissues, and cellular and tissue-based products (HCT/Ps) such as corneas, bone, skin, heart valves, and semen used for medical, surgical, or reproductive procedures. Because of this risk, the FDA issued guidance recommending that donors of HCT/Ps be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of those risk factors, within the past six months.

Supporting Diagnostic Development

The ability to accurately detect and diagnose Zika virus infection is critical for a robust response to this public health threat. The FDA is actively working with manufacturers to support their diagnostic development programs, helping to ensure that their tests are properly validated before they are used to inform patient care. This collaboration has been very successful, and since the beginning of the year, we have authorized the use of five diagnostic tests for Zika virus under FDA’s Emergency Use Authorization authority—four tests to diagnose active infection and one test to assess whether individuals who may have recently been exposed to Zika were actually infected. This test is especially important for women given the link between Zika virus infection and microcephaly and other poor pregnancy outcomes in babies of mothers who were infected with Zika virus during their pregnancy.

Strategies to Suppress Mosquito Population

FDA—as well as our colleagues at EPA— are reviewing the use of innovative strategies to help suppress the population of virus-carrying mosquitoes to help mitigate the threat of vector-borne epidemics, such as Zika virus, which is thought to spread to people primarily through the bite of an infected Aedes aegypti mosquito.

Recently, the FDA released for public comment a draft environmental assessment (EA) submitted by Oxitec, Ltd. (Oxitec). The EA assesses the potential environmental impacts of a proposed field trial of the company’s genetically engineered (GE) Ae. aegypti mosquitoes. The FDA also released for public comment a preliminary Finding of No Significant Impact (FONSI) agreeing with the conclusion in Oxitec’s draft EA that the proposed field trial of the company’s GE mosquitoes would not result in significant impacts on the environment.

The goal of the proposed field trial is to determine whether released Oxitec GE mosquitoes will mate with local wild-type Ae. aegypti and suppress their population at the release site. The FDA is reviewing the thousands of comments received during the public comment period before determining whether to finalize the EA and FONSI or prepare an environmental impact statement (EIS). Oxitec will not proceed with the field trial of the GE mosquitoes until FDA issues its final EA and FONSI or EIS. Oxitec’s GE mosquitoes are one possible approach that could be incorporated into an integrated vector control program to help mitigate the threat of vector-borne epidemics; however, it is too early to say with any certainty whether such an approach would be successful.

Facilitating Medical Product Development

There are currently no vaccines or treatments for Zika virus that have been shown to be safe and effective. Facilitating the development and availability of vaccines is one of the highest priorities for the FDA and the international community. The FDA continues to actively engage with commercial and government developers, including the NIAID and BARDA, to advance the development of investigational vaccines for Zika virus as soon as possible. We are also working with ANVISA to assist in their efforts to expedite the development of vaccines for Zika virus. As was recently reported, a commercial company announced plans to begin evaluating the first investigational Zika virus vaccine in a Phase I clinical study.

Unfortunately, during outbreak situations, fraudulent products claiming to prevent, treat or cure a disease almost always appear. FDA is monitoring for fraudulent products and false product claims related to Zika virus and will take appropriate action to protect consumers when necessary.

More than 120 FDA staff from across the Agency are  responding to the Zika virus outbreak, working together to address the complex range of issues that this evolving epidemic continues to present in order to protect and promote the public health, both domestically and abroad. This type of teamwork exemplifies the capacity of people at FDA to rally together to solve problems, often with little explicit credit other than the satisfaction of meeting the mission of promoting and protecting the public health. There are many fundamental scientific questions that need to be addressed with respect to Zika virus, and our scientists are working to help answer some of these questions in our own laboratories. We stand ready to use our expertise and authorities to the fullest extent to help facilitate the development and availability of products that may help mitigate the Zika virus outbreak.

Visit our Zika response web page for more information, including the latest Zika virus response updates from FDA.

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

Luciana Borio, M.D., is FDA’s Acting Chief Scientist

FDA Advisory Committee Members and ‘Appearance Issues’

By: Michael Ortwerth, Ph.D.

FDA relies on its advisory committees as a source of independent scientific and technical expertise and advice on challenging public health issues. Most advisory committee members are appointed as “special government employees” (SGEs). Like regular government employees, these committee members are subject to Federal conflict of interest laws and regulations.

Michael OrtwerthA lack of understanding about our selection and evaluation process has, at times, resulted in confusion and misunderstandings by the public.  We’ve been working to bring greater transparency to how the financial interests of committee members are evaluated.

In 2008, we published “Guidance for the Public, FDA Advisory Committee Members, and FDA Staff on Procedures for Determining Conflict of Interest and Eligibility for Participation in FDA Advisory Committees.” That guidance describes how we apply financial conflict of interest requirements.

What has not been previously addressed in guidance is something called “appearance issues.” Sometimes FDA advisory committee members who do not have interests and relationships that are financial conflicts of interest nevertheless have interests and relationships that may create the appearance that they lack impartiality. Appearance issues are addressed in a government-wide regulation regarding standards of ethical conduct for government employees at 5 CFR 2635.502 (informally known as “Section 502”).

Some examples include:

  • When a member of the household works or is seeking to work for the sponsor with a product before the committee;
  • When a member has had past financial interests with the sponsor with a product before the committee; and,
  • When a member has a current consulting contract with a sponsor but the contract is not related to the product or issue before the committee.

We have recently published new draft guidance describing FDA’s procedures for evaluating appearance issues and how we determine whether to grant an authorization for a member with an appearance issue to participate in an FDA advisory committee.

Section 502 implements the ethical principle that a government employee should be impartial in performing their official duties, meaning that they must not give preferential treatment to any private organization or individual or use public office for private gain. To the extent that an advisory committee member’s performance of official duties might appear to benefit themselves or certain other individuals who are close to them, they must take appropriate steps to avoid an appearance of violating these ethical principles.

We also explain in the draft guidance the circumstances that FDA considers when determining whether an appearance issue may exist. We evaluate the circumstances and assess whether the interests, relationships, or circumstances would cause a reasonable person with knowledge of the relevant facts to question the advisory committee member’s impartiality in the matter before the committee. For example, if an advisory committee member serves on the board of directors of a nonprofit organization and that organization receives donations from the sponsor that is presenting before the committee, we review the details of the donation to determine whether the member should be cleared for service on the advisory committee.

FDA has flexibility and discretion in deciding whether an advisory committee member with an appearance issue should be authorized to participate in the advisory committee meeting. We evaluate whether the government’s interest in the advisory committee member’s participation outweighs the concern that a reasonable person may question the integrity of the agency’s programs and operations. If so, FDA may authorize the member to participate in the meeting.

Although FDA advisory committees provide advice and input to the Agency, FDA makes the final decisions.

The draft guidance is being issued for public comment before we issue a final guidance. Under Federal law, FDA is not permitted to disclose confidential information provided by advisory committee members related to appearance issues. But we are specifically requesting comments on whether the agency should request that advisory committee members voluntarily disclose if they have been granted an appearance authorization.

FDA is committed to ensuring that appropriate expertise and experience is brought to bear on the critical public health issues facing the agency. Often, we convene advisory committee meetings to obtain independent expert advice and perspective. At the same time, it is important that the process we use to screen advisory committee members for participation in meetings be as transparent as possible, and that we protect the credibility and integrity of advisory committee advice. We welcome your comments on how the agency can continue to meet these important goals.

Michael Ortwerth, Ph.D,. is FDA’s Director of the Advisory Committee Oversight and Management Staff