Addressing Issues Relating to Combination Products: Human Factors

By: Jill Hartzler Warner, J.D., and Thinh Nguyen

Combination products represent an important and growing category of therapeutic and diagnostic products under the FDA’s regulatory authority. These products, which combine a drug, device, and/or biological product (referred to as “constituent parts”) with one another, do not fit into traditional categories for medical products.

Jill Warner

Jill Hartzler Warner, J.D., FDA’s Associate Commissioner for Special Medical Programs.

Combination products come in three basic configurations: their constituent parts may be physically or chemically combined; they may be co-packaged; or they may be separately distributed with specific labeling that provides instructions for their combined use.

The different constituent parts of a combination product can add complexity to the final product. For example, when a medical device is part of the combination product, issues that relate to how the product is used can be as important as the product itself.

Human factors engineering, and the closely related field of usability engineering, both study how people interact with technology, to understand how the design of user interfaces for technology affects the quality, experience, and outcomes of that interaction. The questions addressed by human factors studies overlap with those addressed by “medication error” assessments, another area of user-product interaction evaluation commonly applied to drugs. The understanding gained from these evaluations can be applied to the design and review of the user interfaces for FDA-regulated products to assure their safety and effectiveness.

Thinh Nguyen

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

Because the design of a combination product can have a significant impact on whether a given product is safe and effective for its intended use, human factors evaluations are a central consideration for FDA when it assesses combination products, particularly those that include certain devices.

In February 2016, FDA published draft guidance for industry and FDA staff titled “Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development.” This draft guidance builds on principles articulated in earlier guidances that discuss human factors and medication error considerations for medical devices and drugs. When final, it will represent FDA’s thinking on when and how combination product manufacturers should perform human factors evaluations for investigational or marketing applications.

The draft guidance provides examples of combination products that include devices and describes recommendations for how to approach human factors studies for them, focusing on key challenges for developers such as:

  • The timing and sequencing of human factors studies in relation to overall development and study of a combination product;
  • How human factors studies compare with and relate to other types of clinical studies;
  • When changes to a combination product call for new human factors studies to be performed;
  • The role of simulated-use versus actual-use human factors studies; and
  • What information should be provided to the FDA, and when, to ensure timely feedback for a human factors study.

During the comment period on the draft guidance, FDA is seeking input on the overall guidance, as well as requesting that stakeholders submit examples of combination products in their comments and address whether they believe human factors studies are needed for them. The Agency is also seeking input on what challenges and development risks may arise if such studies are conducted before, in parallel to, or after major clinical studies for combination products. Input from stakeholders will help inform FDA’s final guidance in this important area. The comment period for this draft guidance closes on May 3, 2016.

Watch for more to come from FDA this year to further enhance transparency and predictability of combination products regulation. We are developing additional guidance for combination products, including current good manufacturing practices and a final rule on postmarket safety reporting. We also welcome your feedback regarding topics related to combination products that you would like us to address.

Jill Hartzler Warner, J.D., is FDA’s Associate Commissioner for Special Medical Programs

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

Border Crossings: Working With Partners to Verify the Safety of Imported Produce

By: Michael R. Taylor

One of the vivid images that sticks with me from my tenure at FDA is of the port of entry at Nogales, Arizona. There, I saw large trucks from Mexico lined up as far as the eye could see, awaiting entry into the United States‎, many loaded full with fresh produce. I was told by our FDA team that, during the busy season, as many as 1,500 produce trucks enter the United States there daily, and Nogales isn’t even the busiest port of entry on the 2,000-mile U.S.-Mexico border.

Michael R. TaylorThat visit to Nogales was in the early phase of our food safety modernization initiative at FDA‎, but it had a lasting effect on me. It drove home the degree of difficulty we would face in fulfilling the produce safety vision embodied in the FDA Food Safety Modernization Act (FSMA).

With 50 percent of our fresh fruit and 20 percent of our vegetables coming from growers in other countries, the challenge was not only to establish produce safety rules that would be effective and workable across the hugely diverse produce sector, but also to verify with reasonable confidence that those standards are being met consistently, every day, regardless of where the produce is grown.

‎The FSMA produce ‎safety rule is now on the books, but implementation and the task of achieving and verifying compliance is just getting started. We know that success will take an enormous amount of education, training, and technical assistance to support the vast majority of farmers who will want to comply.

It will take a concerted effort by government and industry alike to verify that compliance is happening. And all of that demands active public-private collaboration and partnership to meet high consumer expectations.

‎‎Within the United States, this means working with our state government partners to build state produce safety programs that will provide our primary interface with U.S. growers on all aspects of produce safety. We will also work with growers and their customers to strengthen the reliability of private audits as a source of verification that can complement, but never replace, the essential role of government inspection.

‎But what about those 1,500 truckloads coming into Nogales daily from Mexican farms? How do we verify their compliance?

‎The answer is this: only by using every tool in our import tool kit‎, and, of course, by building partnerships.

‎I’m writing this while en route to Tubac, Arizona, for the annual Spring Policy Summit of the Fresh Produce Association of the Americas (FPAA). FPAA represents those producing and trading fresh produce across the U.S.-Mexico border. For good business reasons, FPAA and its members focus heavily on ensuring the safety of that huge volume of food.

At this meeting, my colleagues and I will be discussing implementation of the foreign supplier verification program (FSVP) final rule, which places new responsibility on importers to ensure the safety of the food they import. This responsibility includes ensuring and verifying that their foreign suppliers use processes and procedures that meet U.S. safety standards. The result is that importers’ private verification efforts will help ensure the public health. At the same time, they are accountable to FDA.

FSVP is the regulatory linchpin of FSMA’s historic paradigm‎ shift for imported food from reaction at the border to accountability for prevention at the point of production. But Congress recognized that FSVP alone is not enough. FSMA also mandates that FDA conduct more foreign inspections and work more closely with foreign governments to ensure the safety of imported food.

‎So‎ also gathering in Tubac are our regulatory colleagues from the two Mexican agencies responsible for produce safety on the farm (SENASICA) and after the produce leaves the farm (COFEPRIS).

In 2014, we formed the US -Mexico Produce Safety Partnership, through which we are collaborating with our Mexican colleagues – much the way we do with our state partners – on education and technical assistance, inspection and compliance, and response to outbreaks. We’ll be reviewing our progress and discussing our challenges in a partnership working group meeting and sharing our government perspectives with FPAA, which has formed its own working group to collaborate with the government effort.‎

‎This degree of collaboration on food safety is unprecedented‎. But it is necessary because neither government nor industry alone can provide the level of verification FSMA envisions and consumers demand.

And it is possible because of the deep alignment of strategic interests ‎on food safety that exists among industry, government and consumers. We all have a huge stake in seeing that modern preventive practices are being used consistently to make produce safe. That is the foundation for real partnership. We all have different roles to play, but we all have the same goal.

‎That’s why we are gathering in Tubac. And, that’s why I’ll be traveling to Mexico City in April with Dr. Stephen Ostroff, my successor at FDA when I leave the agency in June, to work with our Mexican colleagues and the Mexican industry on FSMA implementation. That’s why we’re holding a public meeting in Washington today to discuss import safety with consumer, industry, and foreign stakeholders.

‎And it’s why hundreds of my FDA colleagues are working tirelessly with partners across the food system to prepare for FSMA implementation. I’m grateful for the opportunity I’ve had to work with so many people dedicated to food safety.  I think we are all fortunate that Steve Ostroff and other leaders across the food system have their hands on the helm.

And I am confident that we are on the way to success in fulfilling the FSMA vision, from the farms of Vermont and California to that line of trucks at Nogales.

Michael R. Taylor is FDA’s Deputy Commissioner for Foods and Veterinary Medicine

FDA and NIH Release a Draft Clinical Trial Protocol Template for Public Comment

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

Enhancing important efforts around clinical trials continues to be a key scientific priority. Another way we can encourage clinical trials is to look for ways to help clinical investigators make clinical trials more efficient, potentially saving development time and money. Today we’re announcing a draft clinical trial protocol template developed by the Food and Drug Administration (FDA) and National Institutes of Health (NIH) that should help with that.

Peter MarksThe clinical trial protocol is a critical component of any medical product development program. It’s defined in the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practice: Consolidated Guidance, as describing “the objective(s), design, methodology, statistical considerations, and organization of a trial…[and] usually also gives the background and rationale for the trial”. Similarly, for medical devices, some direction has been provided in the International Organization for Standardization (ISO) Clinical Investigation of Medical Devices for Human Subjects — Good Clinical Practice (ISO 14155:2011). Although guidance provides information on the important content that should be included in a protocol to help ensure human subject protection and data quality, it does not describe a standardized format for presenting this information. Time spent identifying the specific elements that should be included in a protocol and how best to organize them can delay the start of a clinical trial, and lead to delays in getting important new treatments to patients. What’s more, because up to 85% of investigators have only participated in one clinical trial in their careers, many investigators lack significant experience in protocol development. It’s likely that investigators could benefit from additional help in this area.

NIH, which supports and conducts biomedical research, and FDA, which evaluates the safety and effectiveness of medical products and depends on high quality research to inform its decisions, realized this represents an opportunity to help improve the design of clinical trials. Now, the NIH-FDA Joint Leadership Council (JLC) has launched a project to develop a template that could be used by investigators developing a clinical trial protocol.

Representatives from the NIH institutes and FDA’s medical product centers collaborated to develop a template containing instructional and sample text for investigators writing phase 2 or phase 3 clinical trial protocols that require investigational new drug (IND) or investigational device exemption (IDE) applications. Our agencies hope that the availability of the template and instructional information enables investigators to prepare protocols that are consistent and well organized, contain all the information necessary for the clinical trials to be properly reviewed, and follow the ICH E6 Good Clinical Practice guidance. Better organized, high-quality protocols will also expedite the review process at both agencies.

We are aware of other efforts in this area, including one undertaken by TransCelerate Biopharma Inc. (TransCelerate), which has issued a common protocol template intended to be the basis for a forthcoming electronic protocol. Although our initial target audiences differ, we plan to collaborate with groups like TransCelerate to help ensure consistency for the medical product development community.

We see the template as a way to facilitate creativity and innovation, not inhibit it. In the words of our NIH colleague Dr. Pamela McInnes, “Our goal is to provide an organized way for creative investigators to describe their plans so that others can understand them.” Just as ICH E6 allows considerable flexibility in the actual operations of trials using quality by design principles, the template includes the appropriate elements to be considered, but does not dictate exactly how the trial should be done—that is the work of the investigators.

NIH and FDA are seeking public comment on the draft template, which is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-043.html. Comments are accepted through April 17, 2016. We welcome feedback from investigators, investigator-sponsors, institutional review board members, and other stakeholders who are involved in protocol development and review. We are particularly interested in hearing your views on the utility of the template and whether the instructional and sample text is useful and clear.

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

More information can be found at:

NIH and FDA Request for Public Comment on Draft Clinical Trial Protocol Template for Phase 2 and 3 IND/IDE Studies

Clinical Research Policy

Clinical Trial Protocol Template

A ‘Roadmap’ for Navigating Patient Advocacy

By: John J. Whyte, M.D., M.P.H.

So, you and your organization have a passion for helping people and you want to work with FDA to advance your advocacy work. Are you unsure of the most effective way to enable patients to gain greater access to safe and effective drug therapies?

John WhyteWe know government agencies can be big and confusing. That’s why we’re working on a roadmap to help make your navigation easier.

And you can get involved.

FDA’s Center for Drug Evaluation and Research (CDER) is sponsoring a daylong public workshop on March 31, 2016, titled Navigating CDER: What You Should Know for Effective Engagement. Our presentations will help patient advocates gain a better understanding of FDA and provide specific resources to help you and your colleagues learn ways to effectively advocate and engage with the Agency on behalf of the patients you serve.

We’ll provide a broad overview of patient engagement with various offices within CDER, and drill down into key specifics such as:

  • Who and when to call;
  • How to set up a meeting at FDA;
  • Provide tips on making the most out of your meeting; and,
  • How to prepare an effective presentation for FDA staff.

We’ll also discuss topics such as understanding labeling, generic drugs, and how patients can effectively interact and provide input to FDA. And, we’ll look at some programs including different drug approval processes, expanded access, and FDA’s role in patient focused drug development (PFDD). These are only a few of the many important areas we’ll tackle.

For several years, FDA has been working to focus on the needs and goals of the patient as the Agency makes decisions about drug therapies for the advancement and protection of public health. These efforts can only be as effective as our ability to connect with the patients and their representatives we seek to engage.

Join us if you can. If you can’t, we’ll be making information about the meeting available on our website. We look forward to a productive and informative day!

John J. Whyte, M.D., M.P.H., is Director of Professional Affairs and Stakeholder Engagement at FDA’s Center for Drug Evaluation and Research

FDA Unveils Multilingual Health Fraud Protection Initiative for Consumers

En Español

By: Jonca Bull, M.D., and Jason Humbert, R.N.

Jonca Bull

Jonca Bull, M.D., FDA’s Assistant Commissioner, Office of Minority Health

Consumers are constantly bombarded by advertisements for fraudulent medical treatments and cures — dangerous scams that often target the most vulnerable populations. FDA is fighting back with its own enhanced educational initiative. And we’re urging health professionals and community leaders to help.

During National Consumer Protection Week, from March 6-12, FDA is launching a new multimedia and multilingual initiative, including a new video (see below) and a consumer article, all translated into English, Spanish, Simplified Chinese, Korean, Vietnamese, and Tagalog. The purpose of these materials? Alerting consumers of the dangers of imported tainted products falsely marketed as dietary supplements, and providing tips on how to prevent health fraud scams.

We invite you to share this information with your patients and networks. Additionally, please visit www.FDA.gov/SupplementSafety for information in Spanish and some Asian languages on how to prevent health fraud. You also will find tips and advice by visiting the FDA Health Fraud Scams page.

Sellers of tainted medical products are mostly from the United States, but often sell products that originate overseas and target certain ethnic groups. Sometimes the labels are in languages other than English and such products may be sold at flea markets, swap meets, ethnic stores, or from the homes of individuals.

Jason Humbert

Jason Humbert, R.N.,CDR, U.S. Public Health Service, FDA’s National Health Fraud Coordinator, Office of Regulatory Affairs, Office of Enforcement and Import Operations

Companies also recruit friends, family members and co-workers to market products through word-of-mouth. They advertise on TV and radio, in magazines and newspapers, through direct mail and social media channels such as Facebook, Twitter, and Instagram and through e-commerce platforms.

Sellers prey on underserved populations and people with limited English proficiency who are prone to fall victim to health fraud scams due to limited or inadequate access to health care services, language barriers, low health literacy, and cultural beliefs.

Health fraud scams are a multimillion dollar industry involving the marketing of drugs, medical devices, biologics and cosmetics. Bogus products can cause serious or fatal injuries, and can harm consumers further by delaying the proper diagnosis and treatment of health conditions.

Fraudulent products are often offered to prevent, treat, or cure conditions such as obesity, diabetes, arthritis, cancer, and HIV. Some scammers encourage their clients to stop using their prescribed medications and replace them with their products without consulting their physicians first.

FDA has found that many of these products are mislabeled, and in some instances contain active ingredients that shouldn’t be available without health care provider oversight.

Consumers can report adverse reactions to FDA MedWatch by calling 1-800-FDA-1088 (1-800-332-1088) to request a report form, or file a complaint online. Patients’ names and reports are kept confidential. Additionally, consumers can anonymously report fraudulent products marketed on the Internet through FDA’s website. Consumers who don’t speak English can report problems with the help of their local Consumer Complaint Coordinator.

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

Jason Humbert, R.N.,CDR, U.S. Public Health Service, is FDA’s National Health Fraud Coordinator, Office of Regulatory Affairs, Office of Enforcement and Import Operations

A FSMA Update for our Stakeholders in India

By: Howard Sklamberg

Rice at India Spice Market

Deputy Commissioner Howard Sklamberg, Dr. Mathew Thomas, FDA India Office Country Director, and Ritu Nalubola, Ph.D., Senior Policy Advisor, Office of the Commissioner, observing different varieties of rice offered at a whole produce and spice market near Mumbai, India

In an effort to complement our conversations about the FDA Food Safety and Modernization Act (FSMA) in the United States, FDA is reaching out to our international partners and stakeholders to discuss implementation of this historic food safety law.

I recently visited India, accompanied by Andrew Stephens from the Office of Food and Veterinary Medicine, and Ritu Nalubola, Ph.D., with the Commissioner’s Office of Policy. We had extensive discussions with our regulatory counterparts in the Indian government and with key food industry officials.

Spice Market near Mumbai, India

A Mumbai spice wholesaler describing a range of spices available to Deputy Commissioner Howard Sklamberg and Dr. Mathew Thomas, FDA India Office Country Director, at a whole produce and spice market near Mumbai, India

India is the seventh largest supplier of food to the United States. The Indian food products that end up on the dinner tables of Americans every night — including shrimp, spices, and rice — reflect the increasing globalization of our country’s food supply.

Many of these goods come from any of India’s 29 states, produced by thousands of different companies. Such dispersion and volume makes FDA’s close engagement with our Indian counterparts necessary, especially on the export-related parts of FSMA.

Our most recent trip to India follows a similar trip in March 2015 when Mike Taylor, Deputy Commissioner for Foods and Veterinary Medicine, joined me to introduce FSMA to a wide variety of Indian stakeholders.

On that trip, we explained that FSMA mandates a food safety system that is preventive, rather than reactive. FSMA requires that foreign food producers meet U.S. safety standards.

A variety of spices in India

A selection of spice offerings at a whole produce and spice market near Mumbai, India

At that time, we also signed a Memorandum of Understanding (MOU) with the government of India to engage in regulatory, scientific, and public health protection matters related to food products.

Building upon our 2015 trip, and upon the great work of FDA’s India office, our recent meetings focused on three FSMA rules of vital significance to India stakeholders: Current Good Manufacturing Practice and Hazard Analysis and Risk-Based Preventive Controls for Human Food; Foreign Supplier Verification Programs for Importers of Food for Humans and Animals; and Accreditation of Third-Party Certification Bodies To Conduct Food Safety Audits and To Issue Certifications. The overview my FDA team provided was very useful to our Indian counterparts, many of whom have been engaged with FDA’s India Office in learning the details of the new mandates for exporters.

Howard Sklamberg speaking at the World Spice Congress in India

Deputy Commissioner Howard Sklamberg delivering remarks on FDA’s final FSMA rules at the World Spice Congress in Ahmedabad, India

I finished my trip with remarks to the World Spice Congress. As I noted there, the food system grows more global and trade-driven every year, which means we grow more dependent every year on collaboration and real partnership between government and industry across national boundaries.

We all have three goals: We want food to be safe. We want consumers to have confidence. And we want food safety and consumer confidence to enhance trade between nations. FSMA will help us achieve all three.

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

‘Leaning in’ on Combination Products

By: Nina L. Hunter, Ph.D., and Rachel E. Sherman, M.D., M.P.H.

Medical products that combine drugs, devices, and/or biological products are known as combination products. These products present a number of regulatory, policy, and review management challenges because they include components from multiple regulatory categories (e.g., drug and device, drug and biologic, biologic and device, drug, device, and biologic) with distinct regulatory requirements, and review of a combination product generally requires involvement of more than one FDA Center.

Nina Hunter

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

However, as FDA continues to adapt to the rapidly evolving ecosystem of therapeutic development, it’s more important than ever to find ways to encourage innovation and support the development of these needed technologies.

To that end, FDA has been working on ways to improve the overall efficiency, consistency, and predictability of combination product review. We’ve already shared some of our progress with you in a recent blog post.

An important next step is launching the lean management process mapping approach to build a better system for combination products review – one that’s more cohesive, more collaborative, and more systematic.

What is lean management process mapping, you might ask? It begins with an analysis of what’s being done now, then designs a future state that eliminates waste and maximizes value.

We expect two significant outputs from this mapping:

  • A “current state” map that shows how we’re doing now. Importantly, this initial look will highlight existing sources of delay or redundancy. Creating this baseline map also will allow us to identify metrics for success and to assess the impact of improvements as they are put in place.
  • A “future state” map showing a streamlined, efficient process that will eliminate previously identified delays and redundancies.
Rachel Sherman

Rachel E. Sherman, M.D., M.P.H., FDA’s Associate Deputy Commissioner in the Office of Medical Products and Tobacco

Has lean management already been successfully applied at the FDA? Yes!

Under the leadership of Kyle Hair, the Lean Management Team in the human drugs program in the Office of Strategic Programs has executed strategic work and communication plans for initiatives across the Agency.

For example, when the “Lean Team” consulted with the Office of Clinical Pharmacology within the Center for Drug Evaluation and Research, it helped establish project management staff functions, roles, and responsibilities for the Office’s core processes. The team also has applied its expertise to stand up the new Office of Pharmaceutical Quality, as well as apply its expertise to such topics as drug safety communications and risk evaluation mitigation strategy.

Lean management works. And we’re confident that applying lean management principles to combination product review will allow us to enhance communication and coordination among the groups that oversee the development, review, and approval of combination products.

Of course, we realize that success in this area depends upon meaningful interactions among all FDA Offices and Centers involved with combination products review. The active participation emphasized by lean management principles will ensure that the needed collaboration is present from the start.

Lean methods also encourage critical thinking and problem-solving, with a focus on reliable, efficient, timely, and reproducible evaluation and decision-making. In this case, our efforts will be focused on the ultimate goal of a combination product review system that is transparent, clear, and consistent.

But lean process mapping is only one piece of the puzzle. Stay tuned for more information about other key priorities and initiatives aimed at modernizing the review of combination products!

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

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

Have a Problem? Contact the New Ombudsman in the Office of Regulatory Affairs

By: Melinda K. Plaisier

Melinda PlaisierWhether we are inspecting your facilities, sampling your products, or conducting investigations, the primary goal of FDA’s Office of Regulatory Affairs (ORA) is to protect the public. But I understand the impact our actions can have on you, so I am committed to making ORA’s processes as transparent as possible and quickly addressing problems you may encounter.

That’s why I’m happy to announce a new resource: an ORA ombudsman who can help you with unresolved concerns. While you may continue to bring issues to my staff, Ombudsman Jessica Zeller is dedicated solely to helping you with assessing and resolving problems.

Jessica, who has worked in both industry and government, understands that FDA’s perspective is often different from that of industry and other stakeholders. Her experience makes her an ideal candidate to carry out two primary objectives:

  • To informally and in an unbiased manner, find solutions, when possible, to problems that arise with our external partners, including industry, other governmental agencies, and consumers.
  • To improve communications between ORA employees and stakeholders through outreach and education, helping both sides become more aware of each other’s needs.

“Understanding the pressures that each side faces are critical to working out solutions and allaying fears,” says Jessica. “I intend to hear what you are saying and feel what you are feeling. I will not always be able to get you what you want, but I promise you will have an opportunity to share your concerns, and I will attempt to achieve the best solution possible.”

Although Jessica reports directly to me, and ORA leaders will continue to make final decisions, Jessica is an unbiased third party who will consider and work on your concerns. You may contact her by phone or email, and she will keep conversations as confidential as possible within the limits of the law.

Jessica gained her expert knowledge from more than a decade of work in FDA regulation. During her eight-year tenure at FDA, from 2004 to 2013, she served in the Office of the Chief Counsel and as deputy director of the Office of Compliance and Enforcement in the Center for Tobacco Products. From 2013 until she returned to FDA late last year, Jessica was in-house counsel for Proctor & Gamble. She also previously worked as a congressional staffer, earned a law degree and a master’s degree in bioethics from the University of Virginia, and a bachelor’s degree in biology.

The International Ombudsman Institute defines an ombudsman as a person of prestige and influence who operates with objectivity, competence, efficiency, and fairness. We are proud that Jessica fits that lofty definition so well. I encourage you to reach out to her when issues remain unresolved.

Melinda K. Plaisier is FDA’s Associate Commissioner of Regulatory Affairs

Launching a New Natural History Grants Program: Building a Solid Foundation for Rare Disease Treatments

By: Katherine Needleman, Ph.D. and Gumei Liu, M.D., Ph.D.

Today, on Rare Disease Day 2016, FDA’s Office of Special Medical Programs/Office of Orphan Products Development (OOPD) is proud to announce the launch of a new grants program to fund natural history studies with the hope of bringing new and important diagnostics and therapeutics to patients with rare diseases.

Kathy Needleman

Katherine Needleman, Ph.D., is the Director of the Orphan Products Grants Program of FDA’s Office of Orphan Products Development

A rare disease, by definition, affects fewer than 200,000 individuals in the United States. Its impact, however, is far from rare. Altogether, about 7,000 known rare diseases affect about 30 million Americans. Yet the vast majority of rare diseases do not have adequate diagnostic tools or treatments.

Developing such diagnostics or treatments — whether it’s a drug, biologic, or medical device — has been compared by many to building a house. Both require a solid, sound foundation. For any rare disease treatment development program, that foundation consists of having a thorough understanding of the natural history of a disease.

How do you define the natural history of a disease? Think about it as the course a disease takes – from the time of its onset, progressing through its pre-symptomatic phase and clinical stages, to the end of the disease. Insight into a disease’s natural history can help lead to better, more well-designed trials that can accelerate the development of life-saving diagnostics and therapeutics.

Gumei Liu

Gumei Liu, M.D., Ph.D. is a reviewer and grant project officer in FDA’s Office of Orphan Products Development

A lack of understanding of the natural history is often a major obstacle to developing life-saving products for patients with rare diseases. Without it, it becomes very difficult to decide what to study, know what to look for within a study, and capture the data necessary for approval of a treatment or even a cure.

OOPD’s new Natural History Grant Program is intended to provide much needed support and complement ongoing efforts to help change the trajectory of rare disease product development. The funded studies should help characterize the natural history of a rare disease or condition, identify genotypic and phenotypic subpopulations, and develop and/or validate clinical outcome measures, biomarkers, and companion diagnostics.

There are several ways to conduct natural history studies. They can look back in time (retrospective), look ahead (prospective), or be a survey study (collection of data through questionnaires). Each has its pros and cons and the method will to a great extent depend on what we know about a specific rare disease and the currently available treatment options.

Patient advocacy groups can and do play a critical role in collecting natural history data as is highlighted in FDA’s video discussion (watch video below) on natural history studies featuring perspectives from patient advocates. Often what prevents organizations, like patient advocacy groups, from conducting natural history studies is funding. And that’s where the grants program can make a difference.

The Orphan Products Natural History Grants Program is open to funding all types of natural history studies that are appropriate for the rare disease being studied and can aid in development of diagnostics and treatments. There are two funding levels and durations that will be offered:

  • A maximum of $400,000 in total costs per year for up to five years for prospective natural history studies involving clinical examination of affected individuals; and
  • A maximum of $150,000 in total costs per year for up to two years for retrospective natural history studies or survey studies.

The Orphan Products Natural History Grants Program is built upon OOPD’s Orphan Products Grants program that was established by the Orphan Drug Act more than 30 years ago and which has typically funded clinical trials. OOPD has successfully utilized its budget to help bring over 50 products to market with that clinical trial grant program.

We hope that this new Orphan Products Natural History Grants Program will help build the important foundation necessary to accelerate the development of life-saving diagnostic and treatments for the many rare disease patients who need them.

Katherine Needleman, Ph.D., is the Director of the Orphan Products Grants Program of FDA’s Office of Orphan Products Development

Gumei Liu, M.D., Ph.D. is a reviewer and grant project officer in FDA’s Office of Orphan Products Development

Strengthening our Regulatory Relationships in India

By: Mathew T. Thomas and Dean Rugnetta

India’s economic expansion is in part due to the tremendous growth in the pharmaceutical industry. The United States is a large consumer of medical products, and India is one of the largest suppliers of its drug products. And our important work together remains an FDA priority.

Investigator Daniel Roberts

Investigator Daniel Roberts (FDA India Office) and an Indian Regulator sharing inspectional approaches for current good manufacturing practices for pharmaceuticals during the workshop in Ahmedabad

We are working with our counterparts in the Indian government to ensure the medical products manufactured there, especially those for export to the U.S., meet FDA’s safety and quality requirements. FDA established an office in India in 2008, in part to promote government-to-government interactions like these and to keep pace with rapid developments and innovations in the pharmaceutical sector.

In November 2015, representatives from FDA’s India Office, our Center for Drug Evaluation and Research (CDER), Office of Regulatory Affairs (ORA), and Office of International Programs (OIP), partnered with the India Government’s Central Drug Standards Control Organization (CDSCO), to share inspectional techniques and guidance for conducting current good manufacturing practices of pharmaceutical facilities.

Carmelo Rosa and Denise DeGiulio

Carmelo Rosa (CDER), Denise DiGiulio (CDER), and an Indian Regulator discuss Quality By Design guidance with the workshop participants in Ahmedabad

Training sessions were provided in two cities (Ahmedabad and Bengaluru) for about 200 Indian regulators representing CDSCO and some of the State drug control agencies. The training was an example of the cooperation by both agencies to increase knowledge and skills, thereby contributing to the health and welfare of citizens in both countries.

The collaboration resulted in representatives from both agencies learning more about the regulatory perspectives of the other – and doing so first-hand. It was clear from the interactions that the Indian inspectors had extensive knowledge of FDA and of the international techniques for conducting inspections. The FDA representatives at the sessions benefited from input regarding the differences between FDA and Indian legislation and regulations. And as new inspectors comprised the majority of attendees, there was the opportunity for learning on both sides.

FDA Workshop Team in India

FDA Workshop Team in Bangaluru. Front Row – Denise DiGiulio (CDER), Carmelo Rosa (CDER), Leslie Ball (Office of International Programs), Mathew Thomas (India Office), Thomas Cosgrove (CDER), Thomas Arista (ORA). Back Row: Shiva Prasad (India Office), Daniel Roberts (India Office), Solomon Yimam (India Office)

Senior officials from the Government of India attended both events and affirmed their goals of ensuring patient safety and of collaborating with FDA to make sure that products from India are safe and meet appropriate quality standards.

FDA and Government of India regulators will continue leveraging knowledge and strengths to ensure patient safety in India and product quality of FDA-regulated pharmaceuticals.

Mathew T. Thomas is the Director of FDA’s India Office in New Delhi, India

Dean Rugnetta is the Deputy Director in FDA’s India Office in New Delhi, India