FDA in India – Championing a Culture of Quality

By: Mary Lou Valdez

One of FDA’s most strategic outposts is in India, the seventh largest supplier of food and second largest supplier of pharmaceuticals and biologics to the United States. The agency’s office, located in the capital, New Delhi, works to ensure the safety and security of food and the safety and efficacy of medical products exported from India to the U.S.

Mary Lou Valdez with India Office Staff

from left: Dean Rugnetta, FDA Deputy Director, India Office; Mary Lou Valdez, FDA Associate Commissioner for International Programs; Mathew Thomas, FDA Director, India Office

To achieve that goal, the India Office, directed by Mathew Thomas, conducts inspections of Indian medical products and foods facilities that export to the U.S. The office also assists and trains regulators, industry, and other stakeholders in developing and maintaining the quality, safety, and effectiveness of the FDA-regulated products they export.

It’s important for the office to consult regulatory authorities in India to build confidence in each other and to develop quality standards that both countries can trust.

I had the privilege of joining Director Thomas last month for meetings with our regulatory counterparts – the Indian Export Inspection Council (EIC), the Food Safety Standards Agency of India (FSSAI), the Drugs Controller General of India (DCGI), and the Joint Secretary of the Ministry of Health and Family Welfare.

Despite the diversity of these agencies’ mandates and priorities, a common theme coming out of these meetings was the recognition of the mutual benefits we realize by working together to enhance the effectiveness of our regulatory systems and to advance risk-based and science-based approaches to food and medical product regulation.

Along with other FDA experts, I also participated in a Global Food Safety Partnership (GFSP) Governing Council meeting and the Indian Pharmaceutical Alliance (IPA) Second Forum, titled “Towards Excellence in Quality.” Hosted by the Word Bank, the GFSP is a public private partnership, established in 2012, which brings together governments, industry, multilateral organizations, and other stakeholders in support of stronger food safety systems. Since its founding, the GFSP has worked with China, Indonesia, and Vietnam. During my visit, we had initial GFSP meetings with Indian regulators, to explore potential synergies as they look to bolster their food safety systems and maximize their investments. FDA’s India Office is well-positioned to help the Partnership and India explore how best to meet these goals.

The IPA Forum brings together CEOs of pharmaceutical firms, manufacturers, regulators, and other national and global stakeholders who have a role in shaping India’s complex and diverse manufacturing environment to produce safe, effective, high-quality medical products.

Over the past decade, the Indian pharmaceutical market has grown by nearly 14 percent and continues to experience massive growth. However, in order to fully realize the nation’s potential as an important player in the global pharmaceutical industry, India’s regulatory infrastructure must keep pace to ensure that global quality and safety demands are met. Quality issues are an ongoing challenge for the Indian pharmaceutical industry. Of 42 warning letters issued by FDA’s Office of Manufacturing Quality last year, nine went to Indian facilities. The IPA is working to communicate to its diverse members why quality matters and how to achieve it. Thus, the general theme of its Second Forum “Towards Excellence in Quality,” was an incredibly relevant topic if the global market for FDA-regulated products is to be strong and secure.

No one wants resources wasted on ineffectual development and weak processing or manufacturing systems that could actually impede product success. We all want greater competition, increased options for consumers and patients, and more affordable alternatives to comparable products.

Participants agreed that achieving quality requires regulators and industry alike to champion and advance a quality culture throughout the product life-cycle, by effectively employing the use of data and science and requiring greater transparency.

While I was in India, it was really gratifying to witness the high-esteem and trust Indian regulators and industry have for FDA, and our India Office. In turn, whether it is through their response to inspectional observations, their participation in trainings and seminars or their readiness to share strategic information, we see India committing to quality and compliance. Indian regulators and industry both recognize that a quality culture is imperative if India is to increase productivity, reduce compliance risk, lessen rework, and minimize supply interruptions that result in lost revenue and increased risks to public health.

This greater emphasis on quality will also allow India to participate more fully in existing global venues such as the International Council for Harmonisation (ICH) and the Pharmaceutical Inspection Cooperation Scheme (PIC/S) – which will enable stronger collaboration and synergies among regulators.

Quality is good for economic development, the market, and most importantly, patients and consumers everywhere. FDA’s Office in New Delhi looks forward to continued collaboration with our Indian regulatory colleagues to champion a culture of quality.

Mary Lou Valdez is FDA’s Associate Commissioner for International Programs

This is Not a Test: RMAT Designation Goes Live

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

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

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

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

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

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

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

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

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

Opening the FDA’s History Vault

By: Suzanne Junod, Ph.D., and John Swann, Ph.D.

Welcome to the FDA’s History Vault, which contains more than 10,000 artifacts that provide a journey through American history and document the critical role played by one of the nation’s oldest public health agencies in support of its mission to promote and protect American health.

Suzanne Junod and John Swann

Suzanne Junod, Ph.D., and John Swann, Ph.D., holding FDA artifacts.

The items featured in this new series of short videos reflect the constant changes in science and society. It is the responsibility of the FDA’s history office to document and share these changes through the collection, management, and display of these rare, and in many cases, irreplaceable items.

Besides collecting and maintaining these articles, our office embraces the broader role of history: to inform, explain, and educate, so that future decisions are made with the best available knowledge and science.

The collection includes deceptive and dangerous foods, medicines, and so-called medical products that the FDA helped remove from commerce and that led to important changes in laws and regulations.

For example, it includes:

  • a sample of Elixir Sulfanilamide, a 1937 wonder drug that was formulated with a poisonous solvent that killed more than 100 people, including many children. The 1937 disaster spurred passage of the Federal Food, Drug, and Cosmetic Act of 1938, the basic law under which the FDA still operates.
  • a can of Bon Vivant vichyssoise soup (contents removed) that sparked an outbreak of botulism in the early 1970s and significant new food protections for consumers
  • the Dalkon Shield intrauterine device, an ill-designed product that left thousands of women sterile during the 1970s, and encouraged Congress to craft legislation that specifically addressed the safety and efficacy of medical devices, and,
  • the Relaxicisor, a passive electric muscle stimulation “exercise” device first made famous during the 1950s, and again, more recently, thanks to the television show “Mad Men.”

Artifacts like these tell the story of the origins of many of our laws and regulations, the ways in which the FDA works to carry out its responsibilities to uphold them, and the interactions between the agency, its stakeholders, consumers, patients, and Congress in the interests of public health and product safety.

Other artifacts in our vault  illustrate how FDA’s essential tools, which once seemed pioneering in their time, are eventually superseded as FDA adopts new approaches in response to continuing advances in science and technology.

The first video released today harkens back to the time of the Bureau of Chemistry, the organization that preceded the FDA, when data on foods and drugs was analyzed using a novel early calculating device.

It’s worth noting that like other federal agencies, FDA also hired women to be human “computers,” an important role that was brought to greater attention in the recent movie “Hidden Figures,” which depicted three such women who worked at NASA. By the 1940’s and 1950’s, women at the FDA regularly used statistical methods to distinguish products with therapeutic merit from those “which merely had good copywriters.” Their work played an important role in the analysis of the earliest “cooperative” clinical drug trials. Of course, just like NASA, data analysis at FDA is now made possible by computers and supercomputers.

The series of videos we begin today are designed to be entertaining, informative, fun, as well as highlight some of the items in our collection securely stored in our White Oak facility. We plan to release them once a month, always on Thursday, as part of the popular social media tradition of “Throwback Thursday.” The goal is to educate and increase the understanding of the ways that the FDA has, for more than 100 years, embraced scientific advances to ensure the well-being of the American public.

We hope you enjoy your visit to “the FDA’s History Vault.”

Suzanne Junod, Ph.D., and John Swann, Ph.D., are FDA Historians.

FDA’s Commitment to Women’s Heart Health Research

By: Marsha B. Henderson, MCRP

FDA research has been especially important in helping FDA better understand cardiovascular diseases in women and the effects of drugs on women’s heart health.

Marsha HendersonKnowing that heart disease is the leading cause of death for women, our Office of Women’s Health (OWH) has been committed to using a significant portion of our limited funds to support cardiovascular research from the very beginning of our research program in 1995. We’ve accomplished that by working across several FDA Centers to support studies on issues ranging from sex differences in cardiac interventions to the cardiotoxicity of breast cancer drugs.

One of our earliest funded projects examined the connection between certain drugs and Torsade de Pointes (TdP) – a rare but dangerous heart arrhythmia that can lead to sudden death. Women are more likely than men to have this heart rhythm problem. FDA has been leading an effort to evaluate better ways to screen drugs for their potential to cause this rhythm problem. This is made possible in part because drugs that cause TdP almost always prolong the QT-interval on the electrocardiogram (ECG), which measures the heart’s electrical cycle.

On the heels of Heart Health Month, I wanted to highlight the history of FDA research on QT prolongation and demonstrate the ways ongoing collaborations across FDA research programs are helping to advance policies and projects to protect women’s heart health.

Early Years: Understanding the Sex Differences

The exact reason for the higher rate of drug-induced TdP in women is unknown. OWH funded studies to help FDA better understand the mechanism of the sex differences in drug-induced QT prolongation. OWH also funded research within the Center for Drug Evaluation and Research (CDER) enabling post-market drug analysis to better recognize drug safety effects in women.

Supporting the Development of FDA Guidance

FDA QT Story GraphicBuilding on the previous studies, OWH partially funded additional research on metabolic drug-drug interactions that contribute to QT prolongation. This research contributed to FDA guidance on the assessment of the QT prolongation potential of drugs for both men and women. As part of this guidance, FDA recommended that drug sponsors conduct a comprehensive study, called the Thorough-QT (TQT) study when seeking FDA approval of a new drug. The TQT study, implemented in 2005, has been an effective screening tool. Although certain commonly used drugs, such as antihistamines and antibiotics, had to be withdrawn from the US market because of drug-induced QT prolongation concerns, no such withdrawals have been necessary since 2005.

Moving Forward: Improving Prediction and Prevention

Although the current FDA guidelines are very useful for identifying QT prolonging drugs, not all QT prolonging drugs cause TdP. OWH is currently partnering with CDER to sponsor studies to better screen for the subset of QT-prolonging drugs that have lower or no risks for TdP. This new research has the potential to enhance drug development and safety for both women and men by improving the accuracy of the evaluation of a drug’s potential to cause heart rhythm problems, and by providing this information earlier in drug development.

Improving women’s heart health is an ongoing challenge. So, I encourage you to visit FDA’s website to learn about the research OWH is currently funding and other FDA research programs.

Marsha B. Henderson, MCRP, is FDA’s Assistant Commissioner for Women’s Health