China’s Pharmaceutical Future – Both Complex and Growing

By: Howard Sklamberg, Richard Moscicki, M.D., and Alonza Cruse

中文(Simplified Chinese)

A visit to any one of the cities we visited on this trip – Shanghai, Nanjing and Beijing – would leave anyone marveling at the scale and trajectory of modern China. But it’s not just the sheer size of the population we were struck by. Rather, it was the seemingly tireless dedication to modernity that provided an almost palpable affirmation of what we already knew: that China — its skylines dotted with construction cranes and landscapes crisscrossed by high speed bullet trains — is inextricably connected with our own country’s economy, and increasingly with our agency’s ever-expanding regulatory mission.

Howard Sklamberg

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

We traveled to China for a few reasons. First, we wanted to gain more on-the-ground insight into how its drug industry works. We also wanted to offer some helpful perspective to Chinese regulators and drug companies about the Food and Drug Administration Safety and Innovation Act (FDASIA), which passed three years ago and is in the process of being fully implemented. In part, the law gave the FDA new authorities to ensure the safety of the global drug supply chain, in which China plays an enormous part. How enormous? After the United States, China ranks second for the number of FDA-registered drug establishments that the agency regulates, and is the sixth largest provider of drugs and biologics to the U.S.

Our itinerary also included a meeting with the Chinese Food and Drug Administration (CFDA) and a tour of a Chinese pharmaceutical manufacturing plant. And if you asked us what the most important by-product of our trip has been, it was these face-to-face conversations with our Chinese counterparts.

Specifically, we discussed the responsibilities of firms in the global drug supply chain. These days, the drugs we have in our medicine chests may seemingly come from one company, but the ingredients in them may actually come from numerous companies and countries. China is a major provider of many of the active ingredients in finished drug products Americans rely on every day.

Dr. Richard Moscicki

Richard Moscicki, M.D., FDA’s Deputy Director, Center for Drug Evaluation and Research

We had productive discussions with the Chinese about how seriously we are committed to making sure that everyone in the drug supply chain – from the companies that make the active ingredients to those that provide the packaging –shares in this collective commitment to quality. As we did when we spoke with our counterparts in India, we stressed that we apply the same quality and data integrity standards to all countries shipping drug ingredients into the United States.

We delivered the same message to a huge crowd of students at an event hosted by China’s Pharmaceutical University in Nanjing. In our remarks, we set forth our expectations for the delivery of drug quality, saying: “…ideally, our approach will complement the baseline, legal requirement of compliance with the higher bar of firms’ self-interest in being recognized for providing quality products and engaging in a different way with FDA.

While in Nanjing, we had productive discussions with students and stakeholders about FDASIA, quality in contract manufacturing, inspections, regulatory science, and expedited approval pathways that FDA is using to accelerate the process for making novel drugs available to patients.

Additionally, we toured a Chinese pharmaceutical facility and met with CFDA to discuss the revision of China’s Drug Administration Law, our own FDASIA implementation, regulatory science matters, as well as continued collaborative activities. We also had a productive roundtable discussion with leaders from 17 prominent Chinese pharmaceutical companies. We addressed pharmaceutical quality, data integrity, and the approval process for generic and innovator drugs.

Alonza Cruse

Alonza Cruse, FDA’s Acting Director, Pharmaceutical Quality Program, Office of Regulatory Affairs

As China’s role on the global stage expands, FDA has significantly increased drug and medical device inspections there, but we need to continue to strengthen our efforts. The Office of Regulatory Affairs and our China office have managed a large number of pharmaceutical inspections. The FDA’s office in China has also strengthened relationships with regulators and helped expand the country’s expertise in regulatory operations. And we have worked with industry and academia to explain our regulations and analyze trends and events that might affect the safety of FDA-regulated products exported from China to the U.S.

Given the volume of U.S. trade with China, we are working to expand our presence there to significantly increase the number of inspections we conduct. Staffing increases will allow FDA to enhance its training efforts and technical collaboration with Chinese regulators, industry and others. In fact, in November 2014, we signed a Memorandum of Understanding with the Chinese government that expands our cooperation and will facilitate those staffing increases.

FDA’s priorities in China match its global priorities: we work to ensure the safety and efficacy of FDA-regulated products. China’s size and relentlessly expanding economy have an increasingly significant impact on the products that Americans consume, particularly pharmaceuticals.

We trust our trip to China added to the growing collaboration between FDA and our counterpart agencies there, ensuring the safety of the pharmaceutical products exchanged between our two nations.

Howard Sklamberg is FDA’s Deputy Commissioner, Global Regulatory Operations and Policy
Richard Moscicki, M.D., is FDA’s Deputy Director, Center for Drug Evaluation and Research
Alonza Cruse is FDA’s Acting Director, Pharmaceutical Quality Program, Office of Regulatory Affairs

Strong Review Performance Brings Innovative Medical Products to Patients

By: Margaret A. Hamburg, M.D.

There are many ways FDA supports biomedical innovation as part of our mission to protect and promote public health. We are committed to finding ways to ensure that safe and effective products can get to the people who need them as swiftly as possible. With that in mind, we were pleased with new data in two reports, one looking at FDA’s review performance for prescription drugs, the other for medical devices.

Margaret Hamburg, M.D.A study by the London-based Centre for Innovation in Regulatory Science (CIRS) looked at trends in the number of drug approvals and approval times by FDA and our regulatory counterparts in Europe and Japan for new active substances (NASs). These are similar to what FDA refers to as New Molecular Entities (NMEs). As the study authors said, approvals are often a measure of the pharmaceutical industry’s output and are, along with approval times, used as markers of the regulatory environment.

The study found very little difference between the agencies in approvals of new drugs in 2013: FDA approved 29, Japan approved 28, and Europe approved 30. According to the report, Europe experienced a significant increase in approvals compared to 2012, in part because it was “catching up” on a number of compounds that had been approved by FDA in previous years.

But where the agencies really differed was in drug approval times. FDA’s median approval time in 2013 was 304 days. In Japan it was 342 days, and in Europe it was 478 days. You can read more about our 2013 NME approvals in FDA’s Novel New Drugs Summary, which we blogged about in January 2014.

And it turns out that FDA was consistently faster than its regulatory counterparts over the time frame 2004-2013. In this period, the overall median approval time for new drugs in the United States was 304 days, compared to 459 days in Europe, and 487 days in Japan. Moreover, of the 21 new drugs approved by all three agencies during the latter part of that period – from 2009-2013 – 76% of those drugs were approved first by FDA.

Regulatory systems vary, and making these direct comparisons can be a challenge. Indeed, the CIRS report doesn’t discuss why FDA’s review times are faster than those of our regulatory counterparts. However, our review times certainly benefit from our innovative and flexible approach to drug development and approvals that includes such mechanisms as priority review, fast track designation, and accelerated approval. In the 2004-2013 timeframe, for example, the study pointed out that 44% of the NMEs received priority review from FDA, meaning that FDA’s goal is to take action on the submission within six months rather than 10 months under standard review.

And FDA’s accelerated approval pathway has helped bring innovative drugs to market for patients suffering from serious or life-threatening illness but who have limited treatment options. Such drugs include Sirturo (bedaquiline), to help patients with multi-drug resistant tuberculosis, and Ferriprox (deferiprone), to help patients with thalassemia (a genetic disorder causing anemia) to avoid iron overload from blood transfusions.

Our most recent approach to expedited drug review and approvals, the breakthrough therapy designation, went into effect in July 2012 with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA) – so it isn’t well captured during the timeframe for this particular study. But the breakthrough designation is already helping to ensure that products that treat unmet needs get to patients as quickly as possible. Since July 2012, FDA has received 178 breakthrough designation submissions, granted 44 designations and already approved six of the designated drugs. Just last week we approved a late-stage lung cancer drug under the breakthrough designation – four months ahead of its goal date, using evidence from a trial with 163 patients.

I’m also happy to report new data for medical devices showing that FDA is on track towards meeting the review performance goals that were agreed to with industry and approved by Congress – under the Medical Device User Fee Amendments (MDUFA) of 2012, also part of FDASIA.

FDA committed to posting a quarterly performance report under the medical device user fee program. The latest report, issued in the last few days, covers performance reported through March 31, 2014. Review times, as measured in average total days for 510(k) submissions, have continued to decline since last year. With nearly all of the fiscal year (FY) 2012 submissions now closed, average review times have dropped from a high of 154 total days for submissions received in FY 2010 to 144 total days for FY 2012.   

FDA’s review times for higher risk devices that must go through the premarket approval (PMA) process are showing similar improvements. The same report we recently issued, for example, demonstrates the average time to decision for a PMA has been dropping, from a high of 464 days in FY 2009.

While we continue our efforts to reduce the time for the premarket review of medical devices, we’re also focused on reducing the time associated with product development. A few weeks ago we proposed a new program aimed at providing earlier access to certain medical devices that are intended to treat or diagnose patients with unmet needs for life threatening or irreversibly debilitating diseases or conditions.

The Expedited Access Premarket Approval Application for Unmet Medical Needs for Life Threatening or Irreversibly Debilitating Diseases or Conditions (“Expedited Access PMA” or “EAP”) program features earlier and more interactive engagement with FDA staff. This includes the involvement of senior management and a collaboratively developed plan for collecting the scientific and clinical data to support approval. These features, taken together, should provide patients with earlier access to safe and effective medical devices.

In addition to the Expedited Access PMA Program, the FDA published a separate draft guidance that outlines the agency’s current policy on when data otherwise collected prior to approval can be collected after product approval. To ensure that a device is safe and effective and to provide timely patient access to important devices, it’s critical to get the right balance between pre-market and post-market data collection.

While FDA is always striving to improve in the area of medical product review performance, I’m pleased to be able to report on the progress we’re making. The FDA of the 21st Century, through the creation of new pathways, designations and programs for drug products and medical devices, is actively encouraging innovation and speeding the availability of promising medical products to patients who need them.

Margaret A. Hamburg, M.D., is Commissioner of the Food and Drug Administration

FDA takes step to encourage pediatric drug studies

By: Lynne Yao, M.D. 

We all know that children are not just small adults. Many changes occur in children as they grow and develop that can affect how a drug works. In fact, some drugs that work in adults may not work at all in children. There may be different safety concerns compared to when they are used by adults, or they may need to be given in a different dose. That’s why products that are used in children must be studied in children. 

Congress enacted two laws that will increase the study of drugs in children: The Best Pharmaceuticals for Children Act (BPCA) provides an incentive for drug companies to conduct FDA-requested pediatric studies by granting an additional six months of marketing exclusivity. The Pediatric Research Equity Act (PREA) requires drug companies to study their products in children under certain circumstances. When pediatric studies are required, they must be conducted with the same drug and for the same use for which they were approved in adults. 

Before BPCA and PREA became law, more than 80% of the drugs approved for adult use were being used in children, even though the safety and effectiveness had not been established in children. Today that number has been reduced to about 50%. 

Under PREA, FDA can waive studies in children if the studies are not necessary. For example, if the disease for which the drug is being used in adults does not exist in children, such as prostate cancer, FDA would waive studies for children. In some cases, FDA has allowed sponsors to defer pediatric studies, depending on the circumstances. However, deadlines for deferred studies have often been missed. 

Fortunately, FDA now has tools to discourage companies from missing deadlines for deferred pediatric studies. When Congress reauthorized PREA last year as part of the Food and Drug Administration Safety and Innovation Act, or FDASIA, it gave FDA new authorities. FDA can grant extensions for deferred pediatric studies at a sponsor’s request if there is good cause for a delay in completing the studies. For example, if the sponsor has diligently attempted to recruit patients, but is having difficulty recruiting enough pediatric patients to complete the study, FDA can grant a deferral extension. However, if a sponsor has failed to seek or obtain a deferral extension, has failed to submit deferred pediatric studies by the final due date agreed to with FDA, or has failed to request approval for a required pediatric formulation, FDA can send a non-compliance letter to the sponsor and publish the letters on the web. 

This week, FDA is publishing the first of these non-compliance letters and the sponsors’ responses. They will be posted to a public FDA web page on an ongoing basis. We believe this important step demonstrates our ongoing commitment to getting these studies done for the benefit of all infants and children. 

Lynne Yao, M.D., is Associate Director, Pediatric and Maternal Health Staff, in FDA’s Center for Drug Evaluation and Research’s Office of New Drugs