China Joins ICH in Pursuit of Global Harmonization of Drug Development Standards

By: Theresa M. Mullin, Ph.D.

Increasingly, drug development is a global endeavor. It requires international collaboration to ensure that consistent standards are adopted and adhered to by all drug makers and regulatory authorities, regardless of country of origin or destination.

Group photo from trip to China

FDA’s Theresa Mullin (center) and the FDA delegation engaging in a discussion on ICH and generic drugs with the faculty and students at Yeehong Business School/Shenyang Pharmaceutical University in Beijing China.

I am pleased to have been in China recently, when the China Food and Drug Administration (CFDA) submitted its membership application to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (also known as the International Council for Harmonisation or ICH). As part of a team of FDA officials whom CFDA invited to share regulatory advancements, we discussed how modernizing regulatory review systems can promote public health.

ICH, first created in 1990 by regulatory agencies and industry associations from the United States, Europe, and Japan, was established to facilitate international collaboration, and has been successful in standardizing and elevating drug development practices throughout the world. ICH’s mission helps to increase patient access to safe, effective, and high quality pharmaceuticals, and to ensure that pharmaceuticals are developed and registered efficiently.

As globalization has evolved, the ICH has kept pace and membership criteria are robust. Among those criteria new members must implement a basic set of regulatory requirements for the manufacture of pharmaceuticals, for the conduct of clinical trials, and for stability testing of pharmaceutical products. In fulfilling these and other criteria, CFDA joins the existing ICH Assembly, which includes eight regulatory authorities and six industry associations from across the globe.

Janet Mullin and CFDA Official

CFDA Minister Bi presents FDA’s Theresa Mullin a congratulatory letter for FDA Commissioner, Scott Gottlieb, personally handwritten with Chinese Calligraphy.

During our trip, we met with the head of CFDA, Minister Bi Jingquan, and some members of his senior leadership team. Our discussions revealed that CFDA faces many of the same challenges that our other ICH partners and we do. China needs to ensure that patients have access to innovative products, and that pharmaceuticals are safe and are held to a consistent quality standard. Minister Bi emphasized that CFDA has implemented reforms to align China’s regulations with global standards to address these public health concerns. CFDA has also reformed its drug review system, dedicated additional resources to carry out its important mission, and implemented ICH Guidelines.

International harmonization of regulatory standards means that pharmaceutical manufacturers and developers will be held to the same standards in different markets, which will make the development and delivery of quality pharmaceuticals to the public more timely and efficient. CFDA’s membership in ICH marks a significant milestone in expanding ICH’s impact and promoting global public health.

Officials from CFDA will visit FDA later this year to continue our conversation on regulatory modernization. FDA congratulates CFDA on their progress towards regulatory modernization and membership in ICH. Additionally, FDA welcomes their future contribution to global regulatory harmonization.

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

Why FDA Supports a Flexible Approach to Drug Development

By: Margaret A. Hamburg, M.D.

We all know that just as every person is different, so too is every disease and every drug.

Margaret Hamburg, M.D.And so we weren’t surprised by the results of a new study published in the Journal of the American Medical Association. The study found that FDA used a range of clinical trial evidence when approving 188 novel therapeutic drugs for 208 indications (uses) between 2005 and 2012. These results are entirely consistent with our regulatory mandate. We believe varying approaches to clinical studies to support drug approval is good news, not bad.

Data to support the approvals studied were based on a median of two pivotal trials per indication. A pivotal trial presents the most important data used by FDA to decide whether to approve a drug.

But when the authors looked more closely, they found that more than a third of these drugs were approved on the basis of a single pivotal clinical trial, while still other trials involved only small groups of patients for shorter durations. Of the approvals studied, the new drug was compared with existing drugs on the market only about 40 percent of the time.

The authors concluded that, based on these results, the ways in which FDA arrived at those approvals “vary widely in their thoroughness.” Or, in the words of one study author, “Not all FDA approvals are created equally.” Although I don’t think it was actually the author’s intent, a number of commentators framed this as criticism. But I would be more troubled if FDA used a rigid, “one size fits all” approach.

People with serious or life-threatening illnesses, particularly those who lack good alternatives, have told us repeatedly that they are willing to make some trade-offs in order to gain access.

And, of course, “thoroughness,” such as whether a clinical trial is large enough, is in the eyes of the beholder. There is no reason to expect drugs to be tested on similar numbers of patients, regardless of the disease.

Variation in approach to clinical studies demonstrates FDA’s innovative and flexible approach to drug development and approvals. Such an approach was specifically adopted by Congress in the Food and Drug Administration Modernization Act in 1997 and, most recently, in the Food and Drug Administration Safety and Innovation Act in 2012.

The FDA of today works with sponsors of new drugs to design a development and review pathway for each drug that best reflects the disease and patients it is intended to treat, the drug itself, and other treatment options. Some of the factors that enter into our calculus include whether the drug treats a rare or serious disease or addresses an unmet need and any previous knowledge we might have about the drug.

Thus, for example, FDA approved Imbruvica (ibrutinib), a treatment for mantle cell lymphoma, last year based on an “open-label, single-arm trial,” which means that every patient received the treatment and both patients and researchers knew they were receiving it. The results were compared to how well the 111 participating patients had responded to previous treatment for their disease.

And Elelyso (taliglucerase alfa) – for Gaucher disease – was an orphan drug approved in 2012 based on two trials with 56 patients.

In contrast, some trials require large numbers of patients to demonstrate a drug’s effects. This is often the case in studies in patients with a chronic condition such as cardiovascular disease, where larger populations are studied to capture treatment effects.

No matter what clinical trial design is chosen, the Agency always applies the same statutory approval standards of safety and efficacy to all drugs seeking to be marketed in the United States.

Increased flexibility does not mean abandoning standards, and it certainly does not mean abandoning science. Just the opposite. We need to employ the best science in ways that will increase efficiency, productivity and our shared ability to find creative solutions to the challenges that confront us.

At the end of the day, that is just smart regulation – ensuring that patients can more rapidly have access to the best that science has to offer.

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