FDA: For Oncologic Medications US Beats Europe on Approval Time

Cancer is arguably the most feared disease, or set of diseases, facing humanity. The symptoms of cancer can be severe and debilitating, and a cancer diagnosis is often perceived as a death sentence. Although there are some risk factors that predispose people for particular cancers, cancer can strike anyone at any time. Given that the lifetime risk of developing cancer is 30–50 percent, even those without cancer probably have close friends or relatives who have battled or succumbed to the disease. 

While many cancers can be cured surgically, and some can be cured with radiation and chemotherapy, there is no curative therapy for most metastatic cancers—that is, a cancer that starts in one part of the body and spreads to another—and often not even a therapy that extends the patient’s life. 

This unmet medical need has made cancer a focus of the public’s evaluation of the process and regulation of drug development governed by the Food and Drug Administration (FDA). The media frequently use images of dying cancer patients desperately waiting for FDA-approved therapies to invoke public ire at the time-consuming nature of this process, and particularly how long the FDA review takes. 

Over the past several months, numerous reports and stories have criticized the FDA for being inefficient in its approval process for medical devices compared to its European counterpart, the European Medicines Agency (EMA). This criticism is especially common in the field of oncology, where severely ill patients have few therapeutic options. Critics often argue that given the advances in basic science, America should be able to develop new oncology drugs more quickly than we do. 

One reason critics believe that FDA is too slow, is that we have a regulatory environment that is not sufficiently equipped with the resources and scientific foundation needed to evaluate new approaches to cancer treatment.  Others have claimed that FDA has become so risk-averse and that it is increasingly difficult to obtain approval for effective drugs in the United States. 

However, a recent article published in Health Affairs showed that contrary to repeated public assertions, new oncology medicines are consistently available in the United States before they are in Europe, and they are more likely to be approved by the FDA than by the EMA. The study also found that the median time for approval of new oncology medicines in the United States was just six months. 

Ellen Sigal, who chairs and founded Friends of Cancer Research noted that,“to patients battling cancer, with no treatment options, access to new medicines five-and-a-half months sooner is a very important and potentially life-saving difference.” 

FDA Commissioner Margaret Hamburg, in a statement, said the findings “reflect FDA’s commitment to foster access to effective therapies in a responsive and timely manner.”

Dr. Janet Woodcock, the FDA’s top drug official, said the agency was “not in a race with other regulatory agencies.” However, she recognized that the cancer drug findings could help dispel an “urban myth” that the United States was routinely falling behind Europe on approval decisions.  She asserted that, “FDA review of cancer drugs is efficient. It’s rapid. The real problems are in the scientific development programs and scientific uncertainty” about how to attack cancer.”

Study 

The authors of the study conducted a direct drug-to-drug comparison of the two regulatory agencies’ approvals of 35 new oncology drugs between 2003 and 2010. The EMA cleared three medicines the FDA did not approve and the FDA gave a green light to nine drugs that did not reach the European market. The researchers did not analyze the reasons for the conflicting decisions. Only three of the thirty-two approved by FDA took more than a year to receive approval. 

Findings 

The authors explained two reasons for the difference in the timing of approvals. First, they found that pharmaceutical companies typically submit their clinical findings to the FDA prior to submitting them to the EMA. Second, they found that the FDA consistently took less time than the EMA to review a new oncology medicine. 

The authors found that contrary to public assertions, the median time for approval for new cancer medicines in the U.S. was just six months—and that these new anticancer medicines are typically available in the U.S. before they are in Europe. Specifically: 

• 23 cancer medicines over the seven year period hit the U.S. market first
• Reviews in Europe took about 5.5 months longer, with the median review time being nearly a year, at 350 days. 

The authors noted that their results are consistent with other studies that indicate that the lack of new oncology medicines is due not to slow review processes, but rather to difficulties in carrying out clinical trials in the field of oncology. 

Discussion 

The authors noted that their study looked at only initial approvals and not supplemental applications, and therefore their analysis did not include prominent secondary uses for drugs already on the market. While supplemental approvals for secondary uses constitute a sizable proportion of oncology drug approvals and are a major route of advancing cancer care, once drugs gain initial approval, they can also be used for off-label indications, as is commonly the case in oncology.  In fact, the National Comprehensive Cancer Network, an alliance of twenty-one leading cancer centers in the United States, estimated in 2004 that 50–75 percent of all prescriptions for cancer therapieswere off-label. 

Because it is not feasible to test every new drug against multiple cancers, particularly rare tumors, Medicare is required to cover off-label cancer therapies that are recommended in approved drug compendiums. As a result, the authors concluded that although the rate at which critical new uses are added to labeling is important and will be a focus of future study, the initial approval of new drugs and biologics in the field of oncology serves as a critical market entry point. 

Consequently, the authors asserted that the rapid approval of oncology drugs is not accidental, nor is it surprising because the FDA has long sought to conduct more rapid reviews of drugs with greater therapeutic potential, particularly anticancer drugs.

Oncology drug development is distinctive in that anticancer drugs and biologics are much more likely than drugs in other therapeutic areas to be given priority review ratings or to take advantage of accelerated review mechanisms.

For example, Joseph DiMasi and Henry Grabowski found that in the period 1990–2005, 71 percent of oncology drugs received a priority review designation, and 47 percent received accelerated approval, compared to 40 percent and 13 percent, respectively, for all other drug classes.

A priority review designation is intended for drugs that are expected to offer major advances in treatment or to provide a treatment for a condition that has no adequate therapy. This designation reduces the expected FDA review time for a drug: The goal for completing a priority review is only six months, as opposed to the ten-month goal for a standard review.

Accelerated approval allows the FDA to approve a drug based not on clinical benefits but on surrogate endpoints considered likely to predict those benefits—for example, tumor shrinkage may be considered likely to predict longer survival. The hope is that these advantages will offset the inherent difficulties of conducting clinical trials in oncology, such as the slow acquisition of patients for trials and the particularly long time needed to establish a drug’s efficacy

The authors noted that over the past two decades, the pace at which the FDA reviews drugs has improved considerably, and review times have been shortened, in large part because of the Prescription Drug User Fee Act (PDUFA) of 1992. The law was intended to address a major backlog in new drug applications at the FDA. It gave the agency authority to collect fees from companies that produce certain drugs and biological products, both when the companies submit an application to have a new product approved, and for each drug that they have on the market.

This money is added to the budget that Congress appropriates for the FDA; in exchange, the FDA accepts overall performance goals, which emphasize review timeliness as well as other measures.This set of policy initiatives, as well as the establishment of programs such as accelerated approval, has helped alleviate concerns that potentially life-saving therapies were encountering unnecessary delays in the review process, which prevented patients from taking advantage of them.

Subsequent reauthorizations of PDUFA, which occur every five years, have given the FDA new authorities and increased the user fees to meet other needs of the agency. Some however believe that FDA still needs more resources to address the rapid advances and changes in science and technology.

For example, FDA must transform their drug data into a harmonized format and organize it into a common database so that it can be queried by topic and analyzed to address key questions. This, in turn, will require investments in informatics hardware and software and the development of standardized data models for relational databases and scientific computing. With such a common platform in place, scientists could take advantage of existing historical data as well as new data to make better decisions in the context of regulatory review and oversight.

The authors also discussed how FDA and the EMA have undertaken several initiatives to coordinate their activities, with the goal of speeding the development and entry onto the market of safe, effective new drugs. For example, they have created a program to provide joint scientific advice to pharmaceutical companies. With the help of these initiatives, manufacturers of oncology products are often able to use the same clinical trials to support approval in both the United States and the European Union.

Conclusion

In the end, the authors asserted that their research makes clear that the FDA should be congratulated for its swift review of new oncology medicines. Additionally, they noted that new ideas should be considered to ensure that basic science in the lab and regulatory science continue to advance for the good of patients. This includes permitting adaptive clinical trials, which would allow modifications to be made to an ongoing clinical trial, or a regulatory pathway that would allow for simultaneous development of drugs and diagnostics.

Ultimately, America is in a new era of scientific discovery with the strong potential to lead to new anticancer medicines with greater efficacy and reduced toxicity, allowing patients to live longer and healthier lives.  To ensure that patients continue to benefit from industry breakthroughs, FDA must continue to have strong financial and public support, in the form of user fees and increased appropriations, so that the agency can keep pace with current scientific discovery and so that medicines can continue to be made available speedily to patients in need.