Whenever the number of drug approvals drops, especially for rare diseases, the FDA points a finger at drugmakers, saying its approvals are limited by the applications it receives.

This week, 38 lawmakers – from both parties and chambers – pointed a finger back, reminding the agency that its pre-application guidance and communication with sponsors play a critical role in what flows from the pipeline.

The senators and House members made it clear in a letter to FDA Commissioner Margaret Hamburg that they expect agency reviewers to consistently use the flexibilities Congress has given them to guide orphan drugs through development and then review them expeditiously. Hamburg needs to make this a priority, the lawmakers said.

To ensure consistency, the FDA must clearly define “preliminary clinical evidence” and “surrogate endpoints” and see to it that all offices throughout the agency are familiar with using those standards in guiding sponsors and as the basis for drug approvals, according to the letter.

Consistent use of those concepts and predictable engagement on the standards to be followed would encourage sponsors to use expedited approval paths, spurring development of new drugs for rare diseases or unmet medical needs, the lawmakers said.

The letter noted that of the 27 novel drugs the FDA approved last year, only two received accelerated approval, which is based on one pivotal trial using surrogate endpoints or another measure predictive of a clinical benefit for serious or life-threatening illnesses. (See BioWorld Today, Jan. 17, 2014.)

The lawmakers also reminded Hamburg of a provision in the FDA Safety and Innovation Act that encourages agency reviewers to consult with external experts on rare diseases and subtypes of more common diseases. Such experts include patients, doctors and researchers.

The provision was intended to give FDA officials a “better understanding of the rapidly changing scientific landscape and ensure that they have the best, most complete information when making decisions about treatments under review,” the lawmakers said. “It is imperative that this guidance is implemented uniformly throughout the agency.”

The FDA has been criticized in the past for not looking to experts or including them on advisory committees. For instance, the Oncologic Drugs Advisory Committee (ODAC) that voted against the adequacy of Aveo Oncology Inc.’s single phase III trial to support the approval of tivozanib to treat advanced renal cell cancer (RCC) comprised biostatisticians, breast cancer specialists, hematologists, a pediatric oncologist and a prostate cancer specialist. (See BioWorld Today, May 3, 2013.)

Throughout the ODAC meeting last year, committee members and FDA staff declined to engage in a thoughtful discussion with the renal specialists in the room about how Aveo should proceed with the RCC indication.

They also paid little heed to the patients who were out of treatment options. Instead, an FDA official noted that since multiple drugs are available for RCC, the agency felt no urgency to approve another one based on a single, unblinded phase III trial that it considered flawed with inconclusive data.

It was not an isolated incident of ignoring the experts. The ODAC panel that rejected Amgen Inc.’s Xgeva (denosumab) for prostate cancer two years ago included no urologists. Instead, it was made up of members with backgrounds in breast cancer, hematology, lymphoma, gynecologic oncology, radiation oncology, general oncology and statistics. (See BioWorld Today, Feb. 7, 2012, and Feb. 9, 2012.)

In other instances, FDA reviewers have chided sponsors for using comparator drugs recommended by the experts in the field instead of more recently approved drugs. And reviewers’ opinions about surrogate endpoints and single-trial approvals sometimes color the debate at adcom meetings.

PTO GUIDANCE REFLECTS SCOTUS RULINGS

The Patent and Trademark Office (PTO) issued guidance this week advising its examiners how to apply two Supreme Court rulings in determining whether claims involving laws of nature, natural phenomena or natural products are patent eligible.

The guidance replaces a one-page memo the PTO released June 13, 2013 – the day the court held that naturally occurring, isolated DNA is not patent eligible. The guidance applies that decision in Association for Molecular Pathology v. Myriad Genetics Inc., as well as an earlier decision in Mayo Collaborative Services v. Prometheus Laboratories Inc., to all claims – be they machine, composition, manufacture or process claims. (See BioWorld Today, March 21, 2012, and June 14, 2013.)

In striking down Myriad’s isolated DNA claims to the BRCA1 and BRCA2 genes, the court said the Salt Lake City diagnostics company “found an important and useful gene, but groundbreaking, innovative or even brilliant discovery does not by itself satisfy the §101 inquiry” of the Patent Act, which renders laws of nature, natural phenomena and abstract ideas ineligible for patent protection. (See BioWorld Today, June 14, 2013.)

The new guidance reminds examiners that §101 is not the sole tool for determining patentability of claims involving laws of nature, natural phenomena or natural products, but such claims should be examined for a “marked difference” from what occurs in nature.

The guidance uses a decision tree in discussing how examiners are to analyze subject matter eligibility. It also provides multiple examples and a form to be used when rejecting claims in accordance with the guidance.

QBD PILOT EXTENDED

The FDA and the EMA agreed to a two-year extension to their joint pilot program for the parallel evaluation of quality-by-design (QbD) applications.

The program, which was launched three years ago, enables the two agencies to share knowledge, ensure consistent adherence to international QbD guidelines and approve drugs of consistent quality throughout the EU and the U.S.

Achievements under the program include joint research efforts, interagency agreement on a range of QbD topics and publication of two question-and-answer guidelines for industry and regulators. Additional QbD documents are expected to be published this year.

The QbD approach builds consistent drug quality into the design, development and manufacturing processes by using statistical, analytical and risk-management methodology.