FDA Tackles Device Uncertainty in Clinical Trials

September 10, 2018

The FDA may accept some uncertainty about the safety of a proposed medical device if sponsors carefully collect and report data after it hits the market, the agency says in new draft guidance.

The 21st Century Cures Act requires the FDA to fast-track approval for “breakthrough devices” — innovative gadgets that offer more effective treatment or diagnoses for life-threatening or debilitating diseases than apparent rivals or that don’t have any approved competitors so speeding them to market would be “in the best interest of patients.”

But fast-tracking breakthrough devices — or devices that target extremely rare diseases — may mean that regulators have to accept some unanswered safety questions.

Last week’s 22-page draft guidance is the FDA’s attempt to come to grips with that uncertainty.

“The aim,” Commissioner Scott Gottlieb said in a speech announcing release of the proposed guidelines, “is to support premarket decisions that are based on the totality of scientific evidence available at the time of a device’s market entry.”

Though couched in careful language, the draft suggests that regulators might be willing to exchange unanswered pre-approval questions for post-approval answers.

That means, for example, sponsors should expect strict post-market safety reporting deadlines based on real-world data. They may also have to agree to careful label­ing outlining pending safety questions and to post-market review by an FDA advisory council, which could result in hav­ing marketing approval limited or yanked.

The new measure builds on final guidance the agency issued in 2016, laying out ways regulators would analyze the risk of new drugs and devices. That final guidance focused mostly on the potential harms caused by a proposed device; the new draft suggests that regulators might be willing to accept some uncertainty if sponsors can show “probable” patient benefits from early access to the device and if:

  • A disease or disorder is so rare that gathering clinical data isn’t feasible;
  • Bringing a device to market would allow sponsors and regulators to gather safety data; and
  • Post-market remedies, such as warning labels, would likely to mitigate any harm.

Read the draft guidance here:

Final Guidance, PBPK Analyses
The FDA last week released final guidance for drug sponsors on the content and formatting of physiologically-based pharmacokinetic (PBPK) analyses, including an expanded section on formatting and a simplified section on software.

The agency said any analysis should explain how the PBPK modeling and simulation address clinical, scientific and regulatory questions, adding that the “basis for any requests to waive the conduct of clinical studies should be discussed and well substantiated.”

If simulations are used to support specific dosing recommendations tested in future clinical trials or incorporated into prescription drug labeling, the proposed doses should be “discussed and justified within the totality of evidence, including the context of known exposure-response relationships and the level of confidence in the PBPK model for its intended uses,” the guidance states.

Sponsors should include the dosing regimen in their description of simulation conditions and, when applicable, the numerical methods used to solve differential equations.

When sponsors use library drug and system models within a specific software platform, they need to justify their use and also “identify and justify modifications made to the library models,” the agency said.

Read the final guidance here:

CRISPR, Vertex Launch Trial
A pair of Massachusetts biotech firms has begun recruiting for a clinical trial testing gene-editing techniques on patients who have a rare blood disease.

CRISPR Therapeutics and Vertex Pharmaceuticals last week began enrolling patients suffering from beta thalassemia, a disorder that cuts the number of oxygen-carrying red blood cells and can cause fatigue and even fatal anemia.

The Phase I/II trial hopes to recruit 30 patients to determine whether the CRISPR treatment CTX001 will reduce the amount of blood transfusions they need for at least six months.

The trial is scheduled to run through May 2022.

Trial Access for a Price?
A new U.S. startup, backed by funds from a Hong Kong billionaire, is charging cancer patients for the chance to link up to worldwide treatments and clinical trials.

The company, dubbed Driver, officially launched last week. It charges patients an initial entry fee of $3,000 and then $20 a month for access to about three dozen hospitals, clinics, research sites and other institutions in three countries. The monthly fee covers follow-up service during which Driver promises to monitor patients’ health and offer suggestions on further care.

The way it works: patients turn over their medical records to the company — and can even send tumor samples to Driver’s labs for analysis.

It offers access to 30 health centers in the U.S., four in mainland China and one in Singapore.

FDA OKs Hemophilia A Treatment
The FDA has approved Bayer’s Jivi as a preventive treatment for hemophilia A.

Jivi, the brand name for the treatment BAY94-9027, spent two years in a Phase II/III clinical trial, during which the IV treatment successfully stopped bleeding in patients for an average of nearly two years.

The trial enrolled 141 patients between 2012 and 2014 and split them into two groups: one that received the treatment as needed to stanch bleeding and the other given an infusion of the med as a preventive. In 2014, researchers reported that Jivi seemed effective as an on-demand response to bleeding, resolving 91 percent of severe bleedings with one or two treatments.

Now the trial results have shown it can help ward off bleeding, too.

Hemophilia A is a genetic disorder in which patients lack a protein that helps blood clot. It’s much more prevalent in boys than girls, occurring in about one in every 5,000 males born, according to the National Hemophilia Foundation.

New HIV Drugs Approved
Merck has won FDA approval for two oral drugs designed to treat the most common strain of HIV.

Delstrigo is a once-a-day tablet that contains three different anti-retrovirals. The agency approved the drug with a black box warning because of concerns that it may aggravate hepatitis B infections.

Pifeltro is also an oral medicine that’s designed to be taken along with other anti-retrovirals. In Delstrigo’s trial, researchers recruited 728 HIV-positive patients who had never taken anti-retrovirals and randomly gave them either Delstrigo or another combination therapy daily. At 48 weeks, Delstrigo had suppressed viral loads in 84 percent of the patients, compared to 81 percent of patients taking the other drug combo.

For the Pifeltro trial, researchers recruited another 766 HIV-positive patients who had never taken any other anti-retroviral. They, too, were randomly given daily doses of Pifeltro or another anti-retroviral. After 48 weeks, nearly 84 percent of Pifeltro patients were testing negative for HIV, compared to about 80 percent of participants taking the other treatment.

More than 70 million people worldwide have been infected with HIV and some 35 million have died since the AIDS epidemic began, according to WHO.