Trust the Process: The Structured Variety of Novel Therapy Applications


The FDA has been granting priority review to more pipeline drugs without skimping on application standards. What makes up a viable novel therapy application, specialty by specialty?

Peter Chin, MD, joined Genentech’s multiple sclerosis (MS) research team in the mid-2000s, just in time for a major discovery.

Ocrelizumab, a B lymphocyte-targeting monoclonal antibody, was being investigated for both relapsing and progressive MS. By 2011, a robust clinical program was launched. By October 2015, results from a trio of phase 3 trials involving 1500-plus patients were presented at the European Committee for the Treatment and Research of Multiple Sclerosis (ECTRIMS).

On March 28, 2017, the US Food and Drug Administration (FDA) approved ocrelizumab as the first disease-modifying therapy for MS and the first of any drug indicated for primary progressive MS. Chin, now group medical director of Neuroscience at Genentech, told MD Magazine® that he immediately called academic investigators involved in their trials to thank them for believing in the work. They’d spent more than a decade pursuing clinical trials that challenged conventional wisdom—featuring thousands of patients, countless hours and huge costs—and with a regulatory nod, 6000 US patients had their first approved drug.

It was a historic achievement, and then it was over.

The news of ocrelizumab’s FDA approval as a novel therapy came and went as quickly as another 46 drugs did in 2017. That year, the FDA received 48% more applications for original priority new molecular entities (NMEs) and biologics license applications (BLAs)—the distinctions under which novel therapies are reviewed—than their annual average since 2012. Trends were changing; the FDA wanted more drugs to rule on.

As the FDA implements strategies to streamline the application process, the data procured from the most recently approved drugs show both distinct similarities and differences in what they consider a viable novel therapy.

Improved Lines, Improved Lives

In response to an inquiry on the rate of novel therapy submissions and approvals, representatives from the FDA said the recent increase in both rates is in part due to the agency’s efforts to provide more information on the submission process and their expectations as to what constitutes a market-worthy drug.

“An efficient and effective review process that allows for timely responses to FDA questions can help ensure timely patient access to safe, effective, and high quality new drugs and biologics,” the FDA stated.

According to the administration, this emphasis on improved communication between regulators and applicants can be traced to previous amendments to the Prescription Drug User Fee Act (PDUFA V), in which a new review model dubbed “the Program” was introduced and carried through the current PDUFA VI. “The Program provides opportunities for increased communication by building in mid-cycle communications and late-cycle meetings between FDA and applicants,” the FDA told MD Mag. It applies to all NME NDAs and original BLAs, and expedites the first cycle review process by increasing communication between the 2 parties prior to application submission.

This practice has also led to an immediate explosion of novel therapy applications qualifying for and being granted priority review. While in 2017, the number of applications filed under standard review (n = 100) was slightly less than the mean rate since 2008 (112.22), the number of applications filed under priority review (63) more than doubled (28.89).

Though long-term, real-world analysis is still years away from dictating whether this process positively or negatively affected the overall quality of FDA-approved therapies in these at-need patient populations, immediate data pertaining to the applications indicates it’s not too different from the old practice.

According to data collected from the FDA’s Drug Innovation page on its site, the average rate of clinical trials included in each approved novel therapy application in 2017 was very close to the average rate reported in 2015 (2.15 vs 2.27, respectively).

Though the mean rate of patients participating in each clinical trial included in the approved novel therapy applications varied across the same 2 years (1177 vs 2180, respectively), the difference could be explained by a single trial. On January 8, 2015, the FDA approved edoxaban for the reduction of stroke and systemic embolism risk in certain patients with atrial fibrillation. The approval was based on data from a lone trial involving 21,026 patients.

Big Trials, Bigger Implications

That’s not to suggest the FDA doesn’t have more influence on novel therapy application details; among other guidance factors such as the International Conference on Harmonization (ICH), FDA application expectations differ based on what indication the applicant is pursuing.Deepak L. Bhatt, MD, MPH, executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital Heart & Vascular Center and professor of medicine at Harvard Medical School, has seen firsthand how the FDA altered the future of cardiovascular care—almost inadvertently.

Bhatt served as co-principal investigator on the Savor TIMI-53 trial, in which oral dipeptidyl peptidase-4 (DPP-4) inhibitor saxaglipitin was compared versus placebo for the treatment of type 2 diabetes (T2D). The application for the eventually-approved novel therapy in 2008 was among the first to follow new FDA mandate that new diabetes drugs must be assessed for cardiovascular safety.

The saxaglipitin FDA application had included trials which assessed the drug’s safety and efficacy in more than 16,000 patients. Criticism targeting the FDA’s ruling on cardiovascular outcome assessments in these trials—which tolled on applicants’ resources with seemingly no payoff—was immediate and harsh, Bhatt told MD Mag.

“Some had criticized that it was a bad use of research and development dollars to just show a drug was no worse than placebo in cardiovascular outcomes,” Bhatt recalled. Even recent history shows a significant contrast in common clinical trial size and those assessing therapies indicated for diabetes and heart disease. Since 2015, the FDA has approved 21 novel therapies indicated for a cardiologic or endocrinologic condition. Of those, 14 (66.67%) were approved based on applications that included more than 1000 trial participants.

The massive safety outcome trials proved fruitful; new-age T2D therapies proved not only to be safe for cardiovascular events, but beneficial. Bhatt reflected how, in just a decade, a mandate shifted from causing headaches for researchers to inspiring new secondary or even primary indications.

“(The FDA) have completely revolutionized the field,” Bhatt said, “and stand poised to greatly improve the outcome of patients.” Once these novel therapies reach clinical guideline rulings, and then eventually become available as generic options, it will change the entire world of care for diabetes.

Reaching the Rare Markets

Most would agree that’s worth the extra trial or two.Some research teams don’t have the benefit of a five-figure patient pool. In fact, some would even vie for the 732 patients with PPMS included in part of the ocrelizumab pivotal trials. Since 2015, the FDA has accepted novel therapy applications for 43 drugs all supported by trial results involving fewer than 300 patients each. The most prominent specialties addressed by these drugs included oncology (16; 37.2%), endocrinology (8; 18.6%), infectious disease (4; 9.4%), neurology (4; 9.4%), and pediatrics/genetics (4; 9.4%).

The smallest patient population of trials involving these drugs belongs to uridine triacetate, which was approved in September 2015 for the treatment of patients with hereditary hematologic condition orotic aciduria. At the time, the FDA estimated the disease affected 20 people worldwide—explaining why the pivotal trial size included just 4 pediatric and adolescent patients. That’s not to discredit the significance of the therapy; the rare inherited disease inhibits the body from producing uridine, thereby stopping patients from properly gaining weight, maintaining blood cells, and eventually killing them. Orotic aciduria was proven in its small, singular trial to replace uridine counts.

Other novel therapies approved on a minimal population assessment have faced scrutiny for their trial sizes—regardless if it were indicated for a rare disease. New York University journalism professor and former Science magazine writer Charles Seife filed a lawsuit last May following the September 2016 approval of Serepta Therapeutic’s eteplirsen for the treatment of Duchenne muscular dystrophy (DMD). Seife’s lawsuit was in response to the delayed release of information he had filed a request for in reaction to the drug application’s questionable trial makeup.

According to the FDA, eteplirsen is indicated for patients with DMD who have confirmed mutation of the dystrophin gene amenable to exon 51 skipping—or about 13% of the population with the already rare disease. As such, its approval was based on the results of 3 clinical trials which tested its benefits in 12 patients compared to historical clinical data results, under the requirement that a more comprehensive clinical trial later confirm eteplirsen’s benefits.

Even John K. Jenkins, MD, former director of the Office of New Drugs Center for Drug Evaluation and Research at the FDA, expressed his dissatisfaction with the eteplirsen approval process while speaking at the 2016 National Organization for Rare Disorders Summit. He claimed Serepta’s regulatory path was not a good model for other development programs, and that—regardless of accelerated approval pathway practices—prospective clinical planning should be prioritized by both parties.

A full year before the implementation of the PDUFA V amendments, Jenkins also advocated for the engagement of patients, caregivers, and applicants in the regulatory process. Novel therapies granted priority review or accelerated pathways should expedite the pathway to patients—not the pathway to the FDA.

“Accelerated approval is not about faster review,” Jenkins stated in his presentation, “it is a regulatory pathway to speed availability of drugs for serious unmet need by using an appropriate, more readily measured, surrogate or intermediate clinical endpoint when a lengthy trial would be needed to measure direct clinical benefit of a drug.”

Keeping the Course

Ocrelizumab’s success was actually borne out of early failure. B lymphocyte-targeting therapies for MS had failed in human-stage trials as recently as 2006, Chin recalled. It was only an inkling of belief and a scouring of data that propelled his team into a massive trial program.

Even when they “confirmed to the world” at ECTRIMS that B lymphocytes aren’t just a driver of MS, but that ocrelizumab is capable of fighting both disease subtypes, Chin was trying to digest the discovery. The FDA’s approval was surreal for him. Recalling the moment he realized an entire patient population would have access to its first ever therapy gave him pause.

All he could tell MD Mag was that he would love to do it again—to make history.

The opportunities are there. There have been 36 novel therapies approved by the FDA in 2018, with indications spanning more than a dozen different specialties, and applications including trial populations ranging from 40 to 2500 patients. The FDA reiterated to MD Mag that, despite working with sponsors, organizations, and patient-centric groups to develop treatments in unmet areas, there’s no specific, tangible goal for how many novel therapies reach the market.

They just want them to be the right ones.

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