Is the FDA Biased Against Ortho Device PMAs?

A six year old study of FDA approval patterns has evidence that the FDA takes, on average, more than a year longer to review orthopedic or spine devices, more than two years longer to grant approvals and, finally, requires 171% higher rates of patient enrollment than an average of all other specialties—including oncology, cardiovascular and other, more typically morbid specialties.

These differences are not trivial. They represent how much longer orthopedic patients wait for innovative orthopedic and spine therapies. In every case reviewed by this study, the orthopedic implants were available outside the U.S. during the FDA review period.

Furthermore, the extra years tacked on by the FDA represent significant costs to ortho implant manufacturers and have, perhaps, the unintended consequence of pushing the vast majority of ortho innovation toward the 510(k) route and reducing the number of startup technology firms that can afford to bring ortho and spine innovations to patients.

The following table details the differences between orthopedic/spine FDA submissions and those for all specialties (cardiovascular, oncology, diabetes, audiology, pulmonary, ophthalmology, cranial aneurisms).

The study, “Characteristics of Pivotal Trials and RDA Review of Innovative Devices”, authors Joshua P. Rising and Ben Moscovitch, both with the Pew Charitable Trust in Washington, DC, was published online in PLOS on February 4, 2015 and is available at this web address:  https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0117235

Purpose, Methodology and Results

The authors decided to collect data regarding the FDA’s time to approval for medical devices in general for the period 2006—2013 in order to better understand how the FDA’s priority review program might shorten approval times. In effect, the authors were hoping to set a baseline data set with which to evaluate the FDA’s initiative (in 2015) to safely speed up pre-market approval (PMA) times.

The authors also drew a contrast between the U.S. approval system (which is based on establishing each devices level of safety and efficacy which, in effect, serves to establish a baseline p-value for physicians using these novel devices) and the European Union (EU) notified body system—which does not seek to establish a statistically significant efficacy assessment.

The authors focused on approved devices with priority review status. They used the FDA’s PMA database and the online Summary of Safety and Effectiveness Data (SSED), as supplemented by documents from the FDA advisory committee meetings and the National Institutes of Health clinical trial database for their study.

The authors reviewed 27 device applications and calculated mean duration of pivotal trials, mean length for FDA review time, mean duration of primary measure evaluation follow-up, mean enrollment and whether the device was or was not available outside the U.S. during the approval period.

The author’s bottom line was, in effect, that the FDA takes too long, and that the EU’s system has several advantages over the U.S. approach.

In their own words: “The overall length of pivotal trials is substantially longer than the time needed for evaluating primary outcomes. FDA, manufacturers, researchers, and other federal agencies—including the National Institutes of Health—should work together to develop solutions to reduce the discrepancy between primary outcome completion and overall trial length. FDA’s new policy also has the potential to reduce the time that US patients and their physicians must wait for innovative treatment options, which are often already available abroad. Clinicians require these novel medical devices to save and improve patient lives, so long as the products are safe and effective.”

But Why Is Ortho Treated Differently?

We cherry picked the following three examples of head scratching differences.

• Edward Sapien Transcatheter Valve (2011)
  • Purpose: Heart valve for patients with a high mortality risk
  • FDA Time and Enrollment: 1,328 days (vs 2,750 for ortho) from the start of the pivotal trial to approval. Total study enrollment: 1,057 patients (vs 1,134 for ortho).
• Zenith Fenestrated AAA Endovascular Graft (2012)
  • Purpose: Open surgery treatment for patients with abdominal aortic aneurysms.
  • FDA Time and Enrollment: 2,650 days (vs 2,750 for ortho) from the start of the pivotal trial to approval. Total study enrollment: 42 patients (vs 1,134 for ortho).
• Novocure LTD’s Novo TTF-110A Treatment Kit (2011)
  • Purpose: Treat patients with histologically confirmed glioblastoma multiforme.
  • FDA Time and Enrollment: 1,753 days (vs 2,750 for ortho) from the start of the pivotal trial to approval. Today study enrollment: 237 (vs 1,134 for ortho).

For sure, these are apple and orange comparisons, but shouldn’t the oranges (ortho in this case) be simpler, faster trials than the ones where device failure and patient morbidity rates are much higher?

Why?

We contacted Captain Raquel Peat, Ph.D., M.P.H., Director of the Orthopedic Device office within the FDA’s Office of Product Evaluation and Quality for the agency’s reaction to the apparent different treatment of orthopaedic device approvals. She kicked our question over to the Public Relations department and they’re trying to track down an answer.

While we’re waiting, here’s one hypothetical possibility.

All that fatigue testing.

In 1990, Congress passed the Safe Medical Devices Act (SMDA) which, when it was signed into law, required medical device users (i.e., hospitals and clinics) to report device failures which resulted in either death or severe injury.

The FDA asked device manufacturers to conduct device fatigue testing and include that data as part of their PMA submissions.

The purpose being to ensure that the device would not fail structurally. Over the years, ATSM International has documented standards for device fatigue testing. Hip stem fatigue testing (monolithic and modular) is 10 million cycles.

10 million cycles is supposed to represent ten years of in vivo wear.

1 million cycles per year is, if you’re scoring at home, 2,700 steps per day.

It is also worth noting that the two-year follow up custom (is it a rule?), is not specified in any actual regulations.

One long-time researcher in spine commented to us that cervical disc studies (excluding revision surgery studies) had strong evidence that six-month patient outcomes held up out to ten years. Again, why two years follow up?

Perhaps it is time to re-examine the logic behind these unwritten rules and stop making orthopedic companies and orthopedic and spine patients wait longer and pay more to get innovative treatments.

This coming September 17 (2021), the FDA is putting on a workshop on clinical study design for spinal devices. It is virtual and open to anyone.

Here is a URL link to register:     (https://www.fda.gov/medical-devices/workshops-conferences-medical-devices/virtual-public-workshop-spinal-device-clinical-review-09172021-09172021)

Stay tuned, for sure.