SNOWMASS, COLO. — The Food and Drug Administration appears to be poised to redefine osteoarthritis progression as its required pivotal outcome measure in clinical trials aimed at earning approval for disease-modifying osteoarthritis drugs.

Since 1999, the FDA has defined osteoarthritis (OA) progression as evidence of joint-space narrowing on serial x-rays of the knee or hip. It's an antiquated and unreliable metric that has probably resulted in nonapproval of some therapies that truly are disease modifying, and it has caused pharmaceutical companies to steer clear of OA and focus their research and development efforts elsewhere, Dr. Joanne M. Jordan said at a symposium sponsored by the American College of Rheumatology.

A critical reappraisal of the definition of OA progression and how best to evaluate drugs, devices, and biologics for the prevention and treatment of OA is in the works. It's the culmination of a 2-year OARSI (Osteoarthritis Research Society International) initiative that was carried out in partnership with industry and patient organizations at the FDA's request. The massive report will be submitted to the FDA in the next few months, and then published as a series of papers in the journal Osteoarthritis and Cartilage, according to Dr. Jordan, chief of rheumatology, allergy, and immunology, and director of the Thurston Arthritis Research Center at the University of North Carolina, Chapel Hill.

“We think that we'll be able to convince the FDA, sooner rather than later, that maybe joint-space narrowing on x-ray is not the best way to decide if a treatment is disease modifying or not. What we're hoping to accomplish is to change hearts and minds—not to look at osteoarthritis just as the person who comes in with an end-stage knee, or even moderate radiographic osteoarthritis. Rather, we hope to be able to predict these developments at an earlier point in time with improved technologies such as MRI, functional MRI, and biomarkers. We want to be able to screen the high-risk phenotype and then to be able to intervene to avoid or delay osteoarthritis,” explained the rheumatologist, who chaired the OA prevention/risk reduction working group as part of the larger OARSI initiative.

Joint-space narrowing on x-ray is a poor pivotal measure of OA progression. It's a laborious, error-prone measurement with poor reproducibility. Changes may not be evident for at least 2 years. As a result, clinical trials have a high dropout rate and thus must be large and very expensive. Furthermore, joint-space narrowing on x-ray probably isn't even a good surrogate for OA progression. Originally, the FDA adopted it as its yardstick under the assumption that it reflects cartilage loss, which can't be seen directly on x-ray, but it's now clear from MRI studies that joint-space narrowing can also be caused by meniscal extrusion, Dr. Jordan continued.

“The point is to develop a measure that's valid and a good surrogate for downstream events, something that can be done more quickly and with fewer patients because it's a more accurate measurement. That's the big goal, and we're almost—but not quite—there. With the new technology, you could potentially show a disease-modifying effect much more quickly than 2 years, probably in less than 1 year,” she said.

MRI has the inside track as the replacement technology. Its use allows direct visualization of cartilage in 3-D; measurement of cartilage thickness, surface area, and volume; and assessment of cartilage composition, including key findings such as proteoglycan loss as evidenced by delayed gadolinium enhancement. For these purposes, 3.0-T machines are better than the more widely available 1.5-T MRI devices.

However, current thinking on OA breaks with the past in that saving the cartilage is no longer viewed as the be-all and end-all of therapeutic outcomes. There is enormous interest in targeting other tissues therapeutically, including osteophytes, subchondral bone, meniscal extrusion, bone-marrow edema, and inflamed synovium.

In the future, OA clinical trials will feature a more finely honed preselection of study participants in order to maximize the likelihood of positive results, Dr. Jordan predicted. Also coming will be the eagerly anticipated results of clinical trials of two promising potential disease-modifying OA agents: calcitonin and vitamin D.

The vitamin D study is a 2-year, double-blind, placebo-controlled, randomized trial involving 2,000 IU of vitamin D per day. It has two major outcomes: change in cartilage volume as assessed by MRI, and change in standardized pain scores. The study is just finishing up at Tufts–New England Medical Center, Boston.

The oral calcitonin trial is ongoing in the United States and Europe. This is an agent that has shown potential in earlier studies as both a structure- and symptom-modifying agent in OA, Dr. Jordan observed.

Disclosures: Dr. Jordan has served as a paid consultant to Novartis, Stryker Corp., and NicOx SA. She receives royalties from Algynomics Inc. and Interleukin Genetics Inc.

To watch a video interview of Dr. Jordan, go to www.familypracticenews.com

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The focus on joint-space narrowing has probably resulted in nonapproval of disease-modifying therapies.

Source DR. JORDAN

New Osteoarthritis Measures May Encourage New Therapies