510(k) Guidance Shifts Away Substantial Equivalence in Favor of Performance Testing and Criteria

510(k) Guidance Shifts Away Substantial Equivalence in Favor of Performance Testing and Criteria

FDA issued the Safety and Performance Based Pathway Guidance document, superseding the draft guidance document of April 1, 2018. It applies to CDRH and the Center for Biologics Evaluation and Research (CBER).

This new pathway represents a considerable change for the medical device industry, as it shifts substantial equivalency from testing of predicate devices to well established and robust performance testing criteria and methodologies. It also allows for a less burdensome approach for industry and FDA.

Overview

There are three types of Premarket Notification 510(k)s that may be submitted to FDA: Traditional; Special; and Abbreviated. The Special and Abbreviated 510(k) methods were developed under the “New 510(k) Paradigm” to help streamline the 510(k) review process. The Safety and Performance Based Pathway is an expansion of the concept of the Abbreviated 510(k) pathway for certain, well understood device types.

The FDA expects to begin implementation of this pathway once the first device types and applicable performance criteria have been identified. Once the FDA begins to implement this pathway, a medical device manufacturer will be able to meet FDA-identified performance criteria to demonstrate that its device is as safe and effective as a predicate device.

For more information refer to the guidance Safety and Performance Based Pathway.

What device types will be eligible for the Safety and Performance Pathway?

The Safety and Performance Based Pathway is appropriate when FDA has determined that:

• The new device has indications for use and technological characteristics that do not raise different questions of safety and effectiveness than the identified predicate, and the predicate is within the scope of the list of eligible device types;
• The performance criteria align with the performance of one or more legally marketed devices of the same type as the new device; and
• The new device meets all the FDA-identified performance criteria.

If any of the above factors are not met, the submitter has the option to submit a Traditional, Special or Abbreviated 510(k).

The FDA will issue future guidance to apply this Safety and Performance Based Pathway to certain types of devices with corresponding FDA-identified performance criteria. Industry may suggest device types for which FDA should consider identifying performance criteria. For example, industry may suggest products for which there are comprehensive FDA-recognized consensus standards. We encourage industry and other stakeholders to submit evidence-based suggestions on what the performance criteria should be for eligible device types. Input can be provided using the docket number FDA-2018-D-1387 at www.regulations.gov.

The FDA intends to maintain a list of device types appropriate for the Safety and Performance Base Pathway on this website, accompanied by the guidance documents that identify the performance criteria for each device type, as well as the testing methods recommended in the guidances where feasible, and any other relevant information.

Content of a Safety and Performance Based 510(k)

The amount and type of information necessary to support a finding of substantial equivalence under the Safety and Performance Based Pathway will depend on the underlying source for the performance criteria and testing methods. Table 1 and the Appendix within the guidance summarize the types of information that would be included in a submission based on the submitter’s approach.

Importantly, 510(k) submitters will still need to identify a predicate for certain aspects of substantial equivalence. However, instead of conducting direct comparison testing to demonstrate that a device is as safe and effective as a predicate device despite technological differences, manufacturers will be able to use this pathway, when appropriate.

More information on content that would be included within a Safety and Performance Based 510(k) will be available in the device-specific guidances that will be issued under this pathway.

FDA approves first targeted therapy for metastatic bladder cancer

The U.S. Food and Drug Administration today granted accelerated approval to Balversa (erdafitinib), a treatment for adult patients with locally advanced or metastatic bladder cancer that has a type of susceptible genetic alteration known as FGFR3 or FGFR2, and that has progressed during or following prior platinum-containing chemotherapy. Patients should be selected for therapy with Balversa using an FDA-approved companion diagnostic device.

“We’re in an era of more personalized or precision medicine, and the ability to target cancer treatment to a patient’s specific genetic mutation or biomarker is becoming the standard, with advances being made in new disease types. Today’s approval represents the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “FGFRs regulate important biological processes including cell growth and division during development and tissue repair. This drug works by targeting genetic alterations in FGFRs.”

The most common type of bladder cancer is transitional cell carcinoma, also called urothelial carcinoma. Bladder cancers are associated with genetic mutations that are present in the patient’s bladder or entire urothelium (the lining of the lower urinary tract). Bladder cancer is the sixth most common cancer in the United States. Fibroblast growth factor (FGFR) alterations are present in approximately one in five patients with recurrent and refractory bladder cancer.

The efficacy of Balversa was studied in a clinical trial that included 87 patients with locally advanced or metastatic bladder cancer, with FGFR3 or FGFR2 genetic alterations, that had progressed following treatment with chemotherapy. The overall response rate in these patients was 32.2%, with 2.3% having a complete response and almost 30% having a partial response. The response lasted for an average of approximately five-and-a-half months. About a quarter of patients in the study were previously treated with anti PD-L1/PD-1 therapy, which is a standard treatment for patients with locally advanced or metastatic bladder cancer. Responses to Balversa were seen in patients who had previously not responded to anti PD-L1/PD-1 therapy.

Common side effects reported by patients taking Balversa were increased phosphate level, mouth sores, feeling tired, change in kidney function, diarrhea, dry mouth, nails separating from the bed or poor formation of the nail, change in liver function, low salt (sodium) levels, decreased appetite, change in sense of taste, low red blood cells (anemia), dry skin, dry eyes and hair loss. Other side effects include redness, swelling, peeling or tenderness on the hands or feet (hand foot syndrome), constipation, stomach pain, nausea and muscle pain.

Balversa may cause serious eye problems, including inflamed eyes, inflamed cornea (front part of the eye) and disorders of the retina, an internal part of the eye. Patients are advised to have eye examinations intermittently and to tell their health care professional right away if they develop blurred vision, loss of vision or other visual changes. Health care professionals are advised to check patients’ blood phosphate level between 14 and 21 days after starting treatment and monthly, and to increase the dose Balversa in patients whose serum phosphate is below the target level.

Health care professionals are advised to tell male patients with female partners of reproductive potential to use effective contraception during treatment with Balversa and for one month after the last dose. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with Balversa. Women who are pregnant or breastfeeding should not take Balversa because it may cause harm to a developing fetus or newborn baby. Balversa must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture

The U.S. Food and Drug Administration today approved Evenity (romosozumab-aqqg) to treat osteoporosis in postmenopausal women at high risk of breaking a bone (fracture). These are women with a history of osteoporotic fracture or multiple risk factors for fracture, or those who have failed or are intolerant to other osteoporosis therapies.

More than 10 million people in the U.S. have osteoporosis, which is most common in women who have gone through menopause. People with osteoporosis have weakened bones that are more likely to fracture.

“Today’s approval provides women with postmenopausal osteoporosis who are at high risk of fracture with a new treatment that will reduce this risk,” said Hylton V. Joffe, M.D, M.M.Sc., director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive and Urologic Products. “But Evenity may increase the risk of heart attack, stroke and cardiovascular death so it’s important to carefully select patients for this therapy, which includes avoiding use in patients who have had a heart attack or stroke within the previous year.”

Evenity is a monoclonal antibody that blocks the effects of the protein sclerostin and works mainly by increasing new bone formation. One dose of Evenity consists of two injections, one immediately following the other, given once a month by a health care professional. The bone forming effect of Evenity wanes after 12 doses so more than 12 doses should not be used. If osteoporosis therapy is needed after the 12 doses, patients should begin an osteoporosis treatment that reduces bone breakdown.

The safety and efficacy of Evenity were demonstrated in two clinical trials involving a total of more than 11,000 women with postmenopausal osteoporosis. In the first trial, one year of treatment with Evenity lowered the risk of a new fracture in the spine (vertebral fracture) by 73% compared to placebo. This benefit was maintained over the second year of the trial when Evenity was followed by one year of denosumab (another osteoporosis therapy) compared to placebo followed by denosumab. In the second trial, one year of treatment with Evenity followed by one year of alendronate (another osteoporosis therapy) reduced the risk of a new vertebral fracture by 50% compared to two years of alendronate alone. Evenity followed by alendronate also reduced the risk of fractures in other bones (nonvertebral fractures) compared to alendronate alone.

Evenity increased the risk of cardiovascular death, heart attack and stroke in the alendronate trial, but not in the placebo trial. Therefore, Evenity contains a boxed warning on its labeling stating that it may increase the risk of heart attack, stroke and cardiovascular death and should not be used in patients who have had a heart attack or stroke within the previous year. Health care professionals should also consider whether the benefits of Evenity outweigh its risks in those with other risk factors for heart disease and should discontinue Evenity in any patient who experiences a heart attack or stroke during treatment.Common side effects of Evenity included joint pain and headache. Injection site reactions were also observed.

FDA issues final rule on safety and effectiveness of consumer hand sanitizers

The U.S. Food and Drug Administration today issued a final rule designed to help ensure that hand sanitizers available over-the-counter (OTC) are safe and effective for those who rely on them. The rule establishes that certain active ingredients are not allowed to be used in OTC hand sanitizers, formally known as topical consumer antiseptic rub products, which are intended for use without water, that are marketed under the FDA’s OTC Drug Review. The final rule also seeks to ensure that the agency’s safety and effectiveness evaluations and determinations for consumer antiseptic rub active ingredients are consistent, up-to-date and appropriately reflect current scientific knowledge and increasing use patterns.

“Our action today aims to help provide consumers with confidence that the over-the-counter hand sanitizers they’re using are safe and effective when they don’t have access to water to wash with soap,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “In today’s final regulation we finalized the FDA’s previous determination that 28 active ingredients, including triclosan and benzethonium chloride, are not eligible for evaluation under the FDA’s OTC Drug Review for use in consumer antiseptic rubs. We’ve also reaffirmed our need for more data on three other active ingredients, including ethyl alcohol, which is the most commonly used ingredient in hand sanitizers, to help the agency ensure that these products are safe and effective for regular use by consumers. We believe industry has made good progress toward providing data and we will continue to provide updates to the public about the progress of collecting this data.”

Consumer antiseptic hand sanitizers provide a convenient alternative when hand washing with plain soap and water is unavailable. Millions of Americans use antiseptic rubs daily, sometimes multiple times a day, to help reduce bacteria on their hands. The Centers for Disease Control and Prevention advises that washing hands with plain soap and running water is one of the most important steps consumers can take to avoid getting sick and to prevent spreading infections to others. If soap and water are not available, the CDC recommends using an alcohol-based hand sanitizer that contains at least 60 percent alcohol.

As part of the June 30, 2016 proposed rule on consumer antiseptic rubs, the FDA requested additional scientific data to support the safety and effectiveness of active ingredients used in OTC consumer antiseptic rubs.

At this time, three active ingredients—benzalkonium chloride, ethyl alcohol, and isopropyl alcohol—are being deferred from further rulemaking to allow for the ongoing study and submission of additional safety and effectiveness data necessary to make a determination regarding whether these active ingredients are generally recognized as safe and effective for use in OTC consumer antiseptic rub products. Their status will be addressed either after completion and analysis of the studies or at another time, if these studies are not completed. At this time, the FDA does not intend to take action to remove hand sanitizers containing these three active ingredients from the market.