Testing Times

In April last year, the U.S. Food and Drug Administration (FDA) put out a draft guidance document on the topic of medical device compatibility. The document addresses proper use of ISO 10933, the international standard for evaluating the biocompatibility of a medical device prior to clinical testing.
For obvious reasons, therefore, the document has numerous implications for testing services providers. Since orthopedic devices overwhelmingly are devices that end up in the body for prolonged periods of time (e.g., staples, rods and pins for broken bones; joint replacements; spinal implants), new, more stringent or just different expectations for biocompatibility testing will particularly impact the orthopedic sector. This is not necessarily bad, but certainly something the industry will have its eyes on in the coming year. The draft is expected to be finalized in the first quarter of 2014. It will update and replace the previous guidance, the G95-1, which was published in 1995.

The draft guidance, titled “Use of International Standard ISO-10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation and Testing,’” has been drafted to “assist industry in preparing premarket applications, humanitarian device exemptions, investigational device applications, premarket notifications—510(k)s—and de novo requests for medical devices that come into direct or indirect contact with the human body in order to determine the potential toxicity resulting from contact of the component materials of the device with the body.”

For an industry that is somewhat on high alert due to significant concerns over the toxicity of all-metal hip implants, this new focus on ensuring near-perfect biocompatibility and non-toxicity was inevitable. Orthopedic device makers Zimmer Holdings Inc. and Smith & Nephew plc each had to recall their all-metal hip implants, and Smith & Nephew had to do the same for its metal liners for its implants.
Concerns, which have now become lawsuits, arose among patient and physician populations regarding metal fragments being deposited into the tissue surrounding the implants, sometimes causing the need for revision surgery, and in very rare cases, resulting in illness or death.

A Brief Summary
Chief Strategy Officer John S. Bolinder and Consultant & Biocompatibility expert Thor Rollins from Nelson Laboratories Inc., a Salt Lake City, Utah-based microbiology lab, provided a brief summary of the draft guidance, outlining how it differs from its previous iteration and how it may affect orthopedic implant manufacturers.

1. New materials:

• Several new materials and technologies have been introduced since G95-1;
• Assessment of known or potentially toxic chemicals (e.g. color additives)—as an example, FDA may want to know the material characterization of polymers with and without colorants, as it is advisable to understand the toxicity through leaching properties of the colorant; and
• In situ assessment of new materials such as polymerizing and bioabsorbables components. FDA wants manufacturers to understand how these materials are absorbed over time in the body and metabolized—where it goes, how long it dwells, when it is excreted.

2. FDA test plan review: Scope portion of the document specifically advises sponsors to discuss test plans with the appropriate reviewer division at the FDA’s Center for Devices and Radiological Health (CDRH) prior to commencing, specifically for long-term testing of any new device materials.

3. Test reports: FDA recommends that full test reports be provided as ISO 10993 includes general methods with multiple options. Simply referencing an ISO 10993 category is not sufficient.

4. Finished device for biocompatibility:

• While this has been understood for some time, the document now specifically states FDA does not clear or approve individual materials used in the fabrication of medical devices; and
• Biocompatibility depends not only on the materials but the processing of the materials, manufacturing methods (including sterilization) and manufacturing residuals that may be present on the device. Justification for not testing is limited and guidance is provided in the new draft.

5. GLP required: For all biocompatibility tests related to regulatory submissions the FDA states in the new guidance that testing according to good laboratory practice (GLP) is required and any study submitted not in accordance to GLP must be fully justified.

6. Pyrogenicity tests: Implants, as well as sterile devices, should meet pyrogen limit specifications. This may imply that the new guidance requires pyrogen (bacterial endotoxin testing) for routine production monitoring of implant devices.

Bolinder and Rollins found the document’s focus on pyrogen testing particularly intriguing.

“The draft document’s wording of pyrogen testing requirements [see point 6] almost implies that with this new guidance, orthopedic manufacturers need to do ongoing bacterial endotoxin testing as part of the routine production monitoring process,” Bolinder told Orthopedic Design & Technology. “To date, that’s typically only been true for injectable products that go into, for instance, the cerebral spinal fluid, or cardiovascular pathways. It’s usually limited to that or anything specifically marked as non-pyrogen. This almost implies that any implant has to have pyrogen testing as an ongoing lot release.”

As is permitted by the regulatory agency, Bolinder and his team at Nelson Labs have submitted a query regarding this portion of the document, which reads, “Implants, as well as sterile devices in contact directly or indirectly with the cardiovascular system, the lymphatic system, or cerebrospinal fluid (regardless of duration of contact), and devices labeled as ‘non-pyrogenic’ should meet pyrogen limit specifications” (emphasis added). However, a response is still pending, thought it should be imminent as they expect the finalized document to be released this quarter.

Sylvester Williams, director of regulatory affairs at WuXi AppTec, an outsourcing service provider for the healthcare industry, also has noted a particular pressure from the FDA on manufacturers knowing the chemical characteristics of a device inside and out in every way.

“We’ve noticed over time that the FDA has pushed to have a thorough chemical characterization of various devices and products,” Williams said. “We do see the agency wanting device manufacturers to have a thorough understanding of what’s in their devices and so we stand ready to assist them with the actual analytical testing and risk assessment. The agency is expecting OEMs to be acutely aware, familiar and have knowledge of the materials in their devices. In part, this is because of the metal-on-metal [hip implant] issue and the need to identify the effect of shed materials from such devices and components.”

Williams referred to the recently updated guidance document from the FDA on intravascular stents and other associated drug delivery systems issued in August last year. The document focuses on four topics, three of which are related to corrosion: pitting corrosion potential, galvanic corrosion, and nickel ion release as a result of corrosion.

“Clearly, the agency wants OEMs to be aware and understand the impact of these types of issues on their devices,” said Williams.

One more significant way in which this draft guidance is changing requirements is the potential change to predicate requirements for earning a 510(k) clearance from the agency.

“If there’s a predicate device on the market and you want to make something comparable, unless you have the exact formulation, the exact materials, and use the exact same storage conditions, it’s going to be really hard to justify not doing full biocompatibility testing even though the device may be made of comparable materials,” said Bolinder. “[The FDA] is making it a little bit more difficult to say, ‘Look, it’s the same device, and we want to exempt our biocompatibility because it’s substantially equivalent.’ They want us to be absolutely sure.”

‘“The FDA actually proposed to congress a new change where if you use a predicate device for your 510(k) and that device comes back as a recall, then they want to be able to recall your device,” added Rollins. “In the past, 510(k) predicate choices have been really loose, and there has been a lot of investigation as far as the quality of predicates go. The agency just wants to be more careful with the choices of predicates available, and wants to make sure that they examine every aspect of a predicate so you’re not just looking at contact type and duration but you’re taking into consideration all these other end points like duration [of exposure to a product], shape, material and processing so that you can really have a true predicate.”

These new justification requirements for testing could work to a manufacturer’s benefit, though, Bolinder pointed out. If a manufacturer makes one finished prototype, and then makes second, slightly different version, the document will help the company justify not doing a new biocompatibility test.

“Because if you’re making the product in the same facility with the same materials and you only made minor modifications through a change control but you have to go through resubmission because it was a significant enough change, this document will help you justify not doing biocompatibility testing,”
Bolinder said. “It’s just going to be more limiting if you’re trying to make a product for the first time, even if there are existing predicates on the market, even if you know everything about those products.”
As a physician, William M. Mihalko M.D., Ph.D, chair of the American Academy of Orthopaedic Surgeons Biomedical Engineering Committee, believes the draft guidance to be a very useful document.

“If you consider the current materials that are being used mostly in orthopedic implant devices, most of the [biocompatibility] questions have already been answered,” Mihalko said. “Really most of the materials we’re using and most of the implants coming onto the market now are using predicates where pretty much all those questions have been answered to date. I think this is a good move because anything that’s new in the future is going to have more stringent testing regiments through this guidance document. I think the FDA needs more guidance documents like this, and I think this is something we’re going to see more of.”

Mihalko also is an orthopedic surgeon practicing at the Campbell Clinic in Memphis, Tenn. and the J. R. Hyde Chair of Excellence in biomechanical engineering at the University of Tennessee Health Science Center.

Other Guidances and Rules
The FDA also released two major final guidances/rules last year: the final guidance on mobile apps and a final rule on a unique device identification system.1 Outside of the two major September guidances/rules that will have a significant effect on the medtech industry—particularly the health IT sector—in the months and years to come, the FDA did not put out a large number of guidances in 2013. However, in the past two to three years, the number of total guidances amounted to more than 50, forcing medical device companies to struggle to stay abreast of rapid-fire new rules and regulations.

“Working with FDA over the last two to three years has been quite challenging,” said Penny Northcutt, president and CEO of FDA regulatory consultant company REGSolutions LLC, based in Atlanta, Ga.
“There are many new guidances and the regulatory professional must be current on FDA’s latest review requirements and stay informed on how FDA interprets their need for additional testing.
Additionally, the agency is changing with FDA’s senior review staff retiring, leaving behind more junior reviewers who are disposed to extreme caution and excessive conservatism. FDA is under many constraints with the mandated review clock and the new guidance containing interactive review. The junior reviewers have a team to assist in the technical areas so if their subjective matter expert is not available, they often have trouble discussing and making decisions based on industry questions and testing rationales. It is imperative that regulatory professionals produce better-written 510(k) submissions that are scientific-based and contain the appropriate testing to substantiate our equivalence arguments. With FDA’s new Refuse to Accept (RTA) guidance, submissions must contain all elements of the RTA before FDA even accepts the submission for review. This is an improvement in the review system in that 510(k)s must be complete when submitted so as not to waste FDA’s time.”

The RTA guidance was released on Dec. 31, 2012. The document, which supersedes the CDRH’s 1993 premarket notification (510(k)) RTA policy and the 1994 blue book memo on 510(k) RTA procedures, explains the procedures and criteria the FDA intends to use from now on in assessing whether a 510(k) submission meets a minimum threshold of acceptability and should be accepted for substantive review. The guidance is intended to focus the agency’s resources more efficiently only on submissions that are complete and ready for review instead of wasting time on submissions that involve less crucial components and need help from agency staffers to complete. The document is one part of the FDA’s effort, in accordance with the enactment of the Medical Device User Fee Amendments of 2012 (MDUFA III), to shorten review times and become more efficient.

“The FDA has responded [to the need for efficiency] by saying, we heard you, we have spent money on educating our reviewers, and we’ve also developed what we believe is a more expeditious 90-day review process,” said George Stone, quality engineering manager at Stratos Product Development LLC, a Seattle, Washington-based full-system product engineering and design consultancy. “But what that means for the industry is that the FDA is not going to hold your hand anymore. If you miss something in your submission, they’re going to say you forgot this, we’re sending it back and your 90-day cycle starts over again so we can focus on someone who submitted everything they were supposed to.”

Barbara Atzenhoefer Stegmeier, a medical research manager (regulatory) at NAMSA, a medical research organization based in Northwood, Ohio, called the RTA check list “the biggest thing to come out of the FDA” of late.

“They’re trying to systematize things more in their attempt to try and make a clearer path to acceptance,” Atzenhoefer Stegmeier said. “I’m not sure if they’re completely succeeding, but I think they’re making an effort.”

The Moment of Truth: 2014 is First Full Fiscal Year of Medical Device Tax
While other, important changes and trends continue on the regulatory world, the device tax still lingers in the industry’s psyche. It has been a year since the 2.3 percent tax was implemented on Jan. 1 2013, and for all the hue and cry preceding the tax—lawmakers’ attempts at recall, company layoffs, etc.—there has not been a catastrophe in the medical device space. Yet.

“Initially when this device tax was announced there was a lot of concern expressed regarding cutting back in research and development [R&D],” said WuXi’s Williams. “When companies are faced with additional taxes, there’s a tendency to want to compensate and recover those costs in other areas.
There was a concern the tax was going to reduce R&D development but the fact is R&D is a critical component of any medical device company’s pipeline. Products change every two to three years in the medical device arena versus 10 to 12 years in pharmaceuticals. Medical device companies have had to deal with the tax in different ways. Some companies, rather than cut R&D, have elected to enact other cost saving measures. [2014] will be the first full fiscal year it will be in effect, so we’ll see. It’s anticipated that most of our clients rely on us for our R&D efforts, and that does not seem to be significantly affected at this point. It’s too soon to say how big of an impact it’s going to have on us, but I imagine that if there is an significant impact, it will be apparent by around June or July.”

Several major orthopedic companies completed rounds of layoffs before the device tax came into effect, confirming Williams’ thesis that companies would rather take other measures than cut R&D spending. Stryker Corporation laid off 1,050 employees in 2012; Medtronic Inc. let 1,000 workers go; Smith & Nephew trimmed 770 from its payroll; and Zimmer cut 450 staffers.

But like Williams, Mihalko doesn’t believe the industry has seen much in the way of direct effects of tax implementation yet, although, as he admitted, he works out of a Veterans Affairs medical center, so it would affect him only minimally.

“I will tell you that really the device tax is going to affect how manufacturers redistribute their funds for education and research,” Mihalko said. “I’m not sure we are going to see any real effects or changes from device manufacturers after only one year of implementation.”

Reference

1. For more on these, see the regulatory update feature from ODT’s sister publication Medical Product Outsourcing http://www.mpo-mag.com/issues/20131101/view_features/regulatory-review-the-price-of-change/