Very Vexing

Very Vexing

Differing standards applied by regulators on biocompatibility testing make things less than clear for manufacturers and testing labs.

Jim Stommen • Contributing Writer

The once-placid waters of biocompatibility testing have been roiled in recent years by the disparity in testing standards applied by the regulatory authorities in the world’s largest medical device markets. Despite the existence of standards set by the International Organization for Standards (ISO), the U.S. Food and Drug Administration (FDA), European Union and Japan’s Ministry of Health and Welfare all have differing ideas on standards, particularly in the important area of genotoxicity, and having to feel their way through that maze has device manufacturers and contract testing organizations gnashing their collective teeth.

Add in the impact of changing requirements for bone replacement materials and growing attention being paid to bioabsorbable products and you have a situation that is far from settled. As Orthopedic Design & Technology found in discussing current issues in testing with a variety of sources, the only thing certain about the present situation is that it is in fact uncertain.

The uncertainty dates back to FDA guidance that pretty much turned the biocompatibility testing industry on its head. That marked a departure from the ISO 10993-3 genotoxicity standard, which offers two options: 1) perform a test for gene mutations in bacteria Ames assay, a gene mutation test of mammalian cells (mouse lymphoma assay), and a test for clastogenicity in mammalian cells (chromosome aberration assay), or 2) the same as the above, but include colony sizing in the mouse lymphoma, which eliminates the need for the chromosomal aberration assay.

Based on ISO requirements, in vivo (animal) genotoxicity assays are not needed for the battery unless a positive response is observed in the in vitro assays. The FDA has taken the position that an in vivo assay should be part of the genotoxicity test battery. Besides adding to the tests that industry must perform for the U.S. market, which adds cost, many within ISO have argued that the addition of the animal assay is unwarranted.

‘Unpredictable’ is the Byword

Lisa Olson, vice president of testing and service development in the St. Paul, Minn., facility of WuXi AppTech, a Shanghai, China-headquartered research and development outsourcing firm, said there “still is a tremendous amount of unpredictability” when it comes to dealing with the differences in standards in U.S., Europe and elsewhere.

She said, “The FDA did in fact issue that guidance on genotoxicity, but from what we can tell there are differences between reviewers in how they’re interpreting it. Some of the reviewers are certainly seeming to accept the standard ISO document and not entirely following the guidance as issued by the FDA.”

Olson added that “in all of the testing, not just genotoxicity, there is a certain unpredictability, but people are understanding the FDA expectation is for genotox work they basically have to do more work, rather than less, which is what the ISO guidance was hoping to allow people to do.”

Asked about the impact of the well-documented staffing problems at the FDA that have seen many veteran reviewers leave the agency and be replaced by significantly less-experienced persons in those positions who tend to ask for more, not less, documentation, she said her firm “absolutely” had experienced that trend.

“What we have found is that they have very, very smart people, but they may not be experienced in the particular field of biocompatibility so they struggle with the data and how to use that as the whole picture, whereas some of the staff that have since retired from the FDA could look very quickly at the data,” Olson told ODT. “We’re spending a lot of time both at the contract laboratories and manufacturers in educating the FDA on what makes sense. The newer reviewers are just looking to get all the data because they believe that somehow, in some shape or form, it needs to be there because it was mentioned in a guidance. It has required a lot more time for everybody. The reviewers have to take more time because it’s not as familiar to them and both the manufacturer and testing labs are spending a lot more time having discussions and education sessions.”

As for what WuXi’s customers think of having to deal with those different approaches, Olson said they’re frustrated.

“Because in some cases they’re having to repeat testing, and the U.S. isn’t the only one with freshman reviewers around, so there are cases where manufacturers are going down one path of creating a testing program because they’re going to the EU or they’re going to Japan,” she explained. “They’ll get that done, then they’ll come back sometime later and create a panel that’s really developed with the FDA in mind. So they’re frustrated in the fact that they have to do so much more work and spend that time and money.”

On the question of whether there might be harmonization on the different standards somewhere down the road, or if it’s a matter of what you see now is what you’re going to get, Olson laughed and said, “I see both. All of the scientists that are on the ISO committee, we all want to create a single path forward, a best practices approach. But what we’re finding is that there is still quite a bit of push and pull when it gets to the regulatory bodies and their participation and what they will accept.”

She said that her company has noticed more and more manufacturers saying they’re going to Europe first.

“They’ve done that traditionally because the regulatory barrier was easier to meet and the requirement for clinical trials was definitely less—you could get your product into market sooner. Certainly with FDA taking their very rigorous approach and with the uncertainty about how the 510(k) process is going, and an increase in clinical trials, we’re seeing a hesitancy in stating off in the U.S. for submissions.”

Revisions Coming to ISO standard

Dr. Joseph Carraway, director of toxicology for NAMSA, a device testing laboratory and contract research organization based in Northwood, Ohio, near Toledo, has a slightly different take on the genesis of the different approach by the FDA. He said “they have not recognized the ISO standard for genotoxicity for several years, so that is not actually a recent development.”

Noting that the ISO genotoxicity standard is in the process of being revised, he said, “I wouldn’t necessarily say anything has dramatically changed—the FDA’s official position is they recognize the ICH— the International Conference on Harmonization—standards for genotoxicity testing. The main difference is that ISO allows for the genotoxicity battery to be completed with just in vitro assays, whereas ICH requires an in vivo assay as part of the battery.”

Carraway said another change that’s in the works, but is still in the early stages, is the method of extraction for genotoxicity and sensitization testing.

“The Japanese favor an exaggerated extraction method where devices are extracted using organic solvents and a residue is created,” he said. “That’s a more aggressive extraction method than the standard ISO methods. The Japanese have been working over the years to get the exaggerated extraction method included in the ISO standards. It has been incorporated into part 10 of ISO, the one for sensitization. It’s also being incorporated into part 12, which is the sample prep, and it’s being incorporated into part 3, genotoxicity, but both of those are still in the draft stage.”

He noted that the industry “has some issues” with the Japanese method, because they feel it may be overkill.

“You’re extracting in these more aggressive organic solvents like methanol and acetone, whereas most of the solvents that are used for biological tests are say saline or vegetable oil. The general sentiment from industry is that the exaggerated extraction that the Japanese want is excessive and represents too much of a challenge from conditions of clinical use,” he said.

Carraway said the FDA has been looking at the Japanese method, “and they see some potential merit to that approach, so individuals at the agency are starting to get behind this approach. The problem is that the FDA is not speaking with one voice, saying here is what we would like clients to do. In general, the FDA follows ICH standards for genotox, but individual reviewers may say, ‘We’ll accept ISO standrards,’ or other reviewers might say, ‘We want testing done with exaggerated extraction.’ Part of the issue I’m hearing from people who interact with reviewers is, depending on who the reviewer is, they may get requests for different things.”

Asked if the current efforts to revise the ISO standards represents an effort to get some harmonization across these different jurisdictions, he responded, “I think so. You have representatives from industry, contract labs, and government agencies including the FDA. The FDA reps are taking greater interest in participating in the revision of these standards.”

As for testing in general, Carraway said, “The 510(k) process has had a lot of scrutiny over the past couple of years and it’s still unclear how that process is going to change. My gut feeling is that we probably will see test requirements increase in some future version of 510(k), and it may be that many devices that had been approvable via the 510(k) route may be pushed over into the PMA route or some modified version of 510(k) that requires more testing, i.e., clinical trials.”

A Hard-to-Change Viewpoint

Thor Rollins, section leader for Nelson Laboratories, a Salt Lake City, Utah-based provider of microbiology testing services to life sciences companies, says “not much has changed” regarding the testing situation with the FDA.

“Japan came with some good evidence to show that a chromosome aberration and an Ames test can actually pick up the vast majority of the possible problem areas that are common in medical devices,” he told ODT. “But the FDA came back and said they would not accept a submission without the animal test, so even though Japan has a lot of trust in the chromosome aberration test, and ISO still has two options, with the animal test just used for a confirmation of a positive, the FDA still is hanging on the animal test.”

Rollins added that it doesn’t look like there’s much of a change on the horizon unless there is “some really good scientific evidence” that can change their viewpoint. Noting that the FDA “drives a lot of these international standards, because America is such a big medical device market,” he said, “but they tend to be more stringent than a lot of international standards. A good case in point is that right now we’re rewriting the blood standard, and thereason we’re rewriting it is that the FDA doesn’t recognize it as a standard. So we’re working with two FDA reps to rewrite the whole standard to get to a point where they will approve it.”

As for what his company’s clients think of having to deal with these differing standards, Rollins said, “It’s frustrating. That’s what I spend most of my day doing. If a customer calls up and says, ‘Here’s my device, what testing do I need to do to get into what market?’ it used to be, we’d look at the ISO standard and say, this is the testing you need to do. Now, the first question we ask is what market are you looking to get into first?”

He added: “That’s the frustrating part for the manufacturers, because they have to change their test design depending on where they’re going. It’s interesting because they could have been commercialized for years in Europe, showing that there are no problems or complaints, but they still have to go through basic animal testing to get to the FDA unless they can be chemical or other means show compatibility.”

Rollins said the trend now is for companies to get their products out in Europe first, “especially with spine implants and other orthopedic products like that. What we’ll do is send them the test plan to get them into Europe, and then they’ll plan to spend the first 10 years in Europe, with clinical trials and then actual release of the product. That hinders the American markets, because we’re not seeing the latest technology until 10, 15 years down the road in some cases.”

A Moving Target for Testing

John McCloy, of Accutek Testing Laboratory, located in Fairfield, Ohio, used the phrase “moving target” to describe what’s happening in the testing world these days. McCloy, president of the Cincinnati-area lab, said moving target refers to theacceptance criteria that are imposed by regulatory authorities such as the United States and China FDAs, the European Community, and ANVISA in Brazil.

“The acceptance criteria for these types of implants is increasing, which is a normal development for any kind of regulatory agency, because they want to see improved designs, improved materials,” McCloy said. “So the moving target is going to keep on moving.”

How does a testing laboratory such as his keep up? Accutek participates in ASTM International’s standards-setting committees.

“We get to sit down with consumers, academia and FDA representatives, along with surgeons and engineers from large corporations,” he said. “We discuss different testing standards and attempt to come to 100% consensus. It’s a great way to keep up with what’s currently going on in the industry, and see the direction that development is going. We see all the concerns and advancements that are driving the updates to existing standards and creation of new ones.”

And that is only one of the ways to stay ahead of the curve, according to McCloy.

“We also stay in close contact with our clients,” McCloy said. “We understand getting acceptance by the FDA is a difficult process to go through, and try to assist them in any way can. Right now we’re seeing a reaction by our clients to take a more conservative route, which means they’re going to be testing more, increasing their loads and doing more wear testing—even though it’s not required by the FDA—as a show of good faith to the reviewers.”

As for the problem of dealing with less-experienced FDA reviewers, he said, “I wouldn’t want to be an FDA reviewer right now, because their workload has probably gone up by a factor of five to 10 in the last three to four years. They are finding that the new performance requirements are moving up faster than they can get review outs. And the international scope of the manufacturers is contributing to more 510(k) submittals. Those factors have made the workload for the FDA humongous.”

McCloy said he hears the same criticisms from manufacturers about otherregulatory agencies like the European Community, China FDA and also ANVISA—“They’re too tough on us and won’t let us do what we’ve done all along.” But all these regulatory agencies, like the FDA, are in a very defensive mode; things are moving slowly, and they have a whole lot more to review than ever before. It’s a difficult position to be in right now.”

He said there are some interesting ideas coming from Brazil.

“They have a little different strategy than the FDA—they’re pushing toward a five-year license as opposed to FDAapproval, which is good forever, presumably. In Brazil, the idea is that you have to re-test after five years to see if your product still fits with the market. So it forces the manufacturers to continually innovate to keep up with the rest of the market.”

New Attention for Bone Replacement, Bioabsorbables

Carraway, McCloy, Olson and Rollins also talked about new testing requirements for bone replacement materials and rapid growth in bioabsorbable products, two areas getting increasing attention from the FDA.

On bone replacement materials, Carraway said that potential increases in testing requirements are associated with the evolution of these materials.

“There’s not anything that I would point to as a major shift, but as you have these bone void fillers that are incorporating active ingredients, bone morphogenic proteins as an example,” Carraway said. “The FDA has concerns about those more so than the simple material by itself. I think as device companies are looking at ways to improve their materials, to tweak them by adding things, you’re going to see additional test requirements to support the claims that they want to make about those materials, but also the safety that they need to support as well.”

As for biodegradable devices in the orthopedics area, he said he doesn’t see anything “significantly different” insofar as testing is concerned.

“They still have to do the basic testing that has always been a requirement,” he explained. “What is potentially a challenge for the device companies is that the current standards indicate that you should follow that material to the point that the material is absorbed. Some materials may take two or three years to absorb. So does that mean a company can’t submit until they have implant data out to the two or three year time point? That is causing some potential issues for clients, so the need to have longer implant data can be a challenge for them.”

For her part, Olson said, “We do see a number of those types of bone replacement and biodegradable products, so it has been interesting for us to see how this is changing. Some of the methods for biocompatibility and efficacy and safety testing are not always suitable when you get into tissue-based products. Sometimes they just don’t work really well, so you have to be creative in your methodology, and yet still hit all of the expectations for the study that are required.”

She added that FDA reviewer requests for more information have increased.

“We’re seeing a lot more requests from reviewers for more information, so what would have been a fairly traditional biocompatibility panel are coming back with a lot more questions for information and clarity and expansion,” she said. “It’s not just biocompatibility and perhaps basic chemistry; it’s becoming much more expensive and may actually be going into testing regimes that devices have never had to look at before, like viral clearance studies or viral inactivation studies, to prove that your tissue-based or bone-based products aren’t carrying any viruses That’s something that’s very different for device manufacturers to think about.”

For osteoconductivity, Rollins said there are tests that need to be done to prove functionality.

“There are some promising in vitro models out there that we have been looking at and validating here that have some promise for replacing animal testing,” he said.

As for biodegradable implants, he said, “The problem is that you have to develop your whole test method because of the interaction the body can have with the biodegradable material. Once again, when you’re dealing with inexperienced reviewers, you could have an abnormal reaction based on the material itself. When you start throwing in complex systemic reactions with these absorbable devices, that makes it a little more confusing.”

McCloy said the situation with bio-degradable implants is “pretty much the same as the ones that don’t biodegrade, the metallics and the composites—the screws and plates. The wonderful thing about the human body is that it regenerates, and all implants do is accelerate that process, to a point. There actually haven’t been a whole lot of issues related to implants staying in your body for 30 years. I’ve got screws in my knees that have been there for 38 years and never had a problem,” although he concedes he can tell when it’s about to rain.

Jim Stommen, retired editor of industry publication Medical Device Daily, is a freelance writer focusing on the medical product sector.