|CONDUCTING RISK ASSESSMENT OF MEDICAL MATERIALS|
Medical Plastics and Biomaterials
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Originally published July 1996
In an effort to ensure safe materials and compliance with the various regulatory guidelines--including ISO 10993-1-1994 (Biological Evaluation of Medical Devices, Part 1: Guidance on Selection of Tests)--standards organizations are recommending an increasing battery of biological test procedures. Often, the sensitivity of a particular test together with the inherent nature of a certain material produce an unfavorable (positive) result, even though the material may be an appropriate choice for the device. This article will suggest specific tools for conducting an initial material assessment, a material risk assessment to determine allowable toxic levels (using commonly available toxicity information), and a risk assessment of unfavorable (positive) results.
Initial Material Assessment
To put it simply, there is no way to eliminate all risk. Given the innumerable conditions of use, a method for establishing with absolute certainty the complete safety of materials is not feasible. One can, however, take advantage of a wealth of information in the literature and in numerous material-toxicity databases. Questions such as the following should be explored at the beginning of the material selection process:
* In what manner will the material be exposed to the patient, and for how long? What is the total surface area that will be exposed?
* What are the chemical characteristics of the material being considered? Are there known constituents or additives that could be of concern as possible leachable components, and can these be quantified? Consideration should be given to the potential effect on the material of processing, sterilization, and contact with bodily fluids or drugs.
* Is there any evidence of nonbiocompatibility or toxicity in the literature, material-toxicity databases, or previous clinical applications of the material?
* Are there other available materials that might be more biocompatible while providing the properties necessary to constitute a safe and efficacious medical device?
A more detailed list of questions is available from the CEN Working Group 1 document entitled "Medical Devices--Risk Assessment."
Material Risk Assessment from Available Toxicity Information
As discussed previously, all materials that will directly contact the patient, along with potential leachables, should be identified. The maximum patient exposure to these materials should be calculated based on the total amount of the material contained in the device and the maximum number of devices that a patient could be exposed to. This is commonly calculated in µg/kg, assuming a patient weight of 50 kg. Therefore, if a device contained 10 mg of a material, and two devices were used per patient, the following calculation would apply: 10,000 µg of material/device ÷ 50 kg * 2 devices/patient = 400 µg/kg.
The next step in the risk assessment of any material is to ascertain some preliminary indication of biocompatibility based on published literature and numerous material-toxicity databases. This preliminary check simply compares the calculated maximum worst-case patient exposure to previously reported levels of toxicity. If the potential patient exposure is less than those levels reported to be toxic in the historical review, some confidence in the material's suitability can be assumed.
Once the material has been deemed to be generally biocompatible, an acceptable patient-exposure level must be determined. Because of the limited availability of human data, this often requires an estimate based on extrap- olation from animal studies. Even when the animal testing has shown a defined dose-response curve, there exists a large uncertainty in extrapolating to human applications. This uncertainty arises because dose-response curves are generated from specific experimental conditions with defined animal species and strains, routes of administration, diet, environmental conditions, and test substances.
To ensure an adequate margin of safety when extrapolating the human-limit level for each material or device, one must use a formula that takes into account the animal-to-human variation. The method should incorporate enough of a margin to minimize the impact of any less-reversible effects that may occur with exposure to the material in question. In pharmaceutical or dietary exposure studies, a tenfold factor has often been assumed for animal-to-animal variation. This margin is usually multiplied by an additional tenfold factor to account for potential animal-to-human variation; another tenfold margin to provide a level that would minimize exposure to any less-reversible effects such as carcinogenesis; and, finally, an additional fivefold factor to provide a concentration that should demonstrate a no-effect level.1
Unlike the products tested in pharmaceutical or dietary exposure studies, medical device materials are not intended to continuously expose patients to constituents that require
metabolization. The calculation of human-limit levels may thus be modified to reflect safety margins more appropriate to devices containing materials that are defined, characterized, and inert. The recommended safety margin uses only the tenfold factor for potential animal-to-human variation and a fivefold factor to provide a concentration that should demonstrate a "no-effect level." The overall safety margin should be increased if the material is degradable or exhibits nonreversible, genotoxic, or carcinogenic effects.
Animal-to-animal variation is generally not factored in for devices, as this variable accounts for interspecies differences in metabolism, while the primary interaction of medical device materials is through tissue or fluid contact without degradation or metabolization. However, the animal-to-animal variable must be included in the safety margin if degradation or metabolization is an intended action of the material, or if known leachables that could be metabolized are present. If nonreversible, genotoxic, or carcinogenic effects are demonstrated for the specified material, an additional factor to minimize exposure
to any less-reversible effects should be added.
If we follow the rationale described above, the formula for establishing a human-limit level is as follows:
Limit level = LD50 level x BW,
where LD50 = the lowest median lethal dosage (µg/kg); BW = a human adult body mass of 50 kg; and SM = a safety margin of 50 (safety factor of 10 for species differences * a safety factor of 5 for a safe-concentration adjustment).2
The calculation should use the lowest reported median lethal dose or no-effect level that is applicable for the route and type of material exposure in the end-use device. Body weight is chosen from the lower end of the adult weight range (unless the target is the juvenile population). The safety margin is a self-determined factor, and must represent an informed assessment of the material.
Based on this formula, the human-exposure limit level can be calculated and compared with the estimated worst-case potential patient exposure: total worst-case exposure should be less than the calculated exposure limit. Once again, key points to consider in determining human exposure limits are (1) the stability of the material; (2) the route of administration; (3) the type and duration of patient exposure; (4) the population targeted for the device; (5) any evidence in the literature indicating potential cytotoxic or genotoxic responses in vitro, or any sublethal/reversible effects in animal studies; and (6) the extraction rates and metabolic pathways for any leachables or byproducts of degradation.3 Additional information on the use of risk assessments is available through the National Academy of Sciences.
Risk Assessment of Unfavorable (Positive) Results
Researchers have proposed the concept that that no chemical agent is entirely safe or entirely harmful. The premise is that any chemical can be permitted to come in contact with a biological mechanism without producing an effect on that mechanism, provided the concentration of the chemical agent is below a minimal effective level.4 This idea can be extended into the arena of material toxicity. The single most important factor in determining whether a material will have an adverse effect is the relationship between the concentration of the material and its impact on the biological system. This is further complicated by the fact that the metabolization of a material tested at a high exposure level may be quite different from that of the same material evaluated at a reduced dose level. Therefore, the evaluation of safety or hazard must always take into account the conditions of use of the substance.
Although the ultimate extreme in a toxic response to a material is expressed as a lethal effect, it is well recognized that limited cytotoxic and sublethal or reversible effects can be undesirable or harmful. It is these adverse findings--reported as cytotoxic responses in cell-culture procedures and as sublethal or reversible effects in animal studies--that often serve to confound the unfamiliar investigator. To understand an unfavorable response, it is important to consider the biological variability between the test systems and the application in the patient.
For example, the relative speed, low cost, and extreme sensitivity of cell-culture procedures have made them an excellent tool for materials screening. The very sensitivity of these
techniques, however, can be a double-edged sword when qualifying materials. These test methods look at a
target cell dose significantly greater than seen in most clinical applications, in which potential extractables from a device are often diluted up to a thousandfold by bodily fluids. Given the diverse sensitivities of different test systems, a range of procedures should be used when evaluating materials or components for biocompatibility.
When a cytotoxic response is found, the trained investigator will examine the appropriateness of the test system for the actual application and will often decide to employ an in vivo model designed to address the material's end use. The in vivo test system can then function as a referee procedure for the more fragile in vitro assays, assuming an acceptable host response and sufficient justification.
Because they more closely mimic human applications, unfavorable responses with in vivo methods require a very critical review of the test system and delivery of the test article before such findings can be considered an acceptable risk. Adverse sublethal or reversible effects may be accepted only if a careful examination shows that the animal model is irrelevant to the end use of the material; that the concentration has been wrongly evaluated; or that there is significant biological variability between the test and human systems (perhaps due to mechanisms of selective translocation/absorption or biotransformation/metabolization/elimination).
In summary, unfavorable responses may be deemed an acceptable risk because of justifiable differences in test methodologies or as a result of careful analysis of the patient risk-to-benefit ratio. The following questions can be used for judging the relevance of adverse findings: 5, 6
* Do the effects definitely result from exposure to the material, or was this a random event (content validity)?
* Should the effects be considered toxicologically meaningful or simply adverse in nature (construct validity)?
* Is there correlation among the end points of multiple test procedures (concurrent validity)?
* Is there enough evidence and validity to consider these results predictive of what will happen under conditions anticipated in the actual application of the material or device (predictive validity)?
Today's manufacturers seek to develop new medical devices in a timely and cost-efficient manner while attempting to eliminate all risk. However vigorously they pursue this goal, they realize that it is virtually impossible to establish complete safety with absolute certainty. As one author states, "The best we can do experimentally is to create an arbitrary set of conditions of administration of a test compound that we consider to be as relevant as possible to the conditions of intended human or animal exposure....The best we can hope to achieve is a reasonable assessment from those who are fully conversant with the present state of the art."7
When selecting medical materials, it is critical to be as specific as one can about intended use. For example, the simple act of introducing a device into the body provides the opportunity for inflammation, generally defined as the reaction of vascularized living tissue to local injury. While inflammation serves to contain, neutralize, dilute, or isolate the injurious agent or process, it also sets into motion a series of events intended to heal and reconstitute the implant site.8 As such, the quest for a nonreacting, risk-free material may actually be contrary to the intended action of some devices. In short, the ultimate benefit to the patient must always come first. It is our hope that the tools defined in this article--along with the available literature, numerous biocompatibility databases, and years of clinical history--will provide a framework for knowledgeable investigators to make decisions in the best interest of the patients.
1. Weil CS, "Statistics vs. Safety Factors and Scientific Judgment in the Evaluation of Safety for Man," Toxicol Appl Pharm, 21:454463, 1972.
2. Biological Evaluation of Medical Devices--Part 7: Ethylene Oxide Sterilization Residuals, ISO/DIS 10993-7.3, Annex E, Geneva, International Standards Organization (ISO), 1994.
3. Science and Judgment in Risk Assessment, Report by the Committee on Risk Assessment of Hazardous Air Pollutants, Board on Environmental Studies and Toxicology, Commission on Life Sciences, and National Research Council, Washington, DC, National Academy Press, 1994.
4. Loomis TA, Essentials of Toxicity, Philadelphia, Lea & Febiger, p13, 1970.
5. Sette WF, "Complexity of Neurotoxicological Assessment," Neurotoxicol and Teratol, 9:411416, 1987.
6. Sette WF, and MacPhail RC, "Qualitative and Quantitative Issues in Assessment of Neurotoxic Effects; Target Organ Toxicity Series," in Neurotoxicology, 2d ed, Tilson H, and Mitchell C (eds), New York, Raven Press, 1992.
7. Goldberg L, "Chemical and Biochemical Implications of Human and Animal Exposure to Toxic Substances in Food," Pure Appl Chem, 21:309330, 1970.
8. Anderson J, "Introduction to Biomaterials Short Course, Section 3.2.1," Cleveland, OH, Case Western Reserve University.
Jeffrey M. Lohre is a project biologist with Baxter Healthcare Corp.'s CardioVascular Group CVG Quality Biology Laboratory (Irvine, CA). Tom McCarthy is manager of the CardioVascular Group's Biological Research Center. Jon Cammack, PhD, is a toxicologist with Baxter Healthcare's Corporate Research and Technical Services (Round Lake, IL), where Sharon Northup, PhD, is a senior technical adviser. Sarah Guida was formerly director of the CardioVascular Group CVG Quality Laboratories.