This guidance was written prior to the February 27, 1997 implementation of FDA's Good Guidance Practices, GGP's. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP's.
PLEASE FORWARD YOUR COMMENTS TO:
Orthopedic Devices Branch
Division of General and Restorative Devices
Center for Devices and Radiological Health
U.S. Food and Drug Administration
10903 New Hampshire Ave
Silver Spring, MD 20993
- LABORATORY TEST METHODS
- CLINICAL DATA AND LABELING
- ORGANIZATION OF REPORTED INFORMATION
The purpose of this document is to recommend to the device manufacturer or sponsor of a future premarket notification (510k), Investigational Device Exemption (IDE), Premarket Approval (PMA) application, reclassification petition, or master file important information that should be provided to the FDA so that the FDA will be able to determine the substantial equivalence and/or safety and effectiveness of biodegradable orthopedic fracture fixation implant devices (e.g., plate, pin, screw).
Suggestions and recommendations presented in this document are not mandatory requirements, but reflect data and methodologies which the Office of Device Evaluation (ODE), Division of General and Restorative Devices (DGRD) has determined to be acceptable. In this context, several points should be remembered:
- The guidance document is primarily intended to include scientific recommendations. Therefore, it suggests some important evaluation criteria, test procedures and end points. There may be circumstances where an alternative method or additional information may be useful and this document has included some examples. If the manufacturer or sponsor can answer the same scientific issues by means other than those included in this guidance document, they should feel free to do so. Because the scope of this document does not specify any particular type of bone/suture anchor device, some of the recommended test methods may need modification to address the properties of a particular product.
- The guidance document should be viewed as a living document. As scientific knowledge changes and scientific techniques are improved, FDA will periodically revise the document.
LABORATORY TEST METHODS
All evaluations should be performed on sterilized materials. The storage time and environment of each sample since manufacture should be reported.
ANALYSIS OF THE MATERIALS
The composition and material structure (e.g., phases, reinforcement, matrix, coating) of the product to be implanted should be characterized quantitatively. These analyses may include the following:
COMPOSITION AND MOLECULAR STRUCTURE
- main ingredients
- trace elements (e.g., heavy metals
- low molecular weight (MW) components (separate components which have and have not chemically reacted with the polymer, e.g., contaminants, curing agents, crosslinking agents, dyes, monomer/dimer content, plasticizers, residual solvents)
- polymer stereoregularity and monomer optical purity (if the monomer is optically active)
- polydispersity, number average molecular weight (Mn), weight average molecular weight (Mw) (2 out of 3)
- molecular weight distribution (MWD)
- intrinsic (or inherent) viscosity (specify solvent, concentrations and temperature)
- whether the polymer is linear, crosslinked or branched
- copolymer conversion (e.g., block, random, graft)
- polymer blending
MORPHOLOGY (SUPERMOLECULAR STRUCTURE)
- % crystallinity
- orientation of phases/macromolecules
- types and amounts of phases
- thickness of each ply
- number of plies
- orientation and stacking sequence of plies
- symmetry of the layup
position of reinforcement within the matrix
- location within the part
- 3 dimensional orientation
- fiber density (e.g., distance between reinforcement components or reinforcement:matrix volume and weight ratios)
- fiber contacts and cross-overs per mm
- cross-sectional shape
- surface texture and treatment
- fiber twist
- total number of coating layers
- thickness of each layer
- mean volume percent
- penetration depth and profile
- drawing or photographs of the product illustrating the position of the coating and any variation in coating thickness
- dimensional changes of the material as a function of time
- densities of reinforcement, matrix and composite
- mass of the smallest and largest sizes
- roughness of all surfaces
- surface area of the smallest and largest sizes
- dimensioned engineering drawings of any nonrandom surface structure patterns (e.g., machined structures)
- THERMAL PROPERTIES
- crystallization temperature
- glass transition temperature
- melting temperature
STRENGTH RETENTION TESTING
Mechanical properties are most important because they determine whether the fracture site is adequately fixed to avoid loosening, motion and nonunion. Weight loss and inherent viscosity measurements are optional and may be helpful in screening different materials and in understanding degradation mechanisms, though they may not directly address the mechanical properties of the device.
In the in vitro degradation (or strength retention) test, samples are placed under a load in a physiologic solution at 37 degree C. Samples are periodically removed and tested for various material and mechanical properties at specified intervals (typically 1, 3, 6, 12, 26, 52 and 104 weeks) until strength has dropped below 20% of the initial strength.
In vitro aging might be easier to perform and control than in vivo aging, but in vitro conditions do not include the effects of cells, enzymes and other variables. The in vitro degradation rates should be validated by comparing to the in vivo degradation rates so the in vitro test results can be extrapolated to clinical conditions. Samples should be implanted in an animal model and mechanically tested (as outlined in this section) to determine if there are any significant difference in the outcome of test samples degraded in vitro and in vivo.
Test specimens may be either the product to be implanted or test coupons. The former is preferred unless there is quantitative data which adequately addresses size and surface area considerations in relating in vitro degradation of test coupons to in vivo behavior of the clinical implant. The test specimen model or size which degrades the fastest (e.g., due to a higher surface area or higher stresses) should be evaluated as a worst case. Testing is not required for a device which differs in geometry or dimensions compared to tested samples if it is demonstrated that there is no significant difference in the strength retention test results.
The degradation of the mechanical properties of the test device is compared to a predicate device. The devices are implanted either at the site of actual loaded use or at a nearby site. A range of healing time for the indicated repair should be provided from the literature. The implantation time should be at least twice as long the longest time over which healing of the repair is expected to occur. Data for this set of tests may be from the same animals used in other tests.
DESCRIPTION OF THE TEST SETUP (ENVIRONMENT)
The test solution composition should be justified. For example, bovine serum or phosphate buffered saline solution in a volume at least 20 times the volume of the test sample may be used. Unless a special effect is to be simulated (e.g., infection), the pH of the solution should approximate the pH of a physiologic environment (about 7.4) kept sterile and properly buffered or changed periodically. Additives may be required to inhibit the growth of bacteria and other microbes during the test period. The pH of the soaking solutions should be measured at each specified test interval, or once per month, whichever is shorter. Samples should be discarded if the measured pH is outside the specified value of more than ± 0.2. Each sampling container should be sealable against solution loss by evaporation. Each test specimen should be kept in separate containers and isolated from other specimens to avoid cross contamination of degradation byproducts.
Samples are fully immersed in the physiological solution at 37 degree C (or above for the purpose of accelerated testing) for the specified period of time. One group of samples are stressed during the entire time in solution to simulate clinical worst case conditions while another group of samples are set-up in the same environment (including fixtures) as the first group, without stressing. Cyclic loading of the stressed group is preferable, though not required. The amount of sample agitation, solution flow past test specimens, frequency that the solution is replaced and the clinical significance of these factors should be reported.
DESCRIPTION OF SPECIMEN ANALYSIS
The degradation of the mechanical properties of the submitted device over time is compared to the same changes for a predicate device. For example, pull-out tests may be used to test a bone anchor implanted into cadaveric bone or foam bone analogs. If cadaveric bone is used, the implantation sites should correspond to those intended for the submitted device. If foam bone analogs are used, the density of the foam should be compared to the density of the bone it is intended to model. The degradation values should be validated to in vivo results.
At each specified time period throughout the duration of the immersion/loading time, samples are removed and tested. Unless otherwise deemed relevant, samples should be tested in a non-dried or 'wet' condition. Unless specifically germane to the testing scheme, samples should be retired after the completion of each test.
Test samples should be weighed to an accuracy of 0.1 % of the total sample weight prior to placement in the physiological solution. Upon completion of the specified immersion/loading time, each sample should be removed and dried to a constant weight. Drying conditions may include enclosure in a desiccator at STP, use of a partial vacuum or the use of elevated temperatures. The weight should be recorded to an accuracy of 0.1 % of the original total sample weight. Elevated temperatures may be used to assist drying of the sample provided that the temperature used does not change the sample. The drying conditions used to achieve a constant weight should be stated.
The inherent viscosity (logarithmic viscosity number) or some other justifiable method (e.g., GPC) is measured prior to placement of samples in the physiological solution. Samples should be removed from immersion and loading at each specified time period throughout the duration of the test and tested for inherent viscosity as above. Dilution ratio in g/ml should be reported.
The shelf-life of the final product should be determined.
Material formulations or combinations with limited or no history of safe use as orthopedic implants should demonstrate a biological response at least as good as a predicate or substantially equivalent device when tested according to the ISO TC150 for Medical Devices and in an appropriate animal study. As part of the analysis, the degradation by-products and their metabolic pathways should be identified.
In vivo strength of repair studies are intended to compare the mechanical strength of intact tissue to that of a tissue repaired using the device under review or a predicate device. A range of healing times for the indicated repair should be provided from the literature. The implantation time should be at least twice as long the longest time over which healing of the repair is expected to occur. These studies should determine the degree to which the implant results in inhibition of osteogenesis, resulting in weaker bone, lack of tissue apposition, pseudoarthrosis, etc. The animal implant site should simulate the tissue site for which the device is intended for clinical use. A histological analysis should assess bone remodeling/strss shielding, profgressive degradation/absorption of the material, focal proliferation and subsequent disappearance of cellular elements responsible for degradation/absorption and the replacement of the device by new bone growth at the implant site with time. The time till most of the device (at least 90%) is absorbed and replaced by bone should be determined and the time till 100% absorption estimated by extrapolation.
Histology of the implant site is important to determine the tissue response, normal and abnormal, to the presence of the device and its breakdown products. The submitted device should be implanted into an animal model such that it experiences loading. For example, if the device is a bone anchor, the suture should pull on the device. The study should extend out to one year with comparative analyses made at appropriate intermediate time points.
CLINICAL DATA AND LABELING
Clinical data may be required if the intended use, materials, design or some combination of these differ significantly from a legally marketed predicate device.
Labelling may require a warning concerning site to site variation in blood flow and hence, degradation rate. Users should also be warned of possible adverse reactions (e.g., compliment activation as reported in Tegnander, A.; et al.: 'Activation of the Complement System and Adverse Effects of Biodegradable Pins of Polylactic Acid (Biofix) in Osteochondritis Dissecans'. Acta Orthop. Scand., 65, pp. 472-475, Aug., 1994).
The manufacturing process of the final product and test samples should be described in enough detail to give a general understanding of the origin of the structure as characterized above.
To help FDA in its review and facilitate a determination of substantial equivalence and/or safety and effectiveness, a very brief summary of all information should be organized in the order shown in part VII. ORGANIZATION OF REPORTED INFORMATION. Any additional and important information not specifically mentioned in the above guidance document should be inserted into this organization where appropriate. Detailed test reports from which the summarized data originated should be organized in a similar manner (as much as possible) and included in the submission to FDA. The detailed reports should include, but are not limited to the following:
- Report title
- Investigators' names
- Facility Performing the test
- Phone Number
- Test initiation
- Test completion
- Final report completion
- Test and control samples
- Sample selection criterion
- Processing methods
- Differences between test samples, control samples and marketed device
- Methods and Materials
- Test setup schematic or photograph
- Description of grips or potting medium interfacing with samples
- List of dependent, independent and uncontrolled variables, e.g.:
- Test and control sample parameters
- Environment composition, pH, volume, flow, temperature, replacement
- Electromagnetic fields, applied charges, irradiation
- Load directions, points of application and magnitudes
- Times (e.g. rates, frequencies, number of cycles)
- Rationale for choices of parameters, values, etc.
- Methods of specimen examination (e.g., failure analysis)
- Statistical justification for the number of samples
- Chronological description of the test procedures
- Deviations from referenced protocols and standards
- Time from manufacturing till testing commences
- Discussion of the data and possible mechanisms
- List of conclusions
- Discussion of the objective/hypothesis
- Simplifications and assumptions made and clinical implications of results
- Experimental data
- Bibliography of all references pertinent to the report.