CDG Whitepapers

Medical Device Biocompatibility

A Whitepaper by Dr. Nancy J Stark and Dr. Dan McLain

There are commonly three scenarios in which manufacturers call on CDG for biocompatibility help: a) FDA has raised questions about the safety tests you performed, b) you disagree that you need sensitization, genotoxicity, or carcinogenicity tests, or c) you have a new device and don't have a clue as to what tests to do. Can an expert opinion help?

Materials and the manufacturing process
We usually think about biological safety when selecting the materials for a new device. Many materials may be under consideration for a particular component. The mechanical properties, manufacturability, availability, aesthetics cost, as well as biological safety issues, are all considerations in the material selection process.

Often manufacturers believe they are using "common" material in their medical devices, but when challenged by FDA to give reasonable assurance of the material's safety they cannot offer specifics. You must establish the material is comparable after your manufacturing process. This is why biological safety tests are performed on final manufactured product. Some companies use final manufactured devices, others run a coupon of the material through the manufacturing process to get a material that is representative of the final process.

Back in the day—when one of us started working in the device industry—there were no recognized standards for device biological safety testing. Manufacturers floundered around looking for tests that seemed applicable. I once used US Pharmacopoeia (USP) tests for drug containers when developing a new syringe. Even today, suppliers and manufacturers sometimes assume that materials which meet USP Class V or VI requirements are sufficiently safe for device applications. (1 USP)

 

 

Step Two: "The Matrix"
Because of its long history, most manufacturers base their biological safety testing on "The Matrix". In 1986, regulators from FDA, the UK, and Canada published the Tripartite Biocompatibility Guidance. The guidance built upon standards that had previously been published by AAMI, ANSI, ASTM, and others. It looked at materials based on the type of tissue the material contacted and the duration of that contact. Then a testing category was recommended for each combination of contact and duration. The problem with the Tripartite Guidance was that nearly every category of biocompatibility test was recommended for nearly every combination of material contact and duration (198 out of a possible 240 categories were recommended.) (2 Tripartite) There were other problems too: it didn't tell you how to handle whole devices, and it didn't apply to metals or ceramics.

In 1992, the International Standards Organization (ISO) published ISO 10993 Part 1 "Guidance on selection of tests". The standard was part of a series of biological safety standards, but Part 1 included a matrix similar to the contact and duration matrix of the Tripartite Guidance. The major difference was that far fewer categories of tests were recommended (117 out of 240). (3 ISO 19003-1 Selection of Tests) This matrix was not accepted by FDA.

  

1995 brought us The Matrix as American manufacturers know it today. It is found in FDA's General Program Memorandum G95-1. (4 G95-1) With clairvoyance and foresight FDA modified the matrix presented in a version of the ISO 10993-1 standard that would not be published for another two years. (5 ISO 10993-1 Testing and Evaluation) The goal was to harmonize the agency's biological safety policy with the expectations of the international community. In the modified matrix, an additional 36 categories of tests are "suggested" for manufacturers to consider (for a total of 153 out of 240).

Step One: ISO 10993 Part 18 'Chemical characterization of materials' (2005)
A more ethical and efficient practice is to chemically characterize materials and compare them to materials in existing clinical use before performing animal tests. This is done in conformance to ISO 10993-18 'Chemical characterization of materials' (2005) and it should be done before the matrix is even consulted. (6 ISO 10993-18)

To put it in context, the chemical characterization of materials justify the performance or omission of animal biocompatibility tests, just as clinical evaluations justify the performance or omission of human clinical investigations.

  

Chemical characterization is the accepted method for comparing one finished, manufactured material to another in order to make the argument that they are clinically equal or that one material is no worse than a currently used material. The methodology has been developing over the years and was described in detail in a book by Dr. Stark in 2003. (7 Stark) The characterization is done in the following manner.

[1] Qualitative information
Describe the material and its intended purpose within the device. The description includes qualitative information such as supplier name, common name, chemical name, batch or lot number, visual and physical characteristics such as color, hardness, flexibility, and chemical family, and other specifications. The intended use of the material (type of tissue contact, duration of contact, and function) are also described.

[2] Material equivalence
The new material is compared to an existing material that is used in a device with the same clinical exposure; the device can be a commercial device from your own firm or it can be from your competitor. You can readily visualize a spreadsheet or database listing each material in the device and comparing it to another known material. If you have sufficient information for an expert to make a toxicological risk assessment you can stop here.

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Expert Opinions and Consultation for Biological Safety

Dr. Dan McLain, is an internationally renowned medical device toxicologist. His position as convener of ISO 10993-11 is evidence of his global stature. Dan is available to assist with pre-clinical strategies and chemical risk assessments for your materials and devices. Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

 

[3] Quantitative data
Quantitative data will be needed if a sound risk assessment cannot be made purely on qualitative information. This means a thorough knowledge of the chemical composition, additives, manufacturing residues, and leachables must be obtained through analytical and physical chemistry. The goal is to determine the amount of identified chemicals (such as monomers, anions, radioactive elements, and the like) that are present in the final, manufactured material.

[4] Quantitative risk assessment
In the quantitative risk assessment the amount (in µg, Gy for radiation, or other unit of exposure) of identified chemicals are compared to existing toxicological information, rather than to another material. The objective is to determine which, if any, of the chemicals in the material might be harmful at the calculated exposure.

[5] Estimate clinical exposure
Finally the amount of potentially harmful chemicals, the 'dose', is compared to the clinical dose a patient might receive in a lifetime, a procedure, or other unit of time. Such a comparison seeks to show that the maximum dose of a chemical one might receive is acceptable in light of the lowest dose that could case medical problems. Detailed methods for risk assessments are discussed in ISO 14155-17 'Methods for the establishment of allowable limits for leachable substances' (2008). (8 ISO 10993-17)

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"The Matrix" Is Available as a Mousepad/Notepad

CDG's talented graphic artists have reconfigured The Matrix and printed it on a high-quality mouse-grade paper pad. Now you can always have The Matrix at your workstation, in plain sight where you can find it. You can quickly look up the test categories needed while the boss is quizzing you on the phone. And at ten sheets to the pad, you can take notes on the conversation (or doodle), tear off the sheet, and keep it safe in the technical file.

Find it here, or contact Peggy at 773-489-5706 or cdginc@clinicaldevice.com.

Consider these examples, they are intended to illustrate the kind of issue you'll be addressing: a) Let's say you have a metallic implant that you clean by washing with perchloroethylene. Known to be highly volatile, but also highly toxic, you must ask if enough perchloroethylene remains on the metal implant to preclude its use as a cleaning agent; b) Let's say you make a wound dressing that contains a potassium salt. You know that potassium affects cardiac function and in sufficiently high concentrations could put a patient into cardiac arrest. You must ask if sufficient potassium can leach out of the dressing and into the wound to affect cardiac function.

References
(1 USP) United States Pharmacopeia.
(2 Tripartite) Tripartite Biocompatibility Guidance G87-1, (1987).
(3 ISO 10993-1 Selection of tests) ISO 10993-1 Biological evaluation of medical devices: Selection of tests (1992).
(4 G95-1) "Use of International Standard ISO-10993-1 Biological Evaluation of Medical Devices: Evaluation and Testing", G95-1 (1995).
(5 ISO 10993-1 Evaluation and Testing) ISO 10993-1 Biological evaluation of medical devices: Evaluation and testing (1997).
(6 ISO 10993-18) ISO 10993-18 Biological evaluation of medical devices: Chemical characterization of materials (2005).
(7 Stark) "Biocompatibility Testing & Management" Fourth Edition, Nancy J Stark, Clinical Device Group Inc, 2003.
(8 ISO 10993-17) ISO 10993-17 Biological evaluation of medical devices: Methods for the establishment of allowable limits for leachable substances (2008).

Questions or Comments?
Do you have questions, comments, or additional information? Please post them below.

 

ISO/FDIS 14155 "Clinical Investigations of Medical Devices in human subjects—good clinical practices" (2010)

New Rules for International Device Trials
A Whitepaper and Workshop by Nancy J Stark, PhD
Wednesday, 22 September 2010, 11 AM Central; or OnDemand soon after. 

Sweeping changes to ISO 14155
The international standard for medical device clinical research is about to undergo sweeping changes. The first and most evident change is the change in title; the standard is now known as ISO/FDIS 14155 " Clinical investigations of medical devices in human subjects—good clinical practices". Harmonized with the ICH-GCPs, 'Good clinical practices' was added to the title to signal to the world the Working Group's intention that this is now the standard to be followed for international medical device investigations.

There are other significant changes as well. The mechanical, physical, and engineering nature of devices are taken into account with the integration of the normative reference ISO 14971 "Application of Risk Management to Medical Devices". The contents of Investigator's Brochures looks like a document that reflects a mechanical device rather than a chemical drug, while the requirements for recording and reporting device deficiencies alongside adverse events complements the essential requirements of the MDD and AIMD.

All studies are created equal
Possibly the hardest thing for Americans to grasp is that there is no risk-based categorization of clinical trials in the standard. The concept of non-significant risk studies versus significant risk studies does not exist—all the rules apply equally to all clinical investigations.

An international standard written by international experts
The new standard was written by a team of experts from the US, Europe, and Japan. The team consisted of industry representatives, consultants, and regulators to assure that it was achievable, consistent with country regulations, and in keeping with accepted ethical and organizational practices. It did not come easily; the working group and editing committee met fourteen times, with a dozen or so teleconferences sprinkled in between the meetings.

One result is a standard that will be an an economic leveler—it will be neither easier nor more difficult to conduct a trial in one country over another. Another result is a standard that will be an ethical leveler—it will be neither easier nor more difficult to conduct trials in developing countries than developed countries.

Format and approach
The Part 1 and Part 2 standards from 2003 are now combined into single, comprehensive, 65-page document. The strategy was to approach clinical investigations from a project management perspective. A look at the layout gives an idea of the breadth and depth of the standard.

First, there are four administrative sections:
[1] Scope.
[2] Normative references.
[3] Terms and definitions.
[4] Ethical considerations.
The scope tells us that "the principles ...apply to all other clinical investigations...." The statement has no legal precedence but was clearly important to the Europeans. The scope also makes it clear that the standard does not apply to in vitro diagnostic devices.

"Normative" is ISO-speak for required. It is the one, small sentence under normative references that elevates ISO 14971 to importance. Being listed as a normative reference means that the sponsor is, de facto, non-compliant with ISO 14155 if they are not compliant with ISO 14971. Scattered throughout the document are the many ways in which Risk Analysis Reports are integrated into clinical investigations.

These are followed by three project planning sections:
[5] Clinical investigation planning.
[6] Clinical investigation conduct.
[7] Suspension, termination, and close-out.
It is not that there is anything new in the project management sections, but there is so much more detail and instructive language. If you have never done a clinical study before, you will find these sections to be a welcome reference.

The need for a Clinical Evaluation Report performed according to the principles of GHTF Study Group 5 to justify the design of the clinical protocol is another example of a requirement included to meet the essential requirements of EU Directive 93/42/EEC on medical devices (MDD) and EU Directive 90/385/EEC on active implantable medical devices (AIMD).

These are followed by two responsibilities sections:
[8] Responsibilities of the sponsor.
[9] Responsibilities of the principal investigator.
Sponsor and principal investigator responsibilities follow closely with FDA's new guidance "Investigator Responsibilities—Protecting the Rights, Safety, and Welfare of Study Subjects" and the ICH-GCPs. Principal investigators (aka "investigators" in the States) are still required to sign final reports under ISO, but investigators (aka "co-investigators" or "sub-investigators" in the States) are off the hook.

While much of the detail is laid out in five annexes:
Annex A (normative)—Clinical investigation plan.
Annex B (normative)—Investigator's Brochure.
Annex C (informative)—Case report forms.
Annex D (informative)—Clinical investigation report.
Annex E (informative)—Essential clinical investigation documents.
Annex F (informative)—Adverse event classification decision tree.
Annexes A and B on Clinical Investigation Plans (i.e. protocols) and Investigator's Brochures are required for compliance, the remaining annexes are for the reader's information. They contain extremely valuable information on organizing case report forms, writing a final report, and understanding the relationships between adverse events and effects.

Other extensive changes
Each section was expanded to include sufficient narrative to teach a new sponsor how to conduct a clinical investigation. This controversial move is meant to educate as well as to set a performance bar. Some notable examples of additions or changes include:
[1] Clearer definitions of adverse events, adverse device effects, and unanticipated device effects.
[2] A new definition, recording, and reporting requirements for device deficiencies.
[3] Requirements for recording and reporting adverse device effects in persons other than subjects.
[4] Implied requirement for a clinical research quality management system.
[5] Requirement for Risk Analysis Report.
[6] Requirement for a Clinical Evaluation Report to justify the study design.
[7] Required content for a protocol (clinical investigation plan).
[8] Required content for an Investigator's Brochure.
[9] Suggested content and organization for case report forms.
[10] Discussion of data monitoring committees.
[11] Requirements for document and data control.
[12] Requirements for electronic data systems.
[13] Auditing recommendations.
[14] Procedures for suspension or premature termination of a trial.
[15] Procedures for working with vulnerable populations.
[17] An extensive list of the documents essential for a clinical trial.
[18] Omission of the annex discussing how to do a literature review.
[19] And, very importantly, two differing attempts at adverse event classification.

The publication plan
FDIS stands for 'final draft international standard'. While the document is in the final draft stage it is being translated into French and German. Once this is complete the FDIS will be presented to the ISO members (Standards Bodies from each member country) for a final vote, but the only changes allowed at this stage will be spelling, punctuation, or grammar. After publication by ISO in 2011, each member Standards Body will adopt the standard into its own system; so in the US the standard will be re-issued as an ANSI (American National Standards Institute) standard of the same number.

Oddly enough, a member Standards Body is free to modify the standard, before issuing it under its own name if it wishes. So buyer beware, the French version may be different from the British version or from the US version!

If you liked the whitepaper, take the workshop
The learning objective of this five-hour workshop is to review the changes from the old, 2003 standards to the new, 2010 FDIS. The recording is available by OnDemand or CD at https://www.clinicaldevice.com/mall/Workshops.aspx.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A 5 hour presentation.
[x] Hints for writing Clinical Evaluation Reports and their role in clinical investigations.
[x] Hints for writing Risk Analysis Reports and their role in clinical investigations.
[x] The required contents of clinical investigation plans (i.e. protocols).
[x] The required contents of investigator's brochures.
[x] Steps in planning clinical investigations.
[x] Steps in implementing clinical investigations.
[x] Steps in closing-out clinical investigations.
[x] The monitor's role in clinical investigations.
[x] Responsibilities of sponsors and investigators.
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Clinical research professionals who estimate study costs.
[x] Project managers who want better planning and reporting from their group.
[x] CROs who want to improve their proposal skills.
[x] Executives who are planning the future of their company.

Presenter
Dr. Nancy J Stark has been a member of Working Group 4 since 2001 and was an active participant in shaping the coming ISO 14155 standard. She is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 5 hour workshop will be presented on Wednesday, 22 September 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc