Biocomposites Ltd response

Simon Fitzer, Head of Quality & Regulatory Affairs,

Other Contributors:

June 06, 2011

We read with interest the article "Dangers of bone graft substitutes: lessons from using Genex" (Saadoun, MacDonald, Bell and Papadopoulos, JNNP published online March 8, 2011), notably as it purported the potential for Genex putty to "cause soft tissue inflammation and destruction".

All three patients in the article were reported to have wound related adverse reactions. Since initial certification, in excess of 5,000 packs of Genex have been distributed worldwide and, as a percentage of Genex released in 2010, there were fewer than 0.4% reported complaints. None of the reports were related to soft tissue damage.

The article presents a hypothesis that Genex putty "produces sterile pus which destroys adjacent soft tissues"; a mouse study is used to test this hypothesis.

All manufacturers of bone graft substitutes are required to conduct extensive testing of both the raw materials used in the manufacture of their products and the finished device itself in order to show that their devices are biocompatible with respect to the intended application and duration of contact.

Testing to ISO 10993 Biological evaluation of medical devices is advised, not only to ensure patient safety, but also to comply with the demanding international regulatory requirements that apply to the medical device industry.

It should be noted that allograft, such as cadaver tissue and demineralised bone matrix, is not regulated as a medical device either in Europe or the USA. As such it is not subject to the same strict regulatory demands as synthetic bone void fillers.

All bone void fillers (often referred to as bone graft substitutes) are indicated for use in bony voids or gaps in the skeletal system that are not intrinsic to the stability of the bony structure and should not be used where infection is present. They should not be used to overfill or pressurise the defect site.

Any implanted material has the potential to elicit a foreign-body reaction. This reaction depends upon the property of the material itself and also upon the patient and the site of implantation.

As part of the essential requirements for the regulatory approval of Genex putty an implantation study was performed utilizing the Boden model.[1] This involves an intertransverse process spinal fusion procedure in a rabbit. The graft material is placed adjacent to the decorticated vertebral body and between the transverse processes. Macroscopic, radiographic and histologic appearance of the fusion was performed at 4, 8 and 12 weeks following surgery, 6 animals per time point (total 18 rabbits).

In this model, Genex was shown to be safe and efficacious and promoted increasing fusion with implantation time. At no time point (4 weeks minimum) was there evidence of neutrophil infiltrate, either in the graft bed or within adjacent tissue.

Although it is appreciated that this model does not specifically assess an acute soft tissue response, no adverse events or tissue reactions were reported in this study.

The article mentions bone morphogenic proteins. It is now well known that BMP usage in the cervical spine has been associated with soft tissue inflammation and significant adverse events, but has not shown these reactions when used in other sites. This serves to indicate that adverse events can be indication (and patient) specific.

Medical devices in Europe must be CE marked in accordance with the Medical Devices Directive 93/42/EEC (as amended). This signifies compliance to the Essential Requirements (Annex I), including safety and biocompatibility requirements. All approved bone graft substitutes, including Genex (Biocomposites, UK), have been certified as meeting the requirements for class III resorbable devices in the EEC.

Similarly, Genex has been cleared as a Class II medical device by the US Food & Drug Administration (FDA) and is recognised internationally by other regulatory agencies as a medical device.

Finally, being classified as a medical device does not make adverse incident reporting difficult. On the contrary, the homepage of the Medicines and Healthcare products Regulatory Agency (MHRA website: www.mhra.gov.uk), has a clear selection button to "Report Medical Device Adverse Incidents" taking the user directly to the online reporting system.

Synthetic bone void fillers have a long and safe history of clinical use, when used appropriately. The first reported use of calcium sulphate as a bone void filler was by Dreesmann in 1892.[2] The use of tricalcium phosphate as a bone void filler was first reported by Albee in 1920.[3] Their advantages over autograft and allograft tissue have been well documented.

Based on our knowledge of global use, Genex is a safe and effective bone void filler when used in accordance with the Instructions for Use.

References

1. Boden S, Schimandle J, Hutton W. An experimental lumbar intertransverse process spinal fusion model. Radiographic, histologic and biomechanical healing characteristics. Spine 1995;20:412-20. 2. Dreesmann H, Ueber Knochenplombierung. Beitr Klin Chir 1892;9:804-810. 3. Albee FH, Studies in bone growth: Triple calcium phosphate as a stimulus to osteogenesis. Ann Surg 1920;71:32.

Conflict of Interest:

Simon Fitzer and John Cooper are both employees of Biocomposites Ltd (JS is Technical Research Director)

Conflict of Interest

None declared