COT statement on a further toxicity study in the rat of a hydrogel filler for breast implants - March 2002

Further toxicity study in the rat of a hydrogel filler for breast implants following statement of 2000.

1. During 2000, because of concerns raised by clinicians about the safety of the fillers used in breast implants, the Medical Devices Agency (MDA) had decided to review the safety data on all breast implant fillers available in the UK. These included a hydrogel pre-filled breast implant manufactured by Poly Implant Prostheses. In September 2000, at the request of the MDA, the Committee considered a submission questioning the significance of the findings in a 90-day toxicity study in rats implanted with this hydrogel. We concluded:

i) the conclusion of the study, namely that there were no pathological findings in the organs examined, was not supported by the limited experimental results provided, which were considered to be imprecise and inadequate.

ii) the findings from the study could not be discounted. The Committee was not able to exclude the possibility that the reported lesions [in lymph nodes, liver and kidney] were indicative of a toxic or immunologically-mediated response.

iii) further testing should be undertaken involving the administration of single doses of the filler gel with longer-term follow-up and with more detailed reporting compatible with current guidelines for chronic toxicity tests.

2. The product was voluntarily withdrawn from the UK market in December 2000 and an MDA Device Alert was issued to advise plastic surgeons and implanted women. MDA indicated that further advice on the safety of these implants would be provided as soon as it became available.

The implant

3. The hydrogel filler originally comprised 92% of physiological saline gelled with 8% of a polysaccharide. This filling material has subsequently been modified and the saline replaced by a buffer. It is understood that the polysaccharide is based on a cellulose derivative that forms long, linear chains linked by bridges. This gel is contained within a silicone elastomer shell.

The rat toxicity study

4. The manufacturer had provided results from a new toxicity study to address the concerns raised by the original study. Groups of five female rats were injected once in each flank subcutaneously with 1.2cm3 of the modified gel filler material or with saline as a control. Groups of dosed and control rats were killed after 4 weeks and 12 weeks. Limited observations were made during life and at necropsy. In addition to the organs examined histopathologically in the earlier study (injection sites, liver, lungs, kidney, thymus, spleen and "aortic" lymph nodes), mesenteric and axillary lymph nodes, brain, adrenals, ovaries and mammary glands were also investigated. In a number of cases lymph nodes from only 4 animals per group were examined histologically, with no explanation or identification of the animals omitted.

5. In the groups of rats that were killed at 4 and 12 weeks no abnormal clinical signs or differences in body weight were reported for either treated or control animals. However, in the treated animals residues of the gel and tissue damage were observed at the injection site. The histopathological changes in lymph nodes, livers and, to a lesser extent, the kidneys of the treated animals noted in the earlier study were not reproduced to the same extent in this study. There was reduction in adrenal weight in treated animals but the significance of these alterations in adrenal weight had not been investigated further by looking at the pituitary. Pulmonary vasculitis was observed in 60% of the treated group at 12 weeks but was not observed in the controls. The report described these findings as not being of toxicological significance.

6. The Committee considered that, despite having been carried out in 2001 to address its earlier concerns, the study was unsatisfactory in its design, execution and reporting. No explanation was provided for the discrepancies between the previous and new studies in the incidence of the liver and kidney lesions. The effects seen in the lungs and adrenals in the new rat study could be indicative of a toxic response. These changes and those previously observed in the liver and kidney require further study, including investigation of the reversibility of any changes observed.

Degradation of the filling material

7. Limited data were provided on the potential for in vivo degradation of the filling materials (both buffered and unbuffered). A substantial proportion of the dosed material was not recovered and the fate of this material had not been ascertained. The Committee considered that the potential degradation of the hydrogel had not been adequately addressed.

Conclusions

i. The Committee considered that the conclusion of the new study, namely that there were no pathological findings in the organs examined, was not supported by the limited experimental results provided. There were limitations in the design of the study, the interpretation of its findings and the report was considered to be imprecise and inadequate.

ii. The Committee agreed that the findings from the original and new studies could not be discounted. The Committee was not able to exclude the possibility that the reported lesions were indicative of a toxic or immunologically-mediated response.

iii. The Committee considered that the new studies provided no further information to permit clarification of the extent or significance of toxicological risks.

iv. The Committee repeated its previous conclusion that further testing should be undertaken including the administration of single doses of the filler gel with longer-term follow-up. The Committee stressed the need for the design and reporting of further studies to be compatible with current guidelines for chronic toxicity tests.

Secretariat
March 2002
COT statement 2002/01