Safety evaluation of phytosterol-esters. Part 9: Results of a European post-launch monitoring programme

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Abstract

Phytosterol-esters were developed by Unilever as a cholesterol lowering novel food ingredient for use initially in vegetable oil spreads. In addition to an extensive package of safety studies and clinical studies a programme of post-launch monitoring (PLM) was developed. PLM was used to address the following questions: (a) Is the product use as predicted/recommended? (b) Are the known effects as predicted? (c) Does the product cause unexpected health effects? The overall conclusions from the PLM programme were: the product is being bought by the target population but intakes are less than the original assumptions made in the risk assessment; long-term use of phytosterol-ester enriched spreads results in a reduction in the serum levels of the most lipophilic carotenoids but at current levels of intake this is unlikely to result in reductions in carotenoids that are of biological significance; evaluation of health related consumer complaints have not indicated any unexpected health effects associated with the use of the product in the marketplace. As part of the European approval under Regulation (EC) No. 258/97 on Novel Foods and Food Ingredients the results of the PLM programme had to be submitted to the European Commission (EC) and reviewed by the Scientific Committee on Food (SCF). They concluded that the study provided valuable information, which complemented the pre-market safety evaluation studies, and that the EC mandatory requirement had been met.

Introduction

Unilever developed phytosterol-esters (also known as plant sterol esters) as a novel food ingredient that enhances the cholesterol-lowering activity of vegetable oil spreads. A comprehensive safety testing programme was carried out (Baker et al., 1999, Hepburn et al., 1999, Waalkens-Berendsen et al., 1999, Weststrate et al., 1999, Ayesh et al., 1999, Sanders et al., 2000, Wolfreys and Hepburn, 2002, Lea et al., 2004) to ensure the safe use of this ingredient in food products. In addition to the safety studies, more than 30 clinical trials, involving more than 2000 individuals, have been carried out at different study sites around the world to demonstrate the efficacy of phytosterol-esters (e.g., Westrate and Meijer, 1998, Hendricks et al., 1999, Neil et al., 2001, Maki et al., 2001, Hendricks et al., 2003). Having established the safety and efficacy of phytosterol-esters as a cholesterol-lowering ingredient, vegetable oil spreads enriched with phytosterol-esters have been placed on the market in more than 20 countries worldwide. To support the pre-market safety assessment of phytosterol-esters a programme of PLM was established to accompany the marketing of the product.

In Europe, Unilever sought approval for phytosterol-esters under Regulation (EC) No. 258/97 on Novel Foods and Food Ingredients. Following a review and positive opinion from the Scientific Committee on Food (SCF, 2000) the application was approved in European Commission Decision 2000/500/EC of 24 July 2000 (EC, 2000). Under Article 3 (EC, 2000) of this decision there was a requirement to establish a post-marketing surveillance (PMS) programme to accompany the marketing of the product. In particular, information was requested on

  • (1)

    individual intakes of the product,

  • (2)

    the extent to which the product is reaching its target group.

PMS is the system in place for monitoring the known and unknown side effects of pharmaceuticals. This is a mandatory system that is the responsibility of the pharmaceutical marketing company to administer, but requires that the results be reported regularly to the regulatory agencies. Access to medicines is carefully controlled through the issue of prescriptions and dispensing through pharmacies or hospitals. Therefore, the main sources of information in PMS for medicines are primarily physicians and pharmacists. Foods are widely available without prescription through retail outlets which means that the PMS system for drugs and medicines cannot be directly applied to food products; therefore a different approach needs to be designed for food products.

Although PMS is not standard practice for the introduction of new food products into the marketplace it has previously been made a requirement of regulatory approval of some food ingredients in the United States. The US Food and Drug Administration (FDA) required the marketing of the artificial sweetener, aspartame and the fat substitute olestra to be accompanied by appropriate post-market monitoring programmes. The findings of both these programmes have been reported regularly in the scientific literature (e.g., Slough et al., 2001, Allgood et al., 2001, Butchko and Stargel, 2001). The request for PMS studies on spreads enriched with phytosterol-esters was the first time such a regulatory requirement of a novel food product had been made in Europe. As with the previous instances in the US, no guidelines were given on the design and conduct of the PMS programme. Given the different requirements for monitoring of foods and pharmaceuticals we developed a scheme to encompass our own requirements as well as the regulatory requirements described in Article 3 (EC, 2000), and, in addition, the recommendations of the Scientific Committee on Food to obtain data on possible adverse health effects. Consistent with PMS for pharmaceuticals and the other monitoring programmes carried out for food products the objective of our programme was to monitor for signals of unexpected health effects and not to monitor the efficacy of the product. To distinguish the system from the pharmaceutical case the term post-launch monitoring (PLM) was used.

In the risk assessment for phytosterol-esters a number of assumptions were made concerning the safe use of spreads enriched with phytosterol-esters. These were:

  • the product would contain 20% phytosterol-esters (12% maximum free phytosterols),

  • the typical daily intake of the product would be 20–30 g,

  • upper (95th percentile) intakes would be approximately 57 g in the UK and 70 g in the Netherlands,

  • consumers would be mainly over 45 years old and concerned about their cholesterol level.

Following review of the Novel Foods application the Dutch competent authority recommended that the level of added phytosterols be reduced to 8% (as free phytosterols) and this reduction was endorsed by the SCF. The typical daily intake and upper intake levels were based on published information on the consumption of yellow fat spreads in the UK and Netherlands and were consistent with product marketing information from commissioned trials. The assumption about the consumer profile was based on market research.

The results of the PLM of vegetable oil spreads, covering the first year (September 2000–August 2001) of marketing of the product in Europe, were reported to the EC in January 2002 and the SCF delivered an opinion on the findings which was published in October 2002 (SCF, 2002). With the introduction of more novel and/or functional foods as well as genetically modified foods to the marketplace there is an increasing interest in PLM in the scientific community and regulatory agencies (e.g., Wal et al., 2003, Hlywka et al., 2003, Amanor-Boadu, 2004). Discussion points include when PLM should be applied, what a PLM programme should deliver and who is responsible for such a scheme. Given the current interest in PLM the time is now appropriate to report our approach to PLM and the findings of our European PLM programme of vegetable oil spreads enriched with phytosterol-esters, covering the first year of marketing as reported to the EC. A summary of the preliminary findings have been previously reported as part of the proceedings of a Functional Foods symposium organised by the Senate Commission on Food Safety (SKLM) of the Deutsche Forschungsgemeinschaft (DFG) in 2002 (Lea and Hepburn, 2004).

Section snippets

The product

The subject of the PLM programme was vegetable oil spreads containing phytosterols-esters. The spreads are high in polyunsaturated fatty acids (PUFA) and contain 14% phytosterol-esters (maximum of 8% as free phytosterols). The phytosterols were obtained from vegetable oil sources and the major sterol components were β-sitosterol, campesterol and stigmasterol. The phytosterols were esterified with fatty acids from sunflower oil and added to the spread as fat soluble phytosterol-esters. The

Part A—is the product use as predicted/recommended?

Market research data from approximately 2000 households over a 12- or 13-week period were analysed. Households included were from the Netherlands, UK, France, Germany and Belgium which were the major EU markets for the product at the time of the investigation. Data are provided for both ‘regular’ purchasers (those who have bought the product regularly during the period being monitored) and ‘all’ purchasers, which also includes those that have only bought the product once or infrequently during

Discussion

The household panel data has shown that the intake for regular consumers at 15–18 g per day is less than the 20–30 g intake that was assumed in the original risk assessment. Furthermore, the estimated 95th percentile intakes of between 27 g and 45 g/day were also lower than the 57 g (UK) and 70 g (Netherlands) per day assumed in the risk assessment. The main feature that this household panel data cannot provide is which member of the household actually uses the product (apart from one-person

Acknowledgements

Developing and implementing a new methodology such as PLM is of course a team effect and has involved a large number of individuals with expertise in a variety of different disciplines from different parts of our organisation. The authors would like to acknowledge the valuable contribution of all those involved with this project without which it could not have succeeded. In particular, Mark Chamberlain, Andrea Dickens, John Dudley, Teresa Herd, Gert Meijer, Kevin Povey, Bart Sangster, and the

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