England head coach Stuart Lancaster has dropped Danny Care, Billy Vunipola and Kyle Eastmond from the squad for Saturday's clash with Samoa at Twickenham.
The trio all started the season's first two QBE autumn internationals - three-point defeats to New Zealand and South Africa - but will be replaced in the squad by Richard Wigglesworth, James Haskell and Billy Twelvetrees respectively.
Lancaster said: "We always wanted to use these four games to look at options in our squad and Billy, Richard and James have been in great form for their clubs and pressing hard in training.
"Kyle has not been able to train due to the Graduated Return To Play protocol and will return to Bath to continue that process and hopefully he should be available for his club this weekend along with the other released players."
Twelvetrees appears the most likely to go straight into the starting XV with the likes of Ben Youngs and Ben Morgan pushing for inclusion at scrum-half and No 8 respectively.
Another option available to Lancaster is to switch Owen Farrell to inside centre in order to include the promising George Ford at fly-half, although the Saracens star may be rested having appeared to be limping at various points during Saturday's defeat to the Springboks.
Wasps' Haskell, who can operate at flanker or at No 8, faces competition from incumbents Chris Robshaw, Tom Wood plus Morgan for a starting role in the back row.
Forwards: Attwood, Brookes, Hartley, Haskell, Kruis, Lawes, Marler, Morgan, Mullan, Robshaw (captain), Webber, Wilson, Wood.
Backs: Barritt, Brown, Farrell, Ford, May, Twelvetrees, Watson, Wigglesworth, Yarde, Youngs.
Returned to Premiership clubs: Burrell, Care, Clark, Eastmond, Vunipola.
Watch England's clash with Samoa live on Saturday from 6:30pm on Sky Sports 2 HD. Lancaster will name the team at 4.15pm on Wednesday afternoon - details on Sky Sports News HQ.