Around Â£110million will be provided by the RFU to Guinness Premiership clubs between next summer and June 30, 2016.
And a newly-formed Professional Game Board comprising membership from the RFU, PRL, Professional Rugby Players' Association and First Division Rugby will oversee matters.
Premier Rugby chief executive McCafferty said: "The agreement provides a good balance between what England needs to build on its success and what the clubs need to continue the rapid growth of the professional club game.
"The real work now lies ahead of us to translate this agreement into sporting success and inspiration for those involved in the game at every level."
It is hoped the wide-ranging document, established following years of bitter political dispute that scarred English professional rugby, can bring an end to that feuding.
Rob Andrew, the RFU's elite rugby director, said: "Disputes of the last 10 or 12 years have dogged the game.
"I believe this is an English solution for the English game - not an Irish model, New Zealand model or whatever model - and I hope, once and for all we have put club versus country behind us and we can talk about club and country.
"It is the first time we have reached an agreement, which is a sustainable English solution for the English game, since the game went professional in 1995.
"I think it is the first time that all the parties have fully understood the issues, and this is one of the most significant agreements that has been reached in the past 10 to 12 years.
"It provides a great platform for the English club and the national game, and it will strengthen the excellent work that has already taken place in the Guinness Premiership, the clubs' participation in the Heineken Cup and with England, after successive World Cup final appearances."
From next summer, there will be 32-strong elite player squads established at senior, England Saxons (formerly England A) and under-20 levels, with each player having nominated positions.
Players in the senior squad will be released for autumn international, Six Nations and summer tour block periods, plus a five-day August training camp during non-World Cup years.
Players will be released from their clubs to England duty around two weeks before the autumn Test programme and Six Nations start, remaining with England throughout those periods.
Elsewhere, clubs will be compensated for the number of England-qualified players they include in matchday squads, starting from more than 14 among the 22 between years two and five of the agreement.
And for the first time, there will be separate legally-binding one-year agreements between the RFU, elite player squad member and the player's club.
This will cover subjects like match fees and win bonuses, player intellectual property rights and disciplinary procedures.
For their part, the clubs will retain player contracts, with Premier Rugby solely responsible for Guinness Premiership broadcast and media rights, title sponsorship and partner rights, its marketing and promotion.