In a report, the office said changes in how government departments work with each other, and regional and local bodies, must happen if the government is to achieves its ambitious aims for the Thames Gateway area.
But the National Audit Office said the government must come up with a coherent set of plans, better target investment and identify and manage the risks properly in order to do that.
National Audit Office head Sir John Bourn said: 'The Thames Gateway is the most ambitious regeneration and development programme in Western Europe. If these ambitions are to be realised it is crucial that there is stronger cross-government leadership and clearer objectives for local partners to work towards.'
He added: 'An overall programme plan to coordinate projects and give a live picture of what has been achieved and what remains to be done is an urgent priority.'
In line with one of the audit office recommendations, the department had introduced a cross-government board of senior officials to coordinate central government investment and provide stronger leadership.
But the National Audit Office report stressed the government still does not have a single overall, fully-costed plan for the programme to join up local initiatives, commit central government to key infrastructure projects, and consider progress across funding streams.
Other points in the report include:
--The government has not translated its aspirations for high-quality, low-carbon footprint and sustainable development in the area into clear objectives
--The government wants half of the housing developments to be 'good' or 'very good' by 2010, but a recent audit found only 17% fall into that category
--Estimates by the government of total investment in the region is£7bn since 2003, but the report says more investment is needed to deliver the necessary infrastructure and services for sustainable communities to flourish in the Thames Gateway.
--The number of homes built has risen from around 4,500 in 1995-96 to 6,000 in 2005-06. This rate of increase is below that of the rest of the greater south-east and must double if targets are to be met
NAO report The Thames Gateway: Laying the Foundations
Regeneration & transport