Pharmaceutical innovation has plateaued as patents expire.

History often repeats itself, and the pharmaceutical industry’s current “innovation gap” is one they’ve seen before — the world’s largest companies find themselves in the precarious position of needing to make big new bets before their once reliable cash cows stumble.

The innovation gap, also called the innovation deficit, is happening as companies watch some of their bestselling products of the last decade approach the end of patent protection — and with biosimilar competition on the horizon, revenues are bound to erode. R&D pipelines aren’t likely to make up the difference in time without some major overhaul, experts say.

Patent expirations are expected to put $226 billion in global prescription sales at risk through 2026, according to a  from Evaluate Pharma. And the replenishment rate of R&D is expected to drop by more than 50% over the next five years, EY analysts  in another report.

Contrary to what the term might imply, the innovation deficit doesn’t come from a lack of new scientific advances, says industry analyst Arda Ural, EY’s markets leader for health sciences.

“The innovation deficit is not because productivity is low,” Ural says, noting there were  approved by the FDA last year. “The challenge here is the imbalance between the loss of exclusivity on the top line, and that top line not being replenished by the pipeline for Big Pharma.”

To persevere, pharmaceutical giants will need to look for new acquisition targets that give them a leg up as they tiptoe toward the edge of the patent cliff, and small biotechs might offer some much-needed pipeline rejuvenation.