"If at first you don't succeed, try, try again" is a necessary mantra of drugmakers, especially with the Food and Drug Administration handing down an inordinate amount of complete response letters (CRL).

For most drugmakers, CRLs are more of a to-do list than a flat out we'll-never-approve-this-thing rejection. While going back to the drawing board is never preferable to getting an approval, at least it means there's potential for revenue in the future.

Here are a few to keep your eye on.

The Avandia bystander
The reason the FDA asked Amylin Pharmaceuticals (Nasdaq: AMLN) and Eli Lilly (NYSE: LLY) for more information on their diabetes drug Bydureon was almost certainly because of the heart issues seen in patients taking GlaxoSmithKline's Avandia.

There's not an actual heart side-effect signal that I know of, but the agency wants the companies to run a thorough QT to measure potential heart rhythm problems. Amylin said last week that it plans to resubmit in the second half of this year, so an approval could occur in the first half of 2012.

Breathe deep, third time's the charm?
(Nasdaq: MNKD) got its second CRL this month for its inhaled insulin product Afrezza. The FDA decided that the next-generation device that MannKind plans to sell needs to be compared with the device that the company used in the clinical trials.

It may take the company awhile to run the two clinical trials, but the risk -- assuming nothing else crops up -- seems fairly low. In the worst case scenario, MannKind could probably get the older device approved even if the newer one wasn't deemed the same or better.

A difference of opinions
(Nasdaq: ITMN) got a EU recommendation for its idiopathic pulmonary fibrosis treatment Esbriet, which is tantamount to an approval despite receiving a complete response letter from the FDA. At least the drugmaker will have some revenue coming in while it waits for a U.S. approval.

Good thing, because it could be awhile. This month, InterMune announced that it determined the FDA will need a new trial to gain approval. Passing a new phase 3 trial isn't particularly risky; Esbriet likely works, which is why it'll be on sale in the EU shortly. But investors will have to wait years to see it on sale in the U.S.

A diet duo
Two obesity drugs received CRLs last year, and both are in a state of flux with prognoses that are less certain than the drugs mentioned above.

Arena Pharmaceuticals (Nasdaq: ARNA) has a to-do list for lorcaserin that keeps growing. Based on the recommended experiments, the FDA seems extremely worried about potential carcinogenicity of the drug. It's not easy to explain why a cancer signal that's seen in animals wouldn't be relevant to humans.

You'd think there wouldn't be many surprises for VIVUS' (Nasdaq: VVUS) Qnexa since the drug is made up of two drugs already on the market, but it's the known data that seems to be tripping up the obesity drug. The FDA wants VIVUS to confirm that the potential for a type of birth defect in patients taking Johnson & Johnson's migraine and epilepsy drug, Topamax -- one of the components of Qnexa -- isn't a threat to patients when it's taken for obesity.

Until the pathway to approval is very clear, both Arena and VIVUS are extremely risky.

Try, try, try, and try again
Heading back to the drawing board is no guarantee of gaining drug approval. For every Dendreon's (Nasdaq: DNDN) Provenge, there's a Discovery Labs's Surfaxin, which has had more delays than I can remember.

Investors have to be prepared to cut their losses and move on. Unfortunately, figuring out whether that's necessary is often just as difficult as figuring out whether to invest in the first place.

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Johnson & Johnson is a Motley Fool Inside Value recommendation. GlaxoSmithKline is a Motley Fool Global Gains selection. Johnson & Johnson is a Motley Fool Income Investor selection. Motley Fool Options has recommended a diagonal call position on Johnson & Johnson. The Fool owns shares of GlaxoSmithKline and Johnson & Johnson. Motley Fool Alpha owns shares of Johnson & Johnson. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors.

Fool contributor Brian Orelli, Ph.D., doesn't own shares of any company mentioned in this article. The Fool has a disclosure policy.