Later this year, when the popular statin Lipitor becomes available as a generic drug, many who have taken it faithfully will get a surprise. No longer will their cholesterol-lowering pills be oblong and white.
If they choose a generic alternative, their pills will be anything but that color and shape, and their appearance may change from refill to refill as pharmacists switch among generic competitors.
The result may well be confusion among patients, who often take multiple drugs and have trouble keeping track of them if their shapes and colors change all the time, two researchers at Harvard University say.
With generics accounting for 70 percent of all drugs on the market, the seldom-discussed issue of their ever-changing appearances affects almost anyone who fills a prescription.
"If a patient is on five medications, which is not that unusual, there are over 3,000 possible combinations of pills to navigate," said Dr. Jeremy A. Greene, a physician and historian of science at Harvard Medical School, referring to the number of ways of combining five pills of different shapes or colors.
When patients get confused, many stop taking their drugs. "Everyone has seen a patient who has gone off of a medication because it changed color," Dr. Greene said. "It can lead to disastrous outcomes."
In an article in the current issue of The New England Journal of Medicine, Dr. Greene and Dr. Aaron S. Kesselheim, a physician and lawyer at Harvard Medical School, ask why generic pills look different from their brand-name equivalents and from competitors that the Food and drug Administration certifies as being bioequivalent — having the same effect on the body.
The question seems to have caught many drug makers off guard. Kate Connors, a spokeswoman for the Pharmaceutical Research and Manufacturers of America, a trade group that represents makers of brand-name drugs, said, "We have never seen this come up as an issue."
Bob Lee, a trademark lawyer for Eli Lilly, said patients should know when they are taking something other than a brand-name drug, and a different shape or color communicates this point.
Different appearances also help prevent counterfeiters from flooding the market with look-alikes, he said. By suggesting that generics should look the same as the brand-name drug, Mr. Lee said, the Harvard researchers are advocating a solution that will not help patients.
"What they are really arguing for is a deception," Mr. Lee said.
The shape and color of a particular pill has become a valuable part of its marketing, so much so that generic drug manufacturers sometimes will license the right to make an "authorized" generic — pills that look exactly like the brand-name drugs they are competing with.
Prasco, a maker of authorized generics in Ohio, buys drugs from brand-name manufacturers and puts them in its own bottles. They are identical to the drugs patients are used to, said a company spokeswoman, Kimberly Carroll.
"Wouldn't you like a generic option that provides the identical experience as the brand?" the company asks doctors on its Web site.
A drug's appearance, said Dr. Greene, "has become one more thing that can be sold on the market." The purpose of an authorized generic, he said, is to tell consumers, "Yes, it's a generic, but you can trust it."
He and Dr. Kesselheim report that the idea that generics should look different from the brand-name drugs they replace emerged in the 1960s and 1970s. Some pharmacists began covertly substituting generic pills that looked just like brand-name drugs but were not as effective. Courts agreed that companies had a right to protect the appearance of their drugs.
But in the 1970s and 1980s, the Food and Drug Administration began regulating generic drugs and requiring that they be bioequivalent to their brand-name products they replaced.
As a result, said Dr. Greene, "the problem of poor quality generics became less of a public health concern."
But once in control of the appearance of their brand-name drugs, manufacturers began using a pill's shape and color as a marketing tool. For example, Pfizer featured its distinctive pill for erectile dysfunction, Viagra, in its advertisements, making sure patients knew it was blue and diamond-shaped.
AstraZeneca advertised the gastric acid blocker Prilosec as "the purple pill." When it went off patent in 1989, the company began marketing its replacement, Nexium, as "the new purple pill." Prilosec, on the other hand, was colored pink after it became available as an over-the-counter drug.
Generic drug makers who license an "authorized" generic can start selling their drug as soon as the brand-name drug's patent expires. Not so for most generic drug makers. They compete to get their documentation to the F.D.A. when a drug is going off patent, said David Belian, a spokesman for the Generic Pharmaceuticals Association, an industry group. The first company to get the Food and Drug Administration's approval to sell its generic drug receives, in return, a period of six months when its drug is the only generic on the market, unless an authorized generic also has been licensed.
If so, that six-month period can be a significant advantage for the authorized generic. In the six months after the antidepressant Paxil went off patent, there were two generics on the market. One was authorized and looked just like Paxil. It ended up with two-thirds of the market.
The Generic Pharmaceuticals Association opposes letting authorized generics on the market immediately, during the time when the first ordinary generic is supposed to have the market to itself.
"Exclusivity should be just that," Mr. Belian said.
But Prasco says that authorized generics bring prices down by increasing competition in that six-month period. And look-alike generics make life easier for patients, Ms. Carroll said.
Dr. Greene, however, wonders whether an endlessly multiplying array of drug shapes and colors really makes sense for consumers.
"The current situation reflects an approach to public health law that made sense a half-century ago, but is no longer in sync with how people manage disease with generic drugs today," he said.
