The Selling of Retin-A
By Leslie N. Vreeland Reporter associate: Mary Granfield

(MONEY Magazine) – From the moment of birth, you begin to age. The changes are almost entirely internal and imperceptible. But by your twenties, the sun has probably left its first telltale marks on your most prominent feature, your face. You start to get tiny lines or wrinkles. Or as dermatologists put it, you experience - photoaging. Usually by your early thirties, and with each passing year, those first fine furrows begin to deepen and multiply. To some, the lines are signs of character or a merry disposition, to be neither fretted over nor fought against. To many others, though, they are scars -- reminders of the disappearance of youth. Not surprisingly, then, eliminating wrinkles is a roughly $3 billion business in youth-conscious America. We spend $1.2 billion a year on cosmetic creams and moisturizers plus $1 billion to $2 billion on cosmetic surgery, including a widely publicized procedure that calls for collagen to be injected beneath the skin's surface to puff it up and smooth it out. In the past 15 months, however, we have been told that much of this energy and enterprise may have been rendered obsolete by a drug that purports to improve skin tone and erase wrinkles. Its scientific name is all-trans- retinoic acid, but most of us know it by its brand name, Retin-A. Once a popular acne cream marketed by Ortho Pharmaceutical, a $600 million- a-year subsidiary of $9 billion Johnson & Johnson, Retin-A has been hailed by doctors and the press as the first drug (as opposed to a cosmetic) that shows promise not only in treating the symptoms of aging but also in actually reversing part of the process itself. The Los Angeles Times welcomed it as a ''medical milestone.'' Business Week called it one of the ''the best scientific innovations'' of 1988, and U.S. News & World Report described it as a ''facelift out of a tube.'' Even readers of Doonesbury, Cathy and Mother Goose and Grimm have heard about it. And that's the problem. While Retin-A and its active ingredient, retinoic acid or tretinoin, is unquestionably a promising pharmaceutical, too many of us have heard too much about it too soon. The $20, 20-gram tubes of Retin-A are being prescribed and used primarily as a wrinkle cream, though the Food and Drug Administration has yet to rule that it is safe or effective for that use. One estimate of Ortho's 1988 profit from the drug: $20 million. How this important but unproven drug came to command such attention is the subject of this article, which was prepared over four months and involved interviews with more than 150 medical researchers, dermatologists, corporate executives, government officials, university administrators, health-care analysts, attorneys, medical writers and patients. The reporting revealed disturbing trends in the way many major drugs are brought to market and accepted by the media and the public. Among MONEY's conclusions:

-- The pharmaceutical industry increasingly bypasses clinical physicians and promotes new prescription drugs directly to consumers through the popular press, leaving the products' limitations and dangers largely up to doctors to explain. -- Company publicity efforts, backed by million-dollar budgets and aided by public relations firms, sometimes take place long before the drug has been approved by the FDA for the use the manufacturer is encouraging. -- Medical researchers, who have become more and more dependent on pharmaceutical-company funding, potentially compromise their objectivity by accepting fees from drug firms for consulting and for helping to stage persuasive public-information events. -- These close relationships between pharmaceutical companies and doctors -- while a necessary aspect of drug research -- are rarely disclosed to the public. -- The popular press, too often seemingly satisfied by the promise of a nifty headline, doesn't probe the important qualifiers that lie behind nearly all press releases based on medical research. -- The public's ultimate line of defense, the FDA, is overburdened, understaffed and shackled by laws that have failed to keep pace with the industry's increasingly sophisticated publicity techniques. Nowhere have these unsettling trends been illustrated more vividly than in Ortho's effective campaign to transform its modest acne cream into a $115- million-a-year wonder drug. Retin-A has a long history (see page 84). But it was not until the 1960s that retinoic acid, one of the most pharmacologically active derivatives of vitamin A, got its key boost. It came from Dr. Albert Kligman, 73, a brilliant but controversial University of Pennsylvania dermatologist (see page 76). By 1968, after several years of study, Kligman and his colleagues at Penn had concluded that retinoic acid was an effective treatment for some forms of acne. Kligman eventually won a patent entitling him to 17 years of sales royalties -- assuming that a drug based on retinoic acid would win approval as an acne treatment. Winning a patent, however, is just one step in bringing a drug to market. Before sales can begin, the FDA has to conclude that the drug has been proved safe and effective in rigorous clinical trials, often involving dozens of medical centers and thousands of patients. In 1968, Johnson & Johnson launched the acne tests, which these days can easily cost upwards of $5 million. After nearly two years of trials, the FDA approved retinoic acid as an anti-acne medicine in October 1971. Since then the drug, marketed as Retin-A, has been prescribed millions of times. Total sales to date (including those to people buying it for their wrinkles) have exceeded an estimated $250 million. For his part, Kligman says that for the past 10 years or so he has donated his patent royalties -- an estimated 3% of net sales, or roughly $3.5 million last year -- to the Penn dermatology department. ''We are swimming in cash,'' Kligman told the MacNeil/Lehrer NewsHour last fall. Shortly after the FDA approval, some older acne patients -- those over 35 -- began reporting that Retin-A produced a welcome side effect: smoother, rosier, younger-looking skin. Their wrinkles, they said, actually seemed to diminish. While others said it irritated their skin, like a movie that builds box office momentum, the good word slowly spread. Although the FDA had not endorsed Retin-A as a wrinkle fighter, dermatologists prescribed it for that purpose. In so doing, they did not violate any laws or medical ethics. Doctors have wide latitude to recommend approved drugs for whatever use they deem appropriate. Before Ortho could market Retin-A specifically as a wrinkle fighter, however, the drug would have to go through another round of clinical trials to prove whether it really worked -- and was safe -- for photoaged skin. In 1985, after years of campaigning by Kligman and others, Johnson & Johnson decided to begin the clinical investigations. Eight medical centers would test three concentrations of retinoic acid on 620 patients. The trials would begin in early 1987, and if all went smoothly, Johnson & Johnson might have a wrinkle drug to sell by 1990. It is illegal to promote a drug for an unapproved use. Yet early in 1986, before the clinical trials had even begun, Ortho launched a promotional campaign for Retin-A as a wrinkle cream. The press conferences and speakers' tours that Ortho financed -- all pitched through the press to the public -- skirted the law at least. Ortho kicked off its effort in April 1986 by underwriting a two-day educational symposium in Manhattan. The subject was topical retinoids -- a family of drugs that has only one commercially available member, Retin-A. To organize the affair, Ortho enlisted Dr. Barbara Gilchrest, a leading retinoid researcher who is the chairman of the dermatology department at Boston University's medical school. Gilchrest, who says she had had ''a working relationship with Ortho for eight years,'' acted as organizer of the event. Although Boston University served as sponsor, the event's expenses were paid for by a grant from Ortho that was funneled through KPR InfoMedia, a New York City public relations firm specializing in medical affairs. The costs included a $3,000 honorarium to Gilchrest for acting as the event's co-chairman (along with Kligman) and for drawing up a participants' list of around 25 dermatologic researchers from the U.S and abroad. Such symposia are crucial venues for the exchange of scientific information. And were it not for corporate funding, those beneficial get-togethers would rarely take place. Further, drug companies often pay physicians' expenses, as well as give them stipends for organizing, addressing or sometimes merely attending the meetings. This symposium was no exception. Ortho's extra public relations maneuver took place one day after the event ended. About two weeks before the symposium, the Softness Group, another p.r. firm hired by Ortho, sent a bulletin inviting the press -- including television and radio health and life style reporters, assignment desk editors, photographers and women's-interest and beauty editors -- to a ''video and photo opportunity'' with Dr. Albert Kligman. It said he would present the ''first quantitative evidence that photoaging's effects on the skin can be reversed.'' The more than 20 journalists who showed up, including reporters from the New York Times, Medical World News and Time magazine, were offered a press kit printed on Boston University Medical Center stationery. Then they heard from Kligman and three other doctors, including Gilchrest, who had all stayed behind after the symposium to address the media. The evidence they presented to the press was intriguing -- as far as it went. Kligman reported the results of two studies. In one, he applied Retin-A to one forearm of 16 people and a pharmaceutically neutral cream, or placebo, to their other arm. In the second study, he applied Retin-A to the faces of eight people and a placebo cream to six others. Among other things, Retin-A thickened the skin's outer layers, or epidermis, diminished fine lines and increased blood flow.

Three major points were largely lost on the press, however. First, the findings were highly preliminary. Second, the studies were not ''double- blind,'' or controlled to eliminate bias by preventing the researchers from knowing which patients got the drug and which the placebo. And third, the institution that conducted the experiment -- Kligman's dermatology department at Penn -- stood to benefit from its 3% patent royalties on Retin-A sales. As for whether Ortho's press conference broke the law against promoting a drug for an unapproved use, a company spokesman insists the firm was merely educating the public. The briefing was just the beginning of that education process. After the conference, again with Ortho funding, Gilchrest helped the Softness Group organize a national speakers' tour of eight prominent dermatologists to allow them to discuss Retin-A with, among others, TV and print reporters. In each case, Ortho picked up the doctors' hotel bills and air fares and paid them $500 or so for each day they were out of the office. Ortho's Retin-A promotion paid off. Between April 1986 and the end of 1987, the drug made the NBC Nightly News and the Today show. It also got favorable write-ups in national magazines specializing in beauty (Self), science (Discover), health (Prevention) and even celebrity gossip (Us). Yet Retin-A's biggest splash was still to come. In January 1988, the Journal of the American Medical Association published the results of a University of Michigan experiment. The headline said it all: ''Topical Tretinoin Improves Photoaged Skin.'' The issue included an enthusiastic JAMA editorial entitled ''At Last! A Medical Treatment for Skin Aging.'' Its author: Barbara Gilchrest. Gilchrest did not disclose anything to JAMA or to its readers, however, about her involvement with the company on Retin-A, including the $3,000 she got to host the New York City symposium. Later when M. Roy Schwarz, an American Medical Association assistant executive vice president, was questioned by a Boston reporter, Terry Schraeder of WCVB-TV, about the apparent ethical lapse, he issued a statement that read in part: ''JAMA and other publications of the AMA have specific and explicit policies regarding authors' disclosure of financial conflicts. However, considering the size and nature of her grant, and how commonly such grants are given to scientists, we can understand why Dr. Gilchrest did not think of this as a financial conflict that the editors of JAMA needed to be informed of.'' When Schraeder asked Gilchrest about her work for Ortho, she replied: ''Yes, we have a financial ; relationship in this regard, and we have similar relationships with many, many groups. . . This is a fact of life in American medicine today.'' The Michigan study was not officially part of Ortho's eight-center trials. The company funded the research, however. The Michigan team, led by dermatology department chairman Dr. John Voorhees, used a commercial version of Retin-A -- unlike the retinoic acid creams that Ortho was testing elsewhere. What was more, the Michigan substance was twice as potent as the strongest retinoic acid Ortho was using in its eight-center clinical trials. The Michigan study's 40 patients were asked to apply Retin-A daily for 16 weeks. Ten dropped out, three because of severe skin irritation and seven for reasons unrelated to the trials. Of the 30 who completed the regimen, only 15 put Retin-A on their faces (the other 15 used a placebo cream). A total of 30 also spread the drug on one forearm and the placebo on the other. Retin-A was more effective on forearms than on faces. True, 11 out of the 15 who applied retinoic acid to their faces were described by the researchers as either ''improved'' or ''much improved'' generally. But on the test parameter that may be of greatest importance to consumers -- so-called fine wrinkling -- only one patient was rated in either of those two top categories; 13 were designated as ''slightly improved''; and one was described as ''no change or worse.'' No patient responded to the placebo cream on their faces. And then there were the side effects. In addition to the three test subjects who withdrew with skin irritation, 11 others used potent topical steroid creams to calm the redness, scaling, swelling and abnormal dryness that flared up from time to time during the test. In all, more than nine out of 10 participants experienced skin inflammation. Modest though the results were, it's no surprise that the popular press gave the Michigan report a rousing reception when it was published in JAMA. The press was primed. About a week before the article came out, JAMA's parent organization, the AMA, sent a press release to roughly 3,000 science and health reporters, editors and others saying that a soon-to-be published study in JAMA ''indicates that a topical vitamin A-like compound can actually reverse some of the skin wrinkling, roughness and mottled pigmentation caused by chronic sun exposure.'' The AMA also paid for a 90-second video news release for TV. It featured Voorhees and several satisfied test subjects, including one who declared: ''It's a miracle cream.'' The recipients of the press release were notified of a news conference to be held the day before the article's Jan. 22 release. The place: the swank, refurbished Rainbow Room in New York City's Rockefeller Center. Ortho picked up the bill. About 60 journalists showed up. So did Michigan's Voorhees and Ortho's director of clinical research, Dr. George Thorne, who says he was there only to put the findings ''in perspective.'' The main attraction was a slide presentation of several before-and-after test participants by Voorhees. The photos stole the show. ''Amazing,'' recalls conference attendee Dana Longstreet, American Health fitness editor. ''Extraordinary,'' says Cable News Network general assignment reporter Jeanne Moos, who adds: ''Retin-A really sounded too good to be true. Like the fountain of youth.'' Said Voorhees to a Washington Post reporter: ''The effects were far more dramatic than anything I had anticipated.'' He added that the implications ''are pretty big.''

In the end, Voorhees may be proved right. That won't be known, however, for at least another year, when all the clinical trials are completed and the FDA has had time to evaluate the results. Yet the bowled-over press reacted as if all the facts had been served to them along with the Rainbow Room's tortellini salad. That night, Retin-A was featured on all three networks' national newscasts (see the box at right). The next day the drug made the morning programs as well. The story also was front- page news in the Washington Post and USA Today, among other papers, many of which quoted Gilchrest's JAMA editorial. The American Medical Association's video was aired by 225 of the 800 television stations it was fed to nationwide. Ortho's publicity machine reached Wall Street too. Parent company Johnson & Johnson's stock shot up nearly $6 a share the day of the press conference and another $2.86 the next day to close at $79.86. (It recently traded at $87.13.) Analysts said the Retin-A news could not have come at a better time. Johnson & Johnson's last potential blockbuster, the pain reliever Zomax, had been pulled off the market in 1983 after just three years when it was found to cause seizures and other serious side effects. Yet if the FDA endorses Retin-A for wrinkles, its profits could be boundless, especially if Voorhees is right when he says you may have to apply it three to four times weekly, for life, to maintain the results. At current prices, the regimen could cost $100 a year. To its credit, Johnson & Johnson issued a release the day after the Rainbow Room press conference clarifying its position on the Michigan study. ''This was the first report based on a controlled clinical study of the effects of tretinoin on skin aged by the sun,'' the statement read. This study, the company went on to say, ''is one of a series of extensive clinical trials currently under way.'' Not unexpectedly, Johnson & Johnson's official demurrer got lost in the hoopla. Over the next several months the drug became a media marvel. In a national poll conducted last spring by Ortho, 58% of the 688 women questioned had heard of Retin-A; 53% knew it was an anti-aging product; and only 4% claimed that they first learned about the drug from the only person legally authorized to dispense it -- a physician. Demand quickly exceeded supply. Ortho sold 1,162,000 tubes of Retin-A in February 1988 (the month after the Rainbow Room affair), up from 217,000 in February 1987. For the first seven months of 1988, sales surpassed $62 million -- nearly double the total for 1987 -- and hit $115 million by year-end. Despite its consumer acceptance, physicians and researchers interviewed by MONEY continue to question what Retin-A does and in particular what the key Michigan study showed. For a true reversal of photoaging, many dermatologists said they would expect to see structural changes in the dermis, the skin's deepest layer, where wrinkles originate. The Voorhees team found none. Among other concerns raised by doctors: -- The lighting of Voorhees' initial sets of before-and-after photos is poorly controlled and possibly misleading. None other than Kligman, Retin-A's original booster, says: ''I can't get the kinds of results that Voorhees is reporting. Maybe it's creative photography -- what the hell. I don't know what he's doing, but it just doesn't seem right to me.'' Voorhees concedes that he had trouble controlling some early photo sessions (see page 78). But he's quick to add that the Michigan study's data was based not on photographs but on observations made by the doctors. In light of that fact, says Voorhees, ''pictures are indeed irrelevant.'' -- The wrinkles could simply be diminished when Retin-A irritates the skin, puffing the epidermis and smoothing it out. One way to settle this point could have been built into the Michigan experiment. ''If one were seeking the truth,'' says Rockville, Md. dermatologist Robert Katz, ''Voorhees would have included a mild irritant as a control.'' Voorhees, however, rejects that approach totally. He says using such a control would be enormously complicated. ''I wouldn't consider undertaking that,'' he says. ''It would be an absolute nightmare.'' -- Although JAMA had billed it as a double-blind experiment, Voorhees says his study probably did not meet that standard, nor therefore was it bias-free. Indeed, Voorhees' report in JAMA conceded that researchers may have been able to tell who was getting the Retin-A by the periodic inflammation it caused. ''There is probably some bias,'' Voorhees adds, ''but it's certainly not all biased.'' -- The fact that none of the patients responded to the placebo cream on their faces is highly unusual. ''That's the first time in history that someone could do that,'' says Kligman. ''Maybe it shows a bit more enthusiasm than people should have.'' Voorhees accepts that view. ''Probably some of that is bias,'' he says. -- Like Kligman, Voorhees is a controversial figure in the tight-knit world of dermatological research where, as in other forms of scientific pursuit, grantsmanship, gamesmanship and jealousy are to be expected. In MONEY's 50 or so interviews with leading dermatologists, including about 20 with physicians suggested by Voorhees, critical comments about his research methods and relationships with drug companies surfaced repeatedly. Many praised him: ''He is as careful, discriminating and scrupulously honest a guy as I know in dermatology,'' said Dr. David Bickers of Case Western Reserve University in Cleveland. No fewer than 22 who were familiar with his work, however, questioned his objectivity. ''Another self-promoting Voorhees study?'' asked one former University of Michigan dermatologist who, like many we spoke to, cited dermatology's small professional community as a reason for requesting anonymity. Said another: ''His enthusiasm over this study makes me question his objectivity.'' Doctors are concerned about researcher biases now that drug companies have become so instrumental in funding scientific work. Outside of AIDS research, there are fewer federal dollars available and more competition for them. With money dwindling, Boston University's Gilchrest says: ''There has been an increasing tendency for good university scientific investigators to work with industry.'' Dr. Aaron Lerner, Yale's former chief of dermatology, puts it differently. ''In my generation, the brightest doctors were adept at getting funds from the NIH,'' he says. ''But now the most talented doctors are becoming managers.'' And NIH researcher Walter Stewart adds bluntly: ''The influx of drug company money threatens research objectivity.'' Voorhees' Retin-A studies illustrate the blurred ethical standards of this new environment. Since 1985, Michigan's clinical pharmacology unit -- the dermatology department subgroup that tests new drugs -- has received roughly $390,000 from Ortho. That figure represents about 10% of the money the Michigan department has received for drug testing from pharmaceutical firms in that time. And it includes a $166,750 grant that the Michigan unit got from Ortho to study retinoids in September 1988 -- nine months after Voorhees' first results were published by JAMA. Within a year after the JAMA article, Voorhees had added both Ortho and Johnson & Johnson to the string of a dozen or so companies that pay him to serve as an expert consultant. Patricia Woolf, a Princeton University sociologist and lecturer who has written extensively on scientific misconduct, agrees that a medical researcher's financial relationships with drug companies are ''a fact of life,'' as Gilchrest says. But Woolf adds: ''It is not one that should go unexamined.'' In medicine, she says, full disclosure is the public's guarantee of academic honesty. ''The lack of it,'' she says, ''sets a very dangerous precedent.'' And, observes Bradenton, Fla. dermatologist Dr. David Fulghum, who himself is studying Retin-A for Ortho: ''My concern is that in this case, science and marketing are becoming confused.'' The FDA is concerned as well. Kenneth Feather, acting chief of the agency division that monitors drug advertising and promotion, says: ''Press conferences based on preliminary results are highly inappropriate.'' He sees nothing wrong with a doctor receiving money to pitch a product. But he adds, ''Most people don't know when a doctor is in fact a paid spokesman.'' To carry out his job as the government's point man in ensuring that pharmaceutical companies' public claims are not illegal, misleading or inappropriate -- which theoretically means reviewing every print, radio and television ad for every prescription drug, as well as every press conference and new-style promo video -- Feather has a staff of five and a budget of about $370,000, including salaries. By comparison, Upjohn has spent an estimated $30 million to promote its anti-baldness product, minoxidil (see page 87), since last November alone. The FDA is further handicapped by a sophistication gap. Speaking of Ortho's Retin-A efforts, Feather says: ''Frankly, we are novices at some of this and are kind of feeling our way. The new promotional techniques, such as press conferences, are getting into an area of the law that lawmakers didn't envision.'' Feather's small staff has not been idle. It noted the headlines that came out of Ortho's Rainbow Room press conference, and on March 10, Feather sent a pointed warning to Russell Hume, the company's head of regulatory affairs: ''Your firm, as the sponsor of Retin-A, is fully aware that it is illegal to promote a marketed drug for unapproved indications.'' Ortho's sponsorship of the event, the letter went on to say, ''could be interpreted as a willful attempt to circumvent sections . . . ((of the Federal Food, Drug, and Cosmetic Act)), which prohibits promotion of an investigational drug.'' Feather dismisses the company line that Ortho officials attended the press conference only to put things ''in perspective.'' Says Feather: ''It seems they didn't do a very good job.'' Then last July, concerned by Retin-A's accelerating sales, the FDA's commissioner, Frank Young, issued a news release warning the public that the use of Retin-A for photoaging was ''an expensive therapeutic gamble.'' The release addressed the Voorhees study by underscoring the small number of patients involved and ''the subjectivity of the observations.'' Young added, ''Unfortunately, consumers have apparently accepted the reports of this one small study as gospel.'' There is no conclusive evidence, he said, that Retin- A reduces wrinkles. The search for that evidence continues and, despite the FDA warnings, so does Ortho's apparent effort to promote its drug for photoaged skin. For instance, Johnson & Johnson underwrote an eight-page promotional brochure on aging. The fliers were distributed last September to 750 or so dermatologists' offices nationwide and, among other things, suggested that patients ask their doctors about retinoic acid as a treatment for photoaged skin. In addition, on Oct. 18 the company held another New York City press conference to announce the FDA's approval of a new, lower-dose form of Retin-A as an acne treatment. The new version was aimed at patients who had found the existing formulas too irritating. George Thorne, Ortho's head of clinical research, restricted himself to discussing the new cream's anti-acne applications. But when the inevitable questions about Retin-A's use for photoaged skin came up, he simply referred them to two clinicians Ortho had brought in for the occasion -- Dr. Stephen Mandy of the University of Miami and Dr. Michael Reed of New York University. Both men, who have served as paid consultants for Ortho, praised the new, milder Retin-A as a wrinkle fighter. The new cream, said Mandy, ''is much less irritating, so I suspect this product will be easier to start ((patients on)) for wrinkling.'' And last December, in Washington, doctors and reporters at the American Academy of Dermatology's annual meeting heard Gilchrest break new ground. She announced that preliminary results from two medical center trials suggested that Retin-A might be helpful in arresting precancerous lesions associated with certain forms of skin cancer. No matter that the lesions precede malignancy in a small number of cases -- perhaps as few as 1% -- or that partial data were in for only two of the project's 10 trials. Suddenly, to eager researchers, journalists and patients, Retin-A sounded like a cancer preventive. Today, some answers about Retin-A as a wrinkle cream seem closer at hand. In late January, MONEY met with Ortho's Thorne at company headquarters. He said results coming in from the eight-center double-blind trials indicated that the drug's effects on sun-damaged skin are real -- but modest. ''These ((changes)),'' he said, ''are all pretty mild.'' Still, he maintained that someday the remarkable little drug with the big reputation might become part of a treatment program for sun-damaged skin. Like Voorhees, researchers are taking rolls of before-and-after photographs to document the drug's effects on wrinkles. Thorne offered to show some of the official transparencies. But as he stood over a lighted table to display the pictures, he hesitated. ''Which is 'after?' '' a MONEY reporter asked. Thorne paused. He leaned close to the photos and studied them intently. ''This is a little bit . . . yeah, this is a little difficult.'' He shuffled the photos back and forth. ''Indeed,'' he concluded, ''the changes are all very subtle.''

BOX: For the Record And that's the way it is (these days)

Hours after Ortho's major press conference last year, dividends appeared. The drug was featured on all three network evening news shows. Only the ABC story introduced by anchor man Peter Jennings, however, emphasized that the drug's test results were preliminary and ''in no way indicate that Retin-A is some kind of fountain of youth.''

BOX: Time Line Wonder drug: 1913 to . . . ?

1913. Vitamin A is identified by two University of Wisconsin scientists.

1946. Dutch chemists synthesize retinoic acid, a vitamin A derivative.

1968. University of Pennsylvania researcher Albert Kligman concludes that retinoic acid alleviates acne.

OCTOBER 1971. The FDA approves retinoic acid as an acne medication.

MID-'70S. Acne patients say Retin-A produces younger-looking skin.

1985. Johnson & Johnson's Ortho unit decides to test Retin-A on wrinkles.

APRIL 1986. With Ortho funding, Boston University researcher Barbara Gilchrest helps publicize Retin-A's effect on wrinkles.

JANUARY 1988. Ortho underwrites a major press briefing to promote what was billed as a double-blind study of Retin-A's favorable impact on human skin.

FEBRUARY 1988. Retin-A pops up in Doonesbury as the wonder drug takes hold in the nation's consciousness.

MARCH 1988. The FDA warns Ortho that it is illegal to promote Retin-A for the unapproved use of fighting wrinkles.

JULY 1988. The head of the FDA assails Retin-A publicly as a ''an expensive therapeutic gamble.''

OCTOBER 1988. Ortho hosts another press briefing to introduce a new, milder Retin-A for acne. Reporters focus instead on its suitability for combating wrinkles.

DECEMBER 1988. Gilchrest tells reporters that Retin-A might help arrest certain precancerous skin lesions.

CHART: NOT AVAILABLE CREDIT: Source: Paine Webber estimates and MONEY research CAPTION: ORTHO'S WRINKLE PAYS OFF It took Ortho 16 years to 2* build sales of its acne treatment Retin-A to $33.5 million in 1987. But after a key Ortho press conference pitched it as an effective wrinkle cream, sales nearly doubled to $62.3 million in the first seven months of 1988 and went on to hit around $115 million at year-end.