(Second of four parts: read Part one)
I never got a confirming report from my dinner-meeting colleague on Strattera. Indeed, in the ensuing years, despite a massive marketing campaign directed at both physicians and patients, Lilly failed to get Strattera approved as a first-line ADHD drug by any of the major pediatric or professional child psychiatric organizations. In a head-to-head competition with Concerta, Strattera was found to be only six-tenths as effective as Concerta in ameliorating the symptomatic behaviors of ADHD. It was especially poor in addressing the inattentive behaviors (daydreaming) of the non-hyperactive form of ADHD. (The study was funded by Janssen, maker of Concerta.)
Nonetheless, while the risk of abuse in a child under 13 is essentially zero, parents fear stimulant drugs' reputation, and Lilly's marketing of Strattera as a non-stimulant alternative had some impact. It ultimately occupies only around 5 to 7 percent of the ADHD medication market. While that may not sound like much, 5 percent represents $500 million annually in what is currently a $9 billion market for ADHD medicines overall.
There are many complex and related reasons why, in 2012, the U.S. comprised 4 percent of the world's population but produced and used 70 percent of its legal stimulants. On balance, however, drug companies were -- and continue to be -- the largest single influence. Not only do they fund ADHD research and professional education, they market to doctors, teachers, parents, and, ultimately, even the children of this country.
Of course, drug companies have always promoted their products to doctors, albeit with significant restraints. A century ago, organized medicine began to separate itself from the patent-medicine makers of the time, garnering in the process a newfound respect from the general public. This shift was influenced by the 1910 Flexner Report on the state of American medical schools. By the 1920s, drug company ads in doctors' journals were carefully scrutinized before being run. (This was well before the FDA demanded certain standards of effectiveness and safety in pharmaceutical products.)
There were also innocuous promo inducements. In the 1950s and early 1960s, my father -- a general practitioner in Queens, New York -- let me go through his professional mail looking for drug company boxes and trinkets. I'd find packets of writing pads, a ballpoint pen, sometimes a weird and cheap artifact with the name of the drug and the company on it. I'd play with them for a while, then toss them out.
But by the 1980s, the relationship between doctors and the drug industry was changing. During the Reagan administration, with the passage of the Bayh-Dole Act, academic medical researchers and for-profit corporations were encouraged to integrate their efforts. The act allowed businesses, nonprofits, and universities to claim ownership of discoveries that had been funded by federal money; previously, patents to scientific breakthroughs achieved with federal sponsorship had to be transferred to the government.
For me, the first signs of change came in the mid-1990s, with Shire Pharmaceuticals' introduction and marketing of Adderall. Shire, a company based in the United Kingdom (technically on the Isle of Jersey in the English Channel for tax purposes), was and continues to be the most aggressive and dominant marketer of legal amphetamines in the United States.
Typically, Shire's approach has been to buy smaller drug companies outright. Take, for example, Richwood Pharmaceuticals. In early 1994, Richwood -- a company started by Roger Griggs -- acquired a defunct New Jersey manufacturing plant. Twenty years earlier, the plant had produced Obetral, an amphetamine product used for the treatment of obesity. Under pressure from the FDA, women's groups, and trial lawyers, the market for diet pills was shut down, and Obetral went into obscurity.
Not surprisingly, a change in the national education laws in 1991, which for the first time included ADHD as a covered diagnosis for services and accommodations, led to an upsurge in its diagnosis. Mr. Griggs, whose purchase of the plant had likely been inspired by this development, brought back the former obesity drug and renamed it Adderall. Enter Shire, which bought Richwood Pharmaceuticals for $186 million in 1997.
That same year, I began noticing ads in the major professional journals promoting Adderall as a long-acting stimulant over Ritalin, a methylphenidate product that had been a mainstay ADHD treatment since the 1960s. Ritalin itself had replaced Benzedrine, one of the first legal amphetamine products like Adderall. Methylphenidate, the active ingredient in Ritalin, while not identical to amphetamine, is very similar in both structure and action.
Ritalin became the predominant stimulant prescribed by doctors for two reasons. First, Ciba-Geigy (now Novartis), the makers of Ritalin, organized some modern research that established its short-term effectiveness; Benzedrine was supported by only a few original studies carried out by Charles Bradley, a pediatrician who, in 1937, was the first to note stimulants' effects on children's behavior. Second, Ritalin wasn't an amphetamine. Simple as that.
Parents and doctors had known about amphetamines' risks of abuse and addiction since the 1930s. With Ritalin, doctors could tell their patients' parents that their children weren't taking an amphetamine, which technically, it wasn't, even though the positive effects, side effects, and risks were essentially the same for both drugs when tested in large groups of children and adults.
Thirty years later, Ritalin was the most widely known and frequently reviled of the stimulant-type drugs for children, and part of Shire's advertising campaign was strikingly analogous to the earlier Ciba-Geigy approach. This time, Adderall was marketed as the "not-Ritalin." On a much, much larger scale, doctors could tell parents that this was Adderall, not Ritalin, and everyone could heave a sigh of relief. At least it's not Ritalin!
As someone who knew how similar the two drugs were, I found the switcheroo ironic, almost amusing. But I considered another part of the Shire marketing campaign to be supremely disingenuous. Shire compared Adderall's length of action, which varied from about four to eight hours (depending on the individual), to Ritalin's, which was generally three to four hours. Length of action was quite important, because in the 1990s, there were no real long-acting (ten- to twelve-hour) stimulants as there are today (Concerta, Adderall XR, Vyvanse, Metadate CD, etc.).
Absent this feature, many children required multiple daily doses. In schools across the country, children lined up in potentially stigmatizing and embarrassing queues around lunchtime for their second dose of the day. A long-acting drug that covered at least the school day (six hours) would therefore have great appeal. So, in comparing Adderall's length of action to Ritalin's, Shire executed a masterpiece of marketing.
However, the company didn't mention the Dexedrine Spansule, a stimulant product made up of dextroamphetamine, the active isomer of amphetamine. (All molecules have right- and left-sided mirror images; in ADHD treatment, only the right-sided molecules are active in the brain.) This drug had been available for thirty years and consistently delivered about six to eight hours of more focused, steady behavior. It was also cheaper than Adderall.
Nevertheless, thanks to a relentless advertising campaign in professional journals, regular visits by Shire drug reps to doctors' offices, and a barrage of professional medical educational speakers on the benefits of this new preparation, Adderall quickly passed Ritalin as the most frequently prescribed brand-name stimulant drug in America. Generic methylphenidate (cheaper than Ritalin or Adderall) remained the overall most prescribed drug for ADHD.
Over the years, Shire has become associated with virtually every kind of stimulant and delivery system available. When long-acting Concerta came out, Shire quickly followed with Adderall XR. Another of Shire's drug-company acquisitions had developed Daytrana, a skin patch, which allowed methylphenidate to be absorbed transdermally instead of being swallowed, an obvious benefit for younger children who couldn't be depended upon to swallow pills intact. But Daytrana turned out to be problematic and never really sold well, in part because of persistent skin irritation at the site of the patch and the fact that children could remove the patch themselves if they wanted to.
Shire was much more successful with their 2007 purchase of New Rivers Pharmaceuticals, which developed a compound molecule called lisdexamfetamine, a drug initially created to make abuse more difficult. Shire named it Vyvanse. With Vyvanse, the amphetamine molecule is linked to the amino acid lysine, which renders the amphetamine inactive until digestive enzymes cleave the chemical bond and free it up. In other words, the pill has to be swallowed in order to be effective. The risk of abusing the drug is greatly diminished because, if crushed and snorted (the most common method), its amphetamine component doesn't work.
Yet Shire has never highlighted the anti-abuse aspect of Vyvanse; I suspect they are concerned they'd be criticized for having promoted and sold the most widely misused and abused of the stimulants, Adderall. Instead, they've heavily marketed Vyvanse as "the longest lasting" of the long-acting stimulants. In fact, Vyvanse may last all of an hour or two longer than Concerta or Metadate CD.
(Part three of Witness to Corruption to follow)