Сергей Пузанов – Multiple Sclerosis. Everything you need to know (страница 18)
Why bring this up? When multiple sclerosis patients demanded that interferons slow down their disability, Biogen replied, "Absolutely. But first, let’s define what qualifies as a slowdown." Biogen defined "disability progression" as an increase of 1.0 full point on the EDSS scale, which then had to be verified by a repeat audit six months later. They termed this metric SDP—Sustained Disability Progression. Soon, the industry would rebrand it as CDP, Confirmed Disability Progression, and it remains a core endpoint in DMT trials to this day. But here is the critical catch: if after six months the patient's walking or coordination naturally bounced back to baseline and the deterioration failed to confirm, the "odometer" was entirely wiped clean—the progression was logged as unconfirmed. Furthermore, the calculation completely ignored the patient's starting line, erasing the massive functional difference between shifting from 1.0 to 2.0 versus dropping from 5.0 to 6.0. The non-linear nature of the EDSS manufactures a wall of statistical "noise" spanning dozens of percentage points. Under unblinded conditions, the loose handling of scores below 3.5 leaves researchers massive room to steer the metrics. Once the stage was set for these statistical miracles, all Biogen had to do was navigate the blinding problem.
As their corporate attorneys predicted, the blinding issue resolved itself because the FDA had trapped itself with its 1993 Betaseron ruling. By approving the first interferon despite an entirely compromised trial design, the agency had locked in a legal precedent. Tightening the scientific screws on the very next drug would be an implicit admission that their initial standard was dangerously low. Bureaucratic regulators almost never do this—partly out of sheer institutional inertia, and partly out of fear of nuking public trust in their own past decisions. The FDA officials chose not to rock the boat, likely comforting themselves with thoughts like: "Well, the scientists engineered it, so it must do something useful."
Let’s look at a few numbers to put the scale of this market into perspective:
In its 2007 financial report, Biogen stated that the number of patients on Avonex crossed 135,000, translating to roughly 7 million injections a year.
At launch, a single injection cost about $250. By the early 2000s, that bounced to $400–$500. By the 2010s, it hit $600 per shot.
Over 25 years, anywhere from 600,000 to 700,000 patients cycled through Avonex therapy.
Cumulatively, patients stuck themselves with Avonex between 50 and 70 million times.
Total global sales for Avonex look back on a mountain of roughly $40 billion.
The regulatory compromise the FDA signed under public duress in 1993 did not happen in a vacuum. It forged a precedent that permanently rewrote the rules of the game: clinical trials for DMTs were effectively excused from maintaining strict double-blinding, rigorous efficacy filters, or clinically meaningful endpoints. A drug whose utility was proven purely at the level of loose definitions and statistical assumptions transformed into a multi-billion-dollar corporate juggernaut—and laid down the new baseline framework for how the entire industry would operate for decades. Patients desperately wanted a weapon against multiple sclerosis, and the market gave them exactly what they asked for.
Let's look under the hood of the Avonex trials. The study was exceptionally small, tracking just 301 people: 158 patients injected Avonex, while 143 were given a neutral solution as a placebo. Defining what actually constituted a "relapse" was left entirely to the discretion of the investigators. Because a new interferon molecule was practically pre-ordained for commercial success under the existing rules, Biogen had zero financial incentive to fund a massive, multi-center trial. Nobody wanted to dig into the Pandora's box that Betaseron had opened. In May 1996, Avonex sailed through FDA approval, hit US pharmacies by summer, and locked in the precedent: DMTs could legally claim efficacy without bulletproof double-blinding.
But what about the fact that Avonex actually showed lower real-world efficacy because of its slashed dosage and weekly schedule? The drop in performance was real: the trials proved Avonex lowered relapses by only 18%, compared to Betaseron’s 31%. To spin the launch of a less effective drug to the public, the marketing departments simply deployed a single, devastating counter-punch: "Betaseron had zero proven impact on long-term disability, but Avonex slows it down by 37%." I can easily visualize the Biogen executives trying to smother their laughter in corporate boardrooms. Meanwhile, the team at Schering/Bayer must have been utterly sick to their stomachs when they realized how badly they had botched their own data mapping by failing to lock down a disability endpoint. That single mistake evaporated billions of dollars.
The most incredible part of this narrative? Nobody in the medical community seemed bothered by the logical contradiction: a heavy dose of Betaseron (250 mcg every other day) reduces relapses by 31% but fails to alter disability, while a tiny dose of Avonex (30 mcg once a week) reduces relapses by just 18% but magically slows disability by 37%. Let's look at the weekly math: an Avonex patient takes 30 mcg a week, while a Betaseron patient takes 875 mcg a week—a nearly 30-fold difference in active compound. It brings to mind the old idiom about trying to pass off rain as a divine blessing.
I couldn't find exact global registries for the total MS population in 1996, but the corporate press releases from Biogen and Teva during that era continue to quote the exact same static estimate from 1993: 250,000 patients in the US. It was right around this window that MRI scanners began their rapid, systemic rollout across municipal hospitals. By 2001, the first version of the McDonald criteria was officially adopted, anchoring the MRI as the absolute center of MS diagnostics. Almost instantly, the official patient counts in the United States began a steep, relentless climb.
Subcutaneous Interferons Beta-1a
Patients demanded a slowdown in their disability progression, and now interferons were more than ready to give it to them. In reality, the only limits on these numbers were set by common sense. Pushing a trial design to show a 50% disability slowdown wouldn’t have been that difficult given the elastic nature of the EDSS scale, but doing so would have drawn a dangerous amount of scientific scrutiny to the drugs. By the way, I suspect the relatively high figure of 37% chosen by Biogen was a calculated tactical move. If the manufacturers of Betaseron had been a bit bolder and "proven" a 60% relapse reduction, everyone else in the market would have had far more breathing room to manipulate their own data.
The next titan to step onto the interferon battlefield was Rebif. The molecule was engineered by the Swiss biotech firm Serono in 1998, and it almost instantly sailed through European regulatory approval. However, its launch in the United States got bogged down for years—not because of the FDA, but due to vicious patent litigation between the pharmaceutical giants. Serono wanted to patent their specific manufacturing tech and proprietary formulation of interferon-beta-1a, which was tricky considering Biogen’s near-identical Avonex was already selling out worldwide. Still, Rebif brought one key operational upgrade to the table: it was injected subcutaneously (under the skin) rather than deep into the muscle.
Serono’s legal and marketing teams took a far more aggressive track than their rivals. They set out not just to capture a slice of the market, but to lock down exclusive rights to the underlying tech and freeze out future competitors. They claimed that their signature bio-reactor setup yielded a completely peerless molecule—an interferon so uniquely potent that contrasting it with existing brands was structurally incorrect. Furthermore, they asserted that the scientists at Biogen were dead wrong or had actively misled the medical community: to actually change the course of multiple sclerosis, you had to inject interferon beta-1a three times a week, and it had to go under the skin. Never mind that the molecule was supposed to be highly stable in the human body. Sure, the patient would have to endure a non-stop, three-fold increase in fevers and skin reactions, but we are talking about modifying an incurable disease here! This wasn't the place for soft compromises or comfort.
The US chewing gum market in the 1970s and 1980s was saturated to absolute capacity. Five massive conglomerates led by Wrigley had hit a wall where scaling sales volume was physically impossible: gum was already sold at every cash register, and everyone who wanted to chew was already chewing. Wrigley’s marketing strategists solved this market saturation with a stroke of genius: they decided to force existing consumers to double their consumption. They launched a wave of hypnotic TV commercials showing people experiencing pure bliss by tossing two pieces of gum into their mouths at once. The ad copy hammered home the message: