by Barry Werth
FLEISCHER: 108 and C216 were blinded; 111 was open label.
CLAY: Okay. So my question to that is, you’re conducting a blinded study in which you had a significant difference in rash from one group to the next. So I guess that’s okay if nobody knew that there was the likelihood of a rash occurring.
I was just curious, when the sponsor submitted their material, did they discuss in there how it was managed at the investigator level?
FLEISCHER: The rash?
CLAY: No. The determination as to whether the rash was possibly or probably related to study medication.
FLEISCHER: I think that was in the rash management program. It was in the protocol describing how rash should be assessed and managed, that was given to every site, yes. But Bob can—
CLAY: No, no. I’m not asking about management. I’m asking about the determination in the reporting to the sponsor as to whether or not the investigator felt the rash in and of itself was related to the study drug.
Vertex team members were puzzled and confused by what Clay might be implying. Was he saying they should disqualify patients who developed telaprevir-mediated rash from participating in the trials because the rash presumably gave away who was on the drug, implicitly unblinding the trial? Or were investigators not supposed to talk about it? His words were inscrutable. But his tone was prosecutorial, raising flags. Kauffman, up on the balls of his feet, stepped in, joining with Fleischer to dispel Clay’s concern, whatever it was.
KAUFFMAN: Yes. During the blinded phase, of course, no one knew what the treatment assignments were. The investigators used their judgment to decide whether it was related or not to the treatment that was occurring.
CLAY: But rash was included in the investigational drug brochure provided to the investigators when they were considering taking on this study?
KAUFFMAN: Yes. And by Phase III, there was general acknowledgment that rash was associated with telaprevir, and it was certainly in the investigators’ brochure.
CLAY: Okay. That’s fine . . . My next question actually relates to a different way—maybe it also relates to blinding as well. We talked about an increase in bilirubin within the first two weeks in a fair number of patients. When that sample is drawn and separated, as you need to separate out your samples in order to do viral loads, you’re going to see a nice, pretty, yellow color. I’m wondering, did your placebo color your plasma yellow?
KAUFFMAN: I’m not aware whether it did or not.
CLAY: Because you’re going to spin it down in a serum separator tube to send it off, and you’re either going to have a yellow tube or not. If you did not blind—or unblind and mandate unblinding at the site level for your lab processing personnel—I’m questioning the validity of your blindness.
KAUFFMAN: I mean, I think in most cases the bilirubin levels were not markedly elevated. Therefore, it’s highly unlikely the plasma would actually be icteric [yellowish, jaundiced].
FLEISCHER: Only about four percent were above grade three, so the majority of those were grade one and grade two. And so—
CLAY: Yes. Icteric is a clinical presentation, as I understand it. Now, my disclaimer, I’m just a pharmacist. But I have processed atazanavir drug before, or atazanavir-containing plasma before, and the patient didn’t have to be clinically icteric in order for me to see the yellowing of the serum.
By now it had become widely known among the Vertex group in the audience, and in the packed conference room at JB-II, that Clay had received research funding from Merck. That in itself was common for panel members and Clay received support from many companies. Still, Wysenski, Weet, Pace, and others were anxious that his attack, though relatively inconsequential, could invite other panelists and the public to question whether Vertex had compromised its findings by fudging the impartiality of its trials. Emmens knew the relationship between the FDA and an advisory panel was unpredictable. Safety now trumped all. A few years ago, just one case of Stevens-Johnson syndrome sank a drug, even though dozens of drugs on the market cause SJS. Recently an advisory committee voted 9–0 for approval, and the FDA turned it down. That had never happened before. There were many ways this could go . . .
It can blow at any seam.
While the rest of the Vertex crowd muttered about Clay, Kauffman rose to his full height. He rocked forward slightly, balancing like a crow on a wire.
KAUFFMAN: Bilirubin levels were also elevated in the placebo subjects, as you saw. It’s not very likely that someone, without knowing what the treatment assignment was, would really be able to identify a treatment assignment based on the color of the plasma because elevations occurred in the placebo subjects as well as in the telaprevir subjects.
CLAY: Fair enough, forty percent versus twenty percent.
KAUFFMAN: But those are both high, so in any individual case, it would be hard, I think, for someone to ascertain that. And I think, also, just to go back to your question about rash, as you saw, the rates of rash were quite high in the control arm as well as in the telaprevir arm. True, they were higher. But overall across the study, rash was occurring quite frequently.
Therefore, again, because of that, we think it’s less likely that a patient could be unblinded as to their treatment assignment just by the occurrence of a mild or moderate rash because thirty percent of the control patients had mild or moderate rash. So we felt that, as best we could, that the blind would be maintained.
A cheer went up in the Charles Sanders conference room. Kauffman had rebuffed Clay with science, patience, and logic, while others at the company were reduced to rolling their eyes or cursing under their breath. “And on the seventh day,” someone blurted, “there was Bob.”
Mueller thought the rash discussion reflected the fact that there were no big issues, and he was undismayed by Clay. “I don’t jump out the window because someone has an opinion,” he said. During the public comment period after lunch, the same patient advocates who Wednesday urged the panel to approve boceprevir lined up to support telaprevir. Near the end, a billing supervisor for a Pennsylvania health care provider, Kelly Ann Mann-Hester, told the committee that she got hepatitis C from blood transfusions after childbirth and that she was cured by telaprevir in a clinical trial after having failed six separate yearlong treatments with standard drugs. She was diagnosed in 1993.
“A well-meaning physician at the time told me I would not see my son graduate from high school,” Mann-Hester said. “He had just started kindergarten. I walked out of that doctor’s office that day and told my family that wasn’t an option, obviously . . . I’ve done interferon, interferon with ribavirin, pegylated interferon with ribavirin at half strength, pegylated interferon with ribavirin at full strength, and now with the telaprevir. Telaprevir gave me the clear.”
For seventeen years, Mann-Hester had expected to die young. She didn’t plan for retirement. Now she needed to. Standing at a microphone in the center of the room, she went on: “I did get the telaprevir rash. I had it on my hands, my legs, and my feet. But it was of very little consequence to me, and would it have made a difference if you were telling me it would save my life? Absolutely not. I would do everything in my power to save my life.
“I was in a place where I was living to die. In my mind, I thought this was going to be the thing that would take me. I had already accomplished my goal, which was to see my son not only graduate from high school but from college. And so I had no hope left, that I thought I was going to live with this disease to die. Now I’m living until I die, which is a whole new concept for me, because now I have many windows and many avenues available to me that I did not have before. So I wholeheartedly am asking you to please approve this drug for the general public so that other people can tell my story at some point in time.”
As the panel finished its questioning throughout the afternoon, the mood lifted, markedly. Lawrence Friedman, a gastroenterologist who had written more than one hundred textbook chapters and who teaches at both Harvard and Tufts medical schools, saw telaprevir in hist
oric terms, and he went on record to lavish high praise on Vertex even before the voting, which was conducted by secret ballot, with panelists afforded time afterward to comment. As part of its presentation, the FDA provided a reinterpretation of Vertex’s SVR rate, raising it from 75 percent to 79 percent. Friedman hailed the revised figure. “Considering where we started with non-A, non-B hepatitis, I think that it’s a stunning achievement that we will be able to cure nearly eighty percent of naïve patients and probably the same number of relapsers, two-thirds of whom will only have to take treatment for twenty-four weeks,” Friedman said. “We’ve almost completed a transformation of genotype one into genotypes two and three, which I think is just a remarkable success story.
“The other important aspect of this drug is that the protocol for using it is relatively simple, and it’s familiar because what we’re doing is basically using the same milestones we’ve used for peginterferon and ribavirin and grafting the new protocol onto that. And the drug that is causing us concern in terms of its side effects is only used for twelve weeks. And there’s some wiggle room because if you have to stop it a little early, you might not sacrifice success.
“So I think there are so many positive aspects of this drug, and for those of us who have been in the field, this is a very exciting moment.”
John Alam’s determination to shorten treatment, sparked nearly a decade earlier by his dying father’s illness, as much as any one factor drove Vertex’s clinical strategy. Friedman’s point-by-point endorsement many years after Alam himself had disappeared into the mist of what Ken Boger called “the ghosts of Vertex executives past” testified to his efforts and his urgency. A chorus of accolades built swiftly as the first seven panelists explained their “yes” recommendations. One by one, they thanked Vertex for the thoughtful elegance of its presentation and praised telaprevir—a “tremendous advance,” as Dr. Doris Strader, a Vermont gastroenterologist, called it. Patrick Clay, sitting impassively, was the lone question mark.
Clay explained that he too voted yes, but he downplayed his endorsement, reminding the panel of what he saw as the larger imperative: a better cocktail, soon, while other lives depended on it. “The benefits far outweigh the risk in this, and it is yet another step,” he said. “And that’s all it is. There’s still a long way to go. This is a marathon, not a sprint.”
Nearly all the other committee members effused. Lynda Marie Dee, the patient advocate who’d chided Merck for its purposeful obscurity, raved about Vertex’s careful attention to clarity, transparency, and clinical utility. As Kauffman, Pace, and the company’s image-making team had anticipated, a drug is one thing, a drugmaker’s actions another. Dee said: “You know, there’s a discussion often among activists about whether drug companies should ever get A’s; we do a report card in one of my groups . . . I won’t say that this is an A, but it’s very close to it. I’m very grateful for such clear data, for such concise rules about how to do this, such manageable toxicities. It was a great, really, really excellent application.”
At about four o’clock in the afternoon, an enthusiastic 18–0 vote granted Vertex all it needed and more: a final, unimpeachable seal of approval; the guarantee of a strong label at launch; official parity with Merck; a sense that the last line of the blockade was down and that the ships, at last, after more than twenty years and a total investment of nearly $3.6 billion, could start steaming through. Goldman Sachs immediately sent a note to investors, raising its estimate of Vertex’s chances of approval to 100 percent.
For Vertex, the AdComm was a coronation—its most visible benediction yet, in the arena that mattered most. As for the world beyond, Clay’s point, though voiced begrudgingly, was real. Now that there would soon be available a type of drug—a protease inhibitor—that in combination with the standard medicines could double the cure rate and halve the treatment time for patients with hepatitis C, what then? Dr. Debra Birnkrant, FDA’s director of antiviral products, posed the question, asking panelists to consider what impact the advent of a dramatically improved standard of care would have on the scores of molecules, singly and in myriad combinations, already in human testing. Having to face the rest of the industry, she seemed to want both guidance and cover. Birnkrant:
“Thinking about phrases we’ve heard based on the data we’ve seen over the last two days—that this a game changer, a paradigm shift, and a new era—can you comment on the impact of these drugs on current and future clinical trials with regard to standard of care or control arm? . . . The future is here. It’s not really that far away, and we have to make some tough decisions. And that’s why I wanted to get some input, so that when we go back to companies, we can state the obvious but then have the backing of this committee.”
Two hours later, the team was back in Bethesda, crowded into the wine bar at the Doubletree. Mueller, hoisting a flute of champagne, delivered a long, grateful toast, recognizing one by one the people in the room for their contributions, including the group from Tibotec. Not normally this generous with praise, he was magnanimous, laughing heartily, plainly moved. “Usually I say just something is pretty good,” he said. “This was stellar.”
One of Cumbo’s first decisions after becoming interim vice president of sales was to reschedule Launch Week, moving the traditional sales meeting/pep rally up to the beginning of May even though telaprevir wouldn’t be approved for several more weeks. The chief risk was that Vertex’s field force would train without knowing what was in the final label, but Cumbo wanted his representatives to be ready to start calling on doctors—and outhustling Merck—on “Day One.” Meant both to educate and energize, launch meetings combine the intensity of a maximum-stakes pre-exam crash course with the high-octane buzz of a casino. A recent Hollywood comedy, Love and Other Drugs, included its own version of a Pfizer launch meeting, featuring go-go dancers, the Macarena, and sales leaders who sleep with their trainees.
The commercial purposes of the daylong events—informational sessions, role-playing, KOL lectures, compliance training—were self-evident. Vertex needed to align its reps with the rest of the commercial team, which was rolling out, in waves, a broad educational campaign about hepatitis C and HCV testing; a twenty-four-hour patient hotline; an assistance program to help patients get and, if necessary, pay for its drug; and a city-by city marketing campaign for telaprevir under the trade name Incivek (In-see-veck). Yet, as ever, questions of identity, of values and vision, predominated. Now that Vertex had a drug and a sales force, it could ill afford to have its reps act like, as someone commented, “coin-operated machines.”
Ken Boger planned to retire as general counsel in September—ten years after joining Vertex during the upheaval after 9/11 and the crash of the immunosuppressant VX-745. Standing on the low stage in the America Ballroom at the Westin Copley Place hotel in Boston’s Back Bay in a seasoned sports coat and tie, in front of the undulating digital backdrop that a few reps half-joked might induce seizures, he looked like a hologram of someone’s tough but affectionate uncle, lovable but not to be messed with. He cushioned himself against the pounding rock music that the audiovisual team cranked up to introduce new speaker segments by concentrating on his terse, five-hundred-word speech. Smiling broadly, he began:
“I’m actually very happy to be here today . . . even at eight in the morning. I mean, at this podium, in this city, and at this company, which is on the verge of beginning to achieve a dream that was twenty years in the making. I say ‘beginning’ because our founder—and I understand you heard from him yesterday, and he’s my little brother, and that’s okay—he said, with characteristic hyperbole, that in starting this company that he wasn’t just interested in making drugs, he wanted to change the world. I’m gonna get back to that, but it is, in fact, part of our goals at Vertex. It’s fundamental to our corporate identity, and it’s fundamental to our brand.
“But let me digress for a minute. Who do you suppose was the most admired company in America in 1987, according to a Fortune magazine poll. A
ny guesses? Right, Merck. I’m not going to pick on Merck—actually I am; it’s gonna be a lot of fun. So who do you suppose was the most admired company in America in 1988? Merck. In ’89? Merck. In 1990? Merck. In ’91? In ’92? In ’93? All Merck. In 1993 BusinessWeek called Merck a ‘national treasure.’ ”
For those like Ken who had been with Vertex from its earliest days, the specter/example of that Merck still burned—a sustaining inner flame. Boger’s decision to leave Merck in 1989, at the height of its glory, was their shared backstory for everything since.
“So now let’s fast-forward to 2011,” Ken continued. “Neither Merck nor any other pharmaceutical company was in the Fortune magazine top fifty most admired companies, other than J&J, but people who make powder and Band-Aids don’t count in this analysis. That was despite the same language you see from 1993 about integrity, transparency, and patient focus being used by Merck executives throughout the two decades leading up to the present. An integral part of Merck’s corporate brand was trust, and they lost it, even though they spent a lot of time talking about trust and patient focus.
“The patient wasn’t there when Merck launched a phony journal in 2002 to 2005 in a format designed to convince people it was a real peer-reviewed journal—just to pump their drugs. The patient wasn’t there when Merck made a hit list of doctors to be discredited or intimidated for raising issues about Vioxx, and withheld that data about Vioxx-related adverse events. There are a lot of other examples, not just from Merck, but across the industry over the last two decades.”
Post-Vioxx, Boger’s desire to differentiate Vertex from Merck had taken on a deeper moral gravity, and Ken had been both the company’s wise man and its enforcer. He felt the salespeople needed to understand what Vertex had at stake, not just reputationally, but in what it could become.
“So going back to the founder, who said he wanted to make drugs and change the world, that doesn’t mean that personal goals don’t play a role. One of our earliest advertising slogans was ‘Ambition will cure AIDS before compassion will.’ I really loved that. It wasn’t necessarily the most effective ad, but I loved it. It said a lot to me.