The Antidote: Inside the World of New Pharma (45 page)

Emmens, after spending the day roaming into and out of the Charles Sanders conference room in JB-II, where a shifting crowd of about a
hundred employees munched cold pizza and watched the webcast, was more troubled than he let on. An 18–0 vote meant Vertex could not allow itself to do worse. AdComm votes were nonbinding, but a unanimous recommendation ratcheted up the pressure on Vertex to match Merck’s outcome, lest Merck claim to have the better drug.

As a strong storm system rumbled Thursday morning across Montgomery County toward Silver Spring, the National Weather Service issued a tornado warning. The sky around the modernist, university-scaled White Oak campus was pewter. Inside the Great Room, Kauffman, dressed in a dark grey suit, blue Oxford shirt, and burgundy tie, rocked softly on his heels on the podium, awaiting the next question. As anticipated, rash was the hot topic, and Singhal’s presentation had gone a long way toward reassuring the panelists that telaprevir-related rash was moderate in most cases and that doctors could manage it by following the company’s protocols.

Panelist Patrick Clay sat at the back of the large three-sided conference table. Longish brown hair parted high, he fidgeted with his microphone. He’d grown up in Southern Louisiana Cajun country and worked as an electrician’s helper on offshore oil rigs before getting serious about school and earning a doctorate in clinical pharmacy. He worked eighty-hour weeks and had an expansive résumé, including numerous publications based on his work treating low-income patients with AIDS. He thought the most challenging part of his job was predicting drug interactions and—his confidence in Merck aside—was a persistent advocate for proper DDI studies conducted with real-world drugs and antiretrovirals. Clay leaned in.

C
LAY:
I want to commend Vertex on the array of drug-drug interaction studies they’ve already done as well as the ones they’ve planned. And in your ongoing and planned future studies, I saw on ClinicalTrials.gov that you also are doing one in people who failed telaprevir and continue in that study. So I want to commend you that that’s already up there and listed. But I want to focus in on some of your safety issues.

In the material provided by the Food and Drug Administration, they talk about your metabolite PZA, and they mention PZA is associated or a metabolite of niacin. But I’m more familiar with PZA as a metabolite of pyrazinamide, used in the treatment of tuberculosis.

You’re describing a side effect profile that we expect to see from pyrazinamide. You’ve got increased uric acid, including incidences of gout. You have fever. You have anemia. You have thrombocytopenia. You have a rash. I’m not that familiar with the presentation of the rash in tuberculosis treatment.

But I guess this gets to the fact that you’re giving single therapy to people, and I was curious if in your clinical trials, did you perform a PPD at baseline to see if someone was PPD-positive? And if so, had they already taken medicines for the treatment and prevention of tuberculosis?

It was not a question that Kauffman had anticipated, given its arcane nature. Other members of the Vertex team, scattered among the audience of about three hundred, Googled Clay on their smart phones, tapping to see where he might be coming from or what he might be aiming at with his line of inquiry.

K
AUFFMAN:
We did not provide that information. We did not necessarily test patients. It was really up to the clinicians who enrolled patients to decide if they were eligible for the trial. There was no specific inclusion or exclusion criteria related to prior tuberculosis status.

I’ll point out, though, that the concentrations of pyrazinoic acid—although it is a metabolite of telaprevir—are much lower than the concentrations that are present when pyrazinamide is used as a therapeutic agent.

C
LAY:
I don’t doubt that. But the side effect profile really looks like you’re giving full-dose pyrazinamide. And I’m just curious how much information is provided to the investigators so that they could say, well, we need to test for TB in people before we give
them this medicine. I guess maybe it gets to—I didn’t have a great deal of information about how much of your drug ends up being pyrazinoic acid, and so maybe that would be helpful to me to know that. I don’t really need to know how much of your drug ends up being pyrazinamide or pyrazinoic acid, because it looks like there’s a lot of pyrazinoic acid on board here.

Russ Fleischer, seated farther down one wing of the table amid a lineup of senior FDA officials, delivered the agency’s case for approval. Fleischer had greeted Weet warmly and publicly before the proceedings. He detailed Vertex’s investigations into the most severe cases of rash, discussing at length rare adverse occurrences called SCAR events, and he remarked that a small number of patients on telaprevir—about 1 percent—had increased bilirubin, a yellowish bile pigment indicating a breakdown in a component of oxygen-laden hemoglobin, indicating possible anemia. After the chairwoman invited clarification questions, numerous hands went up. Again Clay importuned.

C
LAY:
I guess the first is just a comment. I have a hard time hearing presentations about dermatology, and your making an abbreviation of a multitude of symptoms and calling it SCAR, because in my mind, a scar is a certain dermatological condition. So that’s neither here nor there. I have a question that relates to how well the study was blinded. These were blinded studies done?

F
LEISCHER:
108 and C216 were blinded; 111 was open label.

C
LAY:
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?

F
LEISCHER:
The rash?

C
LAY:
No. The determination as to whether the rash was possibly or probably related to study medication.

F
LEISCHER:
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—

C
LAY:
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.

K
AUFFMAN:
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.

C
LAY:
But rash was included in the investigational drug brochure provided to the investigators when they were considering taking on this study?

K
AUFFMAN:
Yes. And by Phase III, there was general acknowledgment that rash was associated with telaprevir, and it was certainly in the investigators’ brochure.

C
LAY:
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?

K
AUFFMAN:
I’m not aware whether it did or not.

C
LAY:
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.

K
AUFFMAN:
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].

F
LEISCHER:
Only about four percent were above grade three, so the majority of those were grade one and grade two. And so—

C
LAY:
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.

K
AUFFMAN:
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.

C
LAY:
Fair enough, forty percent versus twenty percent.

K
AUFFMAN:
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.