Pharmacy Blog: Read information and Buy Medication

One year after Novartis won FDA approval for a new type of drug to treat relapsing forms of multiple sclerosis and delay the progression of physical disabilities, the drugmaker is now investigating a death tied to its pill, which is called Gilenya. The disclosure, which was made by a Wall Street analyst, has the potential to cast a pall over a drug that has been expected to generate blockbuster sales.

Specifically, this is the first death of a patient within 24 hours of taking a first dose. For now, an exact cause of death has not been disclosed, and the drugmaker suggests that it remains unclear whether its pill was the reason. However, in an investor note, Sanford Bernstein analyst Tim Anderson write that, “to us, it seems likely the company has a reasonable idea of the cause of death given the fact that this occurred about 20 days ago.”

According to experts he spoke with, the patient was given the drug on November 22 and passed away the next day. And he points out that office monitoring of patients who are starting Gilenya is recommended due to a slowing heart rate associated with initiation. In any event, the case becomes the first involving sudden death among some 28,000 patients who have taken the drug. So far, the drugmaker has not issued a so-called Dear Doctor letter to alert physicians to the death.

A Novartis spokesman tells us the patient had successfully completed six hours of post-dose observation without incident and, meanwhile, all available details are being gathered and have been submitted to the FDA and other health authorities. “At this stage, the exact cause of death has not been established, and a role for Gilenya can neither be confirmed nor excluded at this time,” he writes.

As Anderson points out, “there is often significant safety baggage of different sorts” with MS drugs, and that efficacy “comes with a price…The question becomes whether the scale between safety and efficacy tips against a given drug, in which case its outlook becomes more clouded. With one death like the one we describe, it is not clear whether this will become a significant issue for Gilenya.”

At the time Gilenya was approved, a survey of 43 MS specialists by Leerink Swann found the pill was forecast to grab a healthy chunk of the US market within the first two years, surpassing the competition, including Biogen’s Avonex; EMD Serono and Pfizer’s Rebif; Bayer’s Betaseron and Biogen’s Tysabri. Only Teva’s Copaxone would be a bigger seller (back story).

In his view, Anderson believes that Gilenya sales this year will reach $385 million, or less than one percent of total Novartis revenue of about $60 billion. By 2015, he forecasts sales of $1.4 billion, or 2 percent of companywide revenue. “If uptake of the drug were to falter – either because of new safety issues or because of intensified competition – it could dent sentiment on Novartis but it would not likely have a substantial impact on the company’s overall financial health.”

shock pic thx to ogimogi on flickr

In an attempt to lay to rest a long-standing and controversial concern, a new retrospective study has found no evidence of an increased risk of heart attack, stroke or sudden cardiac death associated with the use of attention deficit hyperactivity disorder, or ADHD, pills among young and middle-aged adults who do not or rarely take these meds.

The reason for undertaking the study has been a growing number of prescriptions for ADHD pills that are written for adults. The study authors noted that, according to a 2006 FDA advisory committee, meeting, more than 1.5 million US adults were taking the meds during the prior year and that adults received about 32 percent of all prescriptions written. But while placebo-controlled studies in children and adults indicted elevated blood pressure levels, which would be expected to increase the rate of cardiovascular events, clinical trials were not large enough to assess the risk.

The study, which was published online today by the Journal of the American Medical Association, analyzed using electronic health care records of more than 150,350 people from four study sites between 1986 and 2005 who used ADHD pills. Most took methylphenidate – otherwise known as Concerta and Ritalin, among other names – which accounted for 43 percent of total usage (here is the study).

The adults examined ranged in age from 25 to 64 years old. During follow-up, there were 1,357 cases of heart attacks, 296 cases of sudden cardiac death and 575 cases of stroke. Besides the top-line finding, the researchers write they also found “little support” for increased risk of any specific pill or longer duration of current use. The results were similar when restricted to new users. Rate ratios did not appear to be influenced by prior cardiovascular disease or prior non-ADHD psychiatric conditions.

In an accompanying editorial, Philip Shaw of the Human Genome Research Institute and formerly of the National Institute of Mental Health, wrote that the findings support the 2006 decision by the FDA not to place a Black Box warning about serious cardiovascular events on ADHD meds for all children and adults but to pursue further research.

“The findings, however, do not directly inform the current black box warning for psychostimulants, which is confined to patients with structural heart lesions. The study focused on very rare events, which prevented examination of specific subgroups such as individuals with cardiac disease. Joint care by cardiologists and other physicians remains necessary for these individuals,” he cautions (read here).

He adds that the study does not provide support for the notion that routine electrocardiograms should be undertaken before treatment begins, although he cites a recommendation that referred to children and adolescents (see here).

heart attack pic thx to bart on flickr

If one wants to make something understandable for the largest possible audience, then it might make more sense to offer language that can be absorbed by an 8th grader, instead of an 11th grader, for instance. Institutional review boards, for example, recommend the lower level. However, a recent analysis of informed consent documents from 15 studies finds the forms aim too high.

The researchers used five validated, standardized readability tests to analyze consent forms for the studies, which were taking place at Duke University and the University of California, Los Angeles, according to Anesthesiology News. These included four observational-noninterventional studies, five observational-interventional studies, three evaluation studies and three randomized controlled trials, the paper notes.

The upshot? They were tested for readability, but the average reading level was consistent with the ability of an 11th grader, the paper reports. The observational-noninterventional studies rated highest, at grade 11.7, which is really 12th grade. “RCTs and evaluation studies were written at a mean reading level of grade 10.7,” the newspaper writes, adding that “RCT consent forms were more readable, but also included the most sentences and words, as well as the most complex words.”

The implications, of course, do not bode well for sponsors and those who carry out clinical trials, since some research subjects may not fully comprehend or appreciate the myriad issues raised by participation. This also speaks to ongoing concerns about clinical trial ethics, specifically the full and proper disclosure of health risks that subjects may encounter.

“Subjects who do not fully understand a consent form may initially consent to participate, but withdraw after realizing they are receiving an intervention or procedure they did not understand or agree with at the outset of the study,” primary investigator Madhav Swaminathan, associate professor of anesthesiology and director of perioperative echocardiography in the Division of Cardiothoracic Anesthesiology and Critical Care Medicine at Duke University School of Medicine, tells the paper.

He offered a qualifier, though, by suggesting the 11th grade reading level may be acceptable for research conducted in more educated populations, such as participants living in urban areas with more educational institutions, according to the paper.” Of course, there are urban settings where educational levels vary widely, which means that tailoring consent forms to specific regions can be dicey.

A row broke out in Australia late last week after the government rejected an official recommendation that drugmakers should follow an industry code of practice before their medicines can be listed on the Australian Register of Therapeutic Goods. The decision, which was part of a review of the Therapeutic Goods Administration, was met by harsh criticism from consumer and industry groups alike.

In explaining its move, the government responded by saying its “preference is to maintain an emphasis on self-regulation and strongly supports industry’s initiative to harmonize their codes of conduct to incorporate the…high-level principles” suggested by the Working Group on Promotion of Therapeutic Products, which was issued last March (read here and this is the government response).

“From time to time, examples are highlighted of industry offering inducements to health professionals to promote products,” the government writes in its response. “This has the potential to influence clinical decisions on grounds other than the best interests of the patient. Strong and enforceable industry codes of conduct are effective in limiting unethical behaviour, but there needs to be consistency across industry codes in terms of their requirements, application, enforcement and penalties. This is currently lacking. There are also concerns that non-members of industry associations may not be bound by industry codes…”

“Further changes will be considered if it is found that there is a need to provide greater encouragement to non-members of industry associations to nominate and sign up to an appropriate industry code, including the TGA seeking notification of a sponsor’s nominated code of conduct at the point of including a product on the ARTG,” they added in their reply, which was reported by Pharma Times.

Nonetheless, Carol Bennett, chief executive the Consumers Health Forum of Australia, said in a statement that the government has missed an opportunity “to protect consumers from the cowboys in the industry who choose not to participate in voluntary codes of conduct.” She also told ABC Radio that “it does tend to indicate that the real client, if you like, is the industry, not the Australian consumer. And really, the whole purpose of the regulatory body, the TGA, is to serve the interests of Australian consumers” (read here).

Equally perturbed was Brendan Shaw, ceo of Medicines Australia, the industry trade group, who called the government response “very disappointing. Thiswas a rare opportunity for stakeholders across the health sector to implement important regulatory reform which was identified by Government as a gap in industry self-regulation…” he said in a statement.

“There is no reason why Medicines Australia member companies should be required to adhere to one standard while non-members adhere to a less standard. We need to make sure our member companies are not disadvantaged by doing the right thing. There needs to be a level playing field that applies to all companies – not just those who choose to belong to Medicines Australia. Appropriate standards of conduct must apply across the board.”

In defense, Catherine King, the Parliamentary Secretary for Health, told ABC Radio that the government “is certainly not frightened to do so. But we want to give the industry time to get its act together to get those codes aligned. We also want to give the opportunity for them to actually get some of the non-members into those codes.

“In terms of promotion to health professionals; it has largely been this place that it’s been self-regulatory. What we have said is that we think there is room for improvement in that self-regulatory approach. So they need to improve their codes of conduct and look at seeing, non-members to become and sign up to those codes.”

“We then are saying, if we need to go further and get the TGA to seek that people need to sign on or nominate a particular code of conduct that they’ll comply with when they’re listing or registering goods, therapeutic products, we’ll do that. But we’re going to do a staged approach to it. We want to actually get the codes right first.”

Last year, Jason Cornish resigned from his information tech job at Shionogi offices in Georgia after a dispute with a senior manager. However, he was subsequently retained as a consultant, but later resigned and then a co-worker and friend was laid off. And so this past February, Cornish hacked into the Shionogi network and wiped out most of the drugmaker’s computer infrastructure.

Having pled guilty this past August, Cornish was sentenced late last week by a federal judge in New Jersey, where Shionogi maintains US headquarters, to 41 months in prison and also ordered to pay $812,567 in restitution. He also faces three years of supervised release, which includes computer monitoring and occupational restrictions, according to court documents (see here).

His hacking, which the Japanese drugmaker initially estimated cost about $300,000, paralyzed communications and order tracking systems for several days. How did Cornish manage this? Several times last fall and winter, he allegedly gained unauthorized access to the Shionogi network from his home Internet connection using administrative passwords to which he had access as an employee (read this).

As we noted previously, Cornish appeared rather cavalier or unsophisticated for an IT specialist. The FBI was called in and examined Shionogi remote access firewalls, which yielded the IP address from where his attack originated. The feds then contacted AT&T, which led them to a McDonald’s, where he used a Visa credit card to spend $4.96 just five minutes before the attack. And Bank of America later confirmed that this card belonged to Cornish.

Hacking by current and former employees is a regular concern, of course. And while not everyone may be as easy to detect as Cornish, disgruntled employees can clearly do damage with seemingly little effort, especially when passwords are not disabled and disaster recovery plans are not tested.

Good morning, everyone, and how are you today? We hope the weekend was relaxing and invigorating. Ours was certainly restful. Now, though, the time has come to prepare for all those meetings and deadlines. To cope, yes, we are, indeed, brewing that mandatory cup of stimulation. Monday mornings are always challenging, as you know. We hope you will join us as we dig in for another busy day. To get started, here are a few items of interest. Have a great day and stay in touch…

Abbott Pays $400M To Extend Deal With Reata (Pharma Times)

Onyx Denied Accelerated Review For Cancer Drug (Bloomberg News)

Ariad Blood Cancer Drug Shows Success In Pivotal Study (Bloomberg News)

Gene Therapy Proves Effective In Treating Hemophelia B (Reuters)

FDA Panel Backs J&J’s Birth Control Patch Despite Risks (Associated Press)

UK’s NHS Prescription Data To Be Opened To Public (The Guardian)

India’s Drugmakers Resist Price Controls (Business Standard)

China To Revoke Pharma Licenses For Using Prohibited Chemicals (Xinhua)

Family Appeals Double-Dosed Digitek Ruling (Daily Record)

EDITOR’S NOTE: Please check this post for updates throughout the morning

Coffee pix thx to chichcacha flickr creative commons

Here’s a report from Science Careers on “A Pharma Industry in Crisis”. Readers here will find much of what’s said to be familiar – partly because they interviewed people like me and Chemjobber for the piece (!) But it’s worth a look as a where-we-are-now perspective.

Johnson & Johnson’s ($JNJ) Janssen Biotech unit has made a big deal with the small biotech Pharmacyclics. Janssen will pay $150 million up front–and $975 million total, if milestones are met–for a midstage blood-cancer treatment. Report

Pfizer ($PFE) has settled a legal dispute with three hormone-drug patients who won $72.6 million in compensatory damages this week. The lawsuit, which claimed that menopause drugs caused the women’s breast cancer, had been scheduled for a punitive-damages hearing beginning today.

Pfizer agreed to wrap up the dispute with Susan Elfont, Bernadette Kalenkoski and Judy Mulderig, after a jury awarded each of them more than $20 million in compensation, Bloomberg reports. “The parties have entered into a mutual agreement to resolve this case under confidential terms,” spokesman Chris Loder told the news service.

The terms of the settlement weren’t disclosed. Ted Meadows, a lawyer representing the three women, said, “They’re just glad to be able to go on with their lives.”

Separately, the Pennsylvania Supreme Court agreed to review Pfizer’s argument against $8.6 million in damages awarded in another hormone-drug case. The company has set aside $772 million to cover claims involving its Wyeth unit’s estrogen drug Premarin, its Upjohn unit’s progestin med Provera, and the combination pill Prempro.

- read the Bloomberg coverage

Related Articles:
Pfizer ordered to pay $72M in Prempro case
Pfizer sets aside $772M for settling Prempro cases

GlaxoSmithKline ($GSK) has suffered a setback in its bid to broaden use of Tykerb to fight early breast cancer. The drug failed to reach its goal in a study testing it as an adjuvant treatment for HER2-positive breast cancer. It’s not the first time Tykerb has flubbed an adjuvant study, either, Deutsche Bank analysts point out. They also predict ”substantial use” of the drug in that setting “is very unlikely.”

The company said Tykerb patients in the TEACH trial had a slightly improved rate of progression-free survival, the difference when compared with placebo wasn’t statistically significant. “Although we are disappointed,” GSK SVP Rafael Amado said, “[Tykerb] remains an important treatment option for patients with metastasis HER2-positive breast cancer.” Amado added that other Tykerb trials, including adjuvant research, are ongoing.

There’s one consolation, however: GSK isn’t alone in reporting not-so-great data at the San Antonio Breast Cancer Symposium. A study of Avastin in HER2-positive breast cancer patients delivered just 3.2 months of additional progression-free survival and no overall survival benefit, The New York Times reports.

The numbers on Avastin’s ability to stave off tumor growth in HER2 patients resemble those in two other studies presented to the FDA. Those trials involved patients whose cancers didn’t test positive for HER2. That data was used by the agency as evidence in revoking Avastin’s breast cancer approval.

Roche’s Genentech unit tells the NYT it won’t be asking the FDA to approve Avastin as a treatment specifically for HER2-positive breast cancer. “Our bottom line is we do not believe that the difference in P.F.S. is of a sufficient magnitude that it is likely to gain regulatory approval,” Genentech’s Sandra Horning told the paper.

- see the Dow Jones story
- get more from Reuters
- read the NYT piece

Related Articles:
Joining FDA, Canada pulls Avastin’s breast cancer indication
GSK stops Tykerb-only arm in cancer trial