FDA Panel, Bayer Birth Control Pills & Blood Clots

By Ed Silverman in Pharmalot

Nearly six months after a pair of studies found that women taking birth control pills containing a hormone called drospirenone are more likely to develop blood clots than those who take an older oral contraceptive, the FDA has decided to hold an advisory panel meeting in December to review the risks and benefits.

Meanwhile, the agency is continuing to review a separate agency-funded study that evaluated the risk of blood clots in users of several different hormonal birth control products (contraceptives). Preliminary results suggest an approximately 1.5-fold increase in the risk of blood clots for women who use drospirenone-containing birth control pills compared to users of other hormonal contraceptives.

And so, the agency will convene the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee to examine the risk of blood clots of drospirenone-containing birth control pills. The most widely known oral contraceptives containing this hormone are the Yaz and Yasmin pills sold by Bayer.

The scrutiny is not good news for Bayer. Nearly 7,000 lawsuits are pending in the US over alleged injuries and deaths relating to Yaz and Yasmin, as well as generics. The lawsuits allege Yaz and Yasmin have risks beyond those of traditional birth control pills and Bayer too aggressively promoted the pills without disclosing higher risks. Bayer was warned by the FDA in 2008 that TV ads were misleading and did not disclose added risks (see here) and recently was chastised in the UK for running a Yasmin ad that boasted the pill could prove beneficial on the same problems it may cause (read this).

As to the data, the FDA says it reviewed six published epidemiologic studies that evaluated the risk of blood clots in women using birth control pills containing drospirenone, but generated conflicting findings. Two were postmarketing studies required by the FDA or European regulators, and did not report any difference in clot risk between the pills and products containing levonorgestrel or other progestins. But two studies in 2009 reported a 1.5- to 2-fold higher risk in women who use pills containing drospirenone as opposed to contraceptives containing levonorgestrel.

More recently, two articles published in 2011 in the British Medical Journal reported a 2- to 3-fold greater risk of clots in women using oral contraceptives containing drospirenone rather than levonorgestrel. However, the FDA notes these were epidemiological studies and, so far, has not reached a conclusion on the risk for blood clots, but remains concerned about a potential increased risk (here is the FDA statement).

Hodgin’s Lymphoma And A High-Priced Drug

Hodgin’s Lymphoma And A High-Priced Drug

Ed Silverman

When is a drug overpriced? The issue has come up repeatedly as various biologics treating cancer and assorted chronic conditions carry price tags in the tens of thousands of dollars. The debate was particularly vociferous last year when the Provenge prostate cancer vaccine was priced at $93,000 (read here). Now, a new entrant may become the focal point of controversy.

This morning, Seattle Genetics disclosed that the annual cost for Adcetris, which the FDAapproved late last week to combat Hodgkin’s disease and another rare lymphoma, will cost $13,500 per dose. In clinical trials, patients received an average of eight infusions, which works out to $108,000 a year, which Xconomy reports was in line with several Wall Street estimates.

There is reason, however, to argue the cost is justified. For one, chemotherapy is also expensive. More to the point, the data for Adcetris is impressive – 73 percent of Hodgkin’s patients had significant tumor shrinkage, including 32 percent showing complete remissions. And 86 percent of anaplastic large cell lymphoma patients also had significant tumor shrinkage.

And not only is Adcetris the first new Hodgkin’s treatment since 1977, but the medication may be a life-saving salve to relapsed patients, who are often young or in mid-life and facing uncertain life expectancy. The FDA approved the drug for patients whose cancer has progressed after autologous stem cell transplant or after two prior chemo treatments for those who cannot receive a transplant (here are the press releases from the biotech andthe FDA).

On the other hand, there is no survival data yet. And of course, insurers and patient advocates are likely to complain about the cost. Yet a price that fails to provide a return on investment will anger investors. This is a common conundrum now facing biotechs as they seek to balance R&D costs, profit targets and patient needs, which is the reason for their efforts in the first place.

“We want to make sure we price this drug so that we can maximize the impact on patients, and maximize the effect for the company as well,” Seattle Genetics ceo Cory Siegall tellsXconomy while insisting months were spent chatting with insurers and doctors. “What we are excited about doing is making sure we can treat as many patients as possible, and also do well for our shareholders.”

Working in his favor are a couple of other points – there do not appear to be any out-of-the-ordinary side effects and a lab test can determine when a tumor expresses enough of the targets that Adcetris is designed to combat. And judging by the trial results, the med can hit anywhere from 73 percent to 85 percent, which are rather decent odds. What do you think? Do the odds justify the price?

Note: There is a poll embedded within this post, please visit the site to participate in this post’s poll.

benjamins pic thx to amagill on flickr

Pfizer Cuts Reps Before Lipitor Patent Expires

Image via CrunchBase

Source: Pharmalot

 Ed Silverman

This should not come as a surprise. The big drugmaker just two months ago disclosed plans to cut another $1 billion or so in expenses, with a first phase that will amount to $500 million in cutbacks taking place this year. The move, of course, comes in response to the loss of patent protection for the Lipitor cholesterol pill, a $10.7 billion seller, and other big-selling meds.

Pfizer sales reps were told to expect phone calls next week about their fate. Some say, however, there is frustration in the ranks. The drugmaker has allegedly indicated more than once that the sales force was “told since the Wyeth acquisition that Pfizer was “right sized” ‘ for the Lipitor patent expiration that will occur this fall, one source tells us.

In response to questions, a Pfizer spokesman wrote this: “While I cannot confirm specific actions related to our US organization, Pfizer remains focused on prudent capital and resource management. We have planned for Lipitor’s loss of exclusivity at a corporate, portfolio, and brand level for several years. The company continues to support the brand where it makes sense prior to the loss of exclusivity to maximize the value of the product.” He declined to say how many rep jobs will be cut.

As part of its newest round of cost cutting, Pfizer plans to eliminate duplicative administrative work at its New York headquarters and offices elsewhere, promotion, travel, entertainment and consultants, as well as materials, supplies and electronic devices for sales reps. The cuts would trim almost 5 percent from selling, informational and administrative expenses, which were $19.6 billion last year. Over the past few years, Pfizer has cut nearly 20,000 jobs to save costs and combine operations after acquiring Wyeth. Overall, Pfizer currently employs nearly 110,000 people (back story).

axe pic thx to brittgow on flickr

Related articles

• Pfizer may seek to sell nonprescription version of Lipitor - @WSJ (online.wsj.com)
• Summary Box: Pfizer sales slump on generic rivals (seattletimes.nwsource.com)
• Report says Pfizer may try to market OTC Lipitor (seattletimes.nwsource.com)
• You: Pfizer Is Said to Pursue Nonprescription Lipitor (nytimes.com)
• Pfizer plans OTC version of Lipitor: WSJ (marketwatch.com)
• Pfizer Eyes OTC Lipitor, but Will FDA Approve? (fool.com)
• Pfizer may sell animal health and nutrition units (theglobeandmail.com)
• Pfizer Eyes OTC Lipitor, but Will FDA Approve? (dailyfinance.com)
• Earnings Preview: Pfizer to report on 2nd quarter (sfgate.com)
• Pfizer's Drop in Pharma Sales Offset by For-Sale Units (fool.com)

Prescription Drug Spending Is Forecast To…

Where is spending on prescription drugs headed? A group of economists in the Office of the Actuary at the Centers for Medicare and Medicaid Services dusted off a crystal ball and are projecting that, between now and 2013, growth will be faster than last year, which amounted to 3.5 percent, but will exceed the 5.3 percent rate notched in 2009.

To wit, spending on prescription drugs is forecast to average 5.7 percent, but this is based on the assumption that economic conditions will improve, according to their article in Health Affairs (read the abstract here). Given the wobbly state of the economy, such assumptions may be optimistic. You may recall that the recession prompted many people to abandon their prescriptions (see this).

In any event, the CMS actuaries note that whatever growth does occur will be offset somewhat by new generic competition to six of the top 50 brand-name drugs, which are losing patent protection this year. The Lipitor cholesterol pill sold by Pfizer is a notable example. This development will actually dampen spending growth the most next year.

By 2014, though, growth in prescription drug spending is expected to increase sharply to 10.7 percent, which is 5.1 percent and $15.8 billion higher than projected in the absence of the Patient Protection and Affordable Care Act, otherwise known as healthcare reform. This projected acceleration is driven mainly by an expectation that the newly insured will substantially increase their use of medicines.

Looking past the horizon, prescription drug spending growth is expected to average 7.2 percent between 2015 and 2020. Why is a decline forecast? The actuaries anticipate a lower dispensing rate for generics, which will cause an uptick in prices. And they expect higher spending for more new molecular entities and biologics that are expected to be approved by the FDA during this period.

For those wondering why spending growth slowed so much last year, the reason given was “continued slow growth in the use of drugs.” This refers to economic factors, such as a change in the mix of drugs that were purchased. “Through tiered copays and other mechanisms, health plans have continued to shift medication use toward less-costly generic drugs,” they write. “Thus, the generic dispensing rate is projected to have increased to 69 percent in 2010, up from 66 percent in 2009.”

crystall ball thx to outdated on flickr

Related articles

• Reader Consult: Would the FDA Swallow an OTC Lipitor? (blogs.wsj.com)
• Pfizer plans OTC version of Lipitor: WSJ (marketwatch.com)
• Costs For Prescription Drugs For Injured Workers Among The Lowest In Washington State, Says A New WCRI Study (prweb.com)
• Should Lipitor go OTC? A cardiologist says yes, an internist says no (kevinmd.com)
• Q1Medicare.com Now Offers an Easier Way to Compare Drug Coverage Details Across all Medicare Part D Prescription Drug Plans (prweb.com)

Massachusetts sues-jj-over-risperdal-marketing Sues J&J Over Risperdal Marketing

Ed Silverman

Yet another state has filed a lawsuit alleging that Johnson & Johnson illegally marketed its Risperdal antipsychotic to the detriment of its citizens. This time, Massachusetts alleges J&J promoted the drug to treat elderly dementia and various unapproved uses in children and adolescents. The state also claims J&J failed to disclose serious risks such as the possibility of excessive weight gain, diabetes and, for elderly dementia patients, an increased risk of death.

“Manufacturers should not promote uses of their pharmaceutical products that have not been established to be safe and effective,” Massachusetts Attorney General Coakley says in astatement. “Janssen put profits ahead of patient safety by promoting Risperdal for uses that had not been approved and by failing to disclose serious risks associated with Risperdal’s use.”

The state also charged the health care giant with making misleading and deceptive statements to prescribers about Risperdal safety, especially such side effects as weight gain and developing diabetes; paying docs to participate in “sham consulting programs” that were “thinly disguised” marketing programs touting unapproved uses; and targeting docs who rarely, if ever, prescribed Risperdal for FDA-approved uses which are schizophrenia and bipolar mood disorder (read the lawsuit here).

The lawsuit comes as J&J holds talks to to resolve a raft of litigation and investigations related to Risperdal marketing. Four months ago, J&J set aside an unspecified amount of money to be used to settle some of the litigation. The Office of the Inspector General of the United States Office of Personnel Management, the US Department of Justice, the US Attorney in Philadelphia and Attorneys General of multiple states have been probing off-label Risperdal marketing for years (see this).

Although reports have suggested J&J may wind up settling much of the litigation for $1 billion or so, the tab may be mounting. In June, a South Carolina judge that J&J must pay $327 million for deceptive Risperdal marketing, and last fall, a Louisiana jury ordered J&J to pay $257.7 million in damages for making misleading safety claims (read here), although $73 million in legal fees were later added. In explaining his decision, the South Carolina judge labeled J&J actions “detestable” (look here).

J&J has scored a couple of victories. A lawsuit brought by Pennsylvania officials, who charged J&J hid the risk of diabetes and misled state regulators into paying millions more than they should have for the medicine, was dismissed (see here). And two years ago, a West Virginia judge awarded $3.95 million, after finding J&J misled doctors about risks and benefits, although the state dropped its claim after J&J won an appeal. Nonetheless, the average loss has so far cost about $150 million (four state lawsuits) or roughly $300 million (when considering two actual defeats).

As we have noted previously, J&J will appeal the losses in Louisiana and South Carolina, and could possibly pay much less than the penalties awarded. By suggesting a global deal might total $1 billion or so, the health care giant may try to get the amounts reduced on a proportionate basis, and use the same argument in talks with any state that does not join a settlement. But if more states file lawsuits, the costs could rise. Perhaps the timing of the Massachusetts lawsuit is not a coincidence.

One looming case is scheduled to go to trial this November in Texas. And J&J potentially faces a much bigger liability in that Texas has a much larger population than Louisiana and South Carolina and, therefore, would encounter a heftier payout. This case, by the way, also involves statutory and common law fraud issues that were not raised in the other states. The focus is on the so-called TMAP program that was allegedly designed to boost Risperdal prescriptions by unduly influencing University of Texas professors and state officials to endorse the effort and promote it nationally (read here).

Reevaluating Studies: A CRO & A Coincidence?

Published 1 agosto, 2011 por Ed Silverman, via Pharmalot

Last week, the FDA announced that any clinical tests conducted between April 2005 and June 2010 by a contract research organization called Cetero Research may have to be reevaluated because two FDA inspections and an outside audit found falsified data and manipulated samples. In explaining its move, the agency maintained there were “significant instances” of misconduct.

The agency says Cetero failed to conduct an adequate internal investigation to determine the extent and impact of the violations, and did not take sufficient steps to assure data integrity during those five years. And so drugmakers must check their databases for trials that were used to support New Drug Applications and Abbreviated New Drug Applications – and may have to repeat or confirm results (back story).

For its part, Cetero subsequently issued a statement saying the CRO initiated its own internal investigation of its Houston bioanalytical laboratory in 2009 after discovering six chemists had misreported the date that samples were extracted prior to analysis. They did this to seek overtime pay for hours when they did not actually work. But the CRO insists reports were filed with the FDA and agency feedback was sought, although none was received. Cetero clients were also contacted.

“We leaned in roughly June 2009 and that’s the time at which we self reported the findings to the FDA,” Cetero ceo Troy McCall tells us. “We requested a meeting at the time that we originally provided them with our preliminary findings and during the course of our 18 month investigation. We were providing them with regular updates…They received all the information we provided to them on an interim basis.

“We took these issues so seriously that we not only terminated the employees who were responsible for these actions, but we also replaced management and ultimately the site leadership,” McCalls continues. “…That was probably another half dozen or so people.” He reiterated that all of the terminated employees were based in the Houston facility.

There is, however, an interesting tidbit concerning some other former and current Cetero employees – several of them have had experience suitable for dealing with the recent troubles. How so? They also once worked for MDS Pharma Services, another CRO that is now owned by INC Research and, notably, had rather similar problems with the validity and accuracy of test results. In fact, in January 2007, the FDAnotified drugmakers to reevaluate pharmacokinetic studies that were conducted for them by MDS from 2000 through 2004 (read here).

Which former and current Cetero employees worked at MDS? And when? Well, there wasJerry Merritt, who was MDS senior vice president and general manager from 2000 to 2006, when he left to run Cetero, although he was succeeded as ceo early last year by McCall. And Murray Ducharme, the chief scientific officer at Cetero, was previously an MDS vice president from 2000 to 2006, although his Cetera bio neglects to mention this (look here).

Then there was John Capicchioni, who was the MDS senior vice president of business development from 1994 to 2006, when he joined Cetero as vice president of business development, although his bio also overlooks time spent at MDS (see this).

There was also Herb Smith, who was MDS senior director of quality assurance from 1999 to 2007, when he became vp of quality assurance at Cetero, although he retired in April. Finally, there is April Johnson, who worked at MDS as a marketing manager from 1999 to 2005 and as a marketing director of early clinical research and bioanalysis from 2005 to 2007, when she joined Cetero as vp, business relationship management (see this). And, yes, her bio fails to mention MDS.

In other words, several current and former members of the Cetero managerial team arrived from another CRO that experienced similar breakdowns affecting the validity of bioequivalence data, which caused regulators to question the ability to conduct a proper audit (read a sample letter the FDA sent to drugmakers with pending ANDAs).

The problems at MDS, by the way, factored into growing concern a few years ago about oversight of CROs. The rise in the number of clinical trials prompted a corresponding growth in the number of such companies, along with complaints about quality and competency. In February 2007, for instance, Gilead reported that the FDA had found “certain irregularities” in studies conducted by MDS (read this).

We asked Cetero for comment about the experience some of their executives brought with them from MDS. Johnson, who also acts as the Cetero spokesperson, declined to comment

Related articles

• Avastin Fight Song: 'It's All About $ And The FDA' (medicinafamiliar.info)
• France Decides Sanofi's Multaq Is 'Insufficient' (medicinafamiliar.info)
• Kiss A Doc For Scripts? No, But I'd Lead Him On (medicinafamiliar.info)
• Pharmalot... Pharmalittle... Good Morning (medicinafamiliar.info)
• Risk Info In Print Ads Is Not Very Comprehensible (medicinafamiliar.info)
• In France, Chantix Subsidies Go Up In Smoke (medicinafamiliar.info)
• How To Report Adverse Events In Trials In India (medicinafamiliar.info)
• Up In Smoke: Pfizer's Chantix Raises Heart Risk (medicinafamiliar.info)

An Avastin Recommendation & Conflicts Of Interest

 Bevacizumab = Avastin

Earlier this month, the National Comprehensive Cancer Network, a non-profit group of oncologists whose guidance is closely followed by leading treatment centers, voted overwhelmingly in favor of maintaining its recommendation that Avastin should be used to treat breast cancer. The vote came shortly after an FDA panel voted 6-to-0 to revoke the breast cancer indication for Avastin.

The endorsement is important because oncologists will likely continue to use Avastin even if FDA commish Margaret Hamburg rescinds the breast cancer indication. Roche and its Genentech unit had appealed a decision last December by the agency to pull the indication for their best-selling med after new studies showed the med does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh significant risks. This prompted the unusual two-day hearing last month (back stories here and here).

However, 10 of the 33 members of the NCCN breast cancer panel members have ties to Roche or Genentech, either as advisory board members, speakers, consultants, expert witnesses or having received clinical research support. These connections are disclosed on the NCCN web site (look here). And 25 members of the panel participated in the recent vote to maintain the recommendation.

Specifically, the NCCN panel voted 24 in favor, 0 against and 1 abstention. The simple math suggests that at least one panel member - and possibly two - with ties to Roche voted to support the metastatic breast cancer recommendation. Perhaps more panel members with connections voted, although there is now way to know ascertain this since the NCCN press release does not specify who participated in the voting.

As we have noted previously, the NCCN endorsement is likely to be a boon for Roche, since treatment for breast cancer has typically generated about $1 billion or more in annual sales. Avastin rings registers - worldwide sales last year totaled about $6.8 billion and rose 9 percent, which meant this one drug accounted for 14 percent of total Roche sales. In other words, much is at stake.

Meanwhile, the stated NCCN policy conflicts of interest requires “disclosure of external relationships and recusal of NCCN Guidelines Panel Members with conflicting interests so that the integrity of the NCCN Guidelines is not compromised or diminished by conflicts or by the perception of conflicts,” according to the NCCN web site.

The policy also states that a panel member with a significant and direct or indirect relationship with “an external entity” that constitutes a conflict shall not participate in NCCN Guidelines Panel discussions, when the panel’s action on the topic under discussion “may advantage or disadvantage an external entity.” An exception is granted when requested by the panel chair “to participate for the purpose of providing or presenting information to the NCCN Guidelines Panel.”

More specifically, certain “direct relationships,” such as a panel member who is a beneficial owner of stock in an “external” entity or a director of such an organization” would be considered to have a de facto conflict. The policy also defines “direct relationships” as anyone “who receives compensation for services including, but not limited to, management or consulting services to the organization” (here is the policy).

So we asked NCCN whether this policy was followed for the recent breast cancer panel, given that the vote tally suggested otherwise. The spokeswoman repeatedly declined to discuss specifics and referred us back to the recent press release which, again, offers no information on the topic. In fact, she refused to answer whether NCCN has a recusal policy, even though this exists on the web site. “I’m only allowed to discuss what is in the press release,” she told us over and over.

We also reached out to the 10 panel members who have ties to Roche and Genentech. One responded. Antonio Wolff wrote us to confirm that “Genentech provides funding to Johns Hopkins University (where I am employed as School of Medicine faculty) to support research costs associated with an ongoing early phase clinical trial, and I am the site PI for that study. As for your specific question regarding my activities within NCCN, I will ask (you) to contact it directly as NCCN requires all panel members to adhere to its confidentiality policy.”

And so, an influential panel with ties to a drugmaker - which has a lot of sales on the line - voted to maintain a key recommendation. In this instance, NCCN panel members fully disclosed their ties to Roche, but is this sufficient? Supposedly, there is a reason NCCN has a disclosure and recusal policy, but in this instance, there would appear to have been a breach. If none occurred, the organization should be willing to discuss specifics and defend its policy. Yet NCCN refused to do so. What do you think?

Source: Pharmalot