The Food & Drug Administration is quickly learning how hard it is to design adequate and reasonable postmarketing safety studies. Faced with implementing new authority to demand mandatory postmarketing trials for drugs instead of the long-time policy of negotiating with sponsors over the nature of the sponsor’s proposed follow-up studies, the agency is finding out just how hard it is to define the right size – and a feasible size – for the trials.

To get some expert advice and political cover for its decisions, the agency is ready to go to the tried-and-true formula of asking its outside advisory committees for opinions and a public record on the decisions to mandate Phase IV trials.

Office of New Drugs Director John Jenkins described the agency’s plan to ask the advisory committees for more help at an Institute of Medicine forum on drug safety on Sept. 2 in Washington, DC.

“As we have been thinking about these large studies that we may be requiring” in the post-market setting, Jenkins said, the agency has decided to ask its existing advisory committees for help deciding “what is an acceptable study design, how large is an acceptable study, what are the right endpoints, what risks are we trying to exclude.”

The advisory committees may get their first large outcomes study proposals for review very soon. Jenkins said.

“You are likely to see some advisory committee meetings coming up in the not-to-distant future asking for input on” the size and duration of specific post-marketing studies, Jenkins informed the IOM meeting.

CDER Director Woodcock Supports Using Advisory Committees

Jenkins did not identify the first Phase IV trial suggestions that the FDA staff might submit to an advisory committee. There are some likely candidates, however. Perhaps the most logical candidate is the Bayer AG and Johnson & Johnson anticoagulation drug, Xarelto (rivaroxaban). The direct thrombin inhibitor got a favorable advisory committee vote in mid-March for use against deep vein thrombosis in patients undergoing hip or knee replacement surgery (See “The Pink Sheet”, March 19). But FDA sent a “complete response” letter in May to allow for time to review additional safety data (See “The Pink Sheet” Daily, May 28). One of the sponsors, J&J, has said that the agency does not want more clinical trials before approval. If the agency were, however, to seek Phase IV safety follow-up, it might need the help of an advisory committee to help determine the size and the search for safety issues from off-label use. For its initial limited indication, the drug might not require a large postmarketing trial but there was interest in monitoring how widespread the use could get for the drug which will offer an alternative to the traditional, oral anti-clotting agent for DVT, warfarin.

The idea for bringing advisory committees into the review of post-marketing drug safety/outcomes trials comes directly from the senior management of the Center for Drug Evaluation & Research.

“This is not my idea,” Jenkins told the IOM meeting. CDER Director Janet Woodcock came up with the idea, he reported. “It seems like a really good way to have some transparency, to have some discussion of all these complex issues.”

Jenkins told the IOM meeting that the agency’s new authority to initiate the discussion of post-marketing trials and to set mandatory objectives and timelines puts FDA in a new position.

Before getting the FDAAA authority to mandate post-market trials, the agency was in the position of reviewing post-approval study proposals coming from sponsors. FDA negotiated with the sponsors on the size, term and objectives of the trials. Now, the agency will be held responsible for requiring the studies and setting the parameters.

That puts a new burden on FDA. There are “a couple of big issues that we are facing now that we did not have to face as much” before FDAAA, Jenkins observed.

“Often we are not very well informed, quite honestly, about how long it might actually take to do a 30,000, 40,000 or 50,000-patient study,” the OND director acknowledged.

In the past, the sponsor proposed the timeline for starting and completing a Phase IV trial. FDA now feels the burden falling on it. “We have to spend a lot of time and energy thinking about is this a reasonable, feasible timeline because we want to limit the number of times that we have to revise it down the road,” Jenkins said.

Prospect of 500,000-patient Phase IV Trials Worries FDA

Initiating the discussion of the size of trials is also tough for the agency. Jenkins noted that within FDA some of the first proposals for outcomes studies have generated very big study numbers. “We are having some real examples of that right now where depending on the endpoint that you choose and the background risk, we have seen sample size estimates of 500,000 patients per arm. Truly, I have seen those within the agency.”

Jenkins said the agency management knows that there has to be “a balance between what is feasible, what is practical and acceptance that that is the best that you can do in that circumstance.”

In addition to providing a way to get practical advice on outcomes trials, the FDA plan to go to advisory committees for review of post-marketing safety trial design provides FDA with political cover on the decisions that it makes.

There is more than a hint of battle-fatigue from Jenkins in his description of the new use of advisory committees. The drug review management has clearly been chastened by the criticism that the agency has faced on drug safety issues in the past six years.

“We think it is important to get some community, societal buy-in” beyond FDA staff on the development of safety requirements, Jenkins said.

FDA frequently asks advisory committees for suggestions on Phase IV trials. But generally these are efforts to get the committees to comment on what subjects should be addressed in the trials. And these discussions can often start to run a bit beyond FDA’s authority.

At the discussion of Merck &Co. Inc.’s application for a genital warts prevention indication for Gardasil in males on September 9, the advisory committee members went beyond discussing the need for postmarketing trials to offering their opinions on how the product should be presented to the public – an example of the dangers sponsors face when issues about postmarketing controls are turned over to advisory committees in public.

The new discussions that FDA has in mind over Phase IV appear aimed less at product control commentary and more specifically to get the advisory committee to react to design protocols generated by the agency. That should keep the discussions more focused but it still threatens to remove an element of control over information about the product in the postmarketing environment away from the sponsor.

Jenkins noted that the agency feels it is being closely watched for how it handles its new postmarketing authority. “There is going to be a lot of scrutiny by outside parties if for very valid reasons we later have to change those timelines – because it will be assumed that we are not exercising our authority to make the companies stick to the timelines” for finishing trials, Jenkins said.

The OND director had the timeline issue on his mind at IOM because he was preparing to hold a press briefing the following day to give updated figures on the number of pending Phase IV trial commitments. (See “The Pink Sheet” September 7).

Coincidentally, the day before Jenkins’ presentation to IOM, one sponsor, Genzyme, was taking criticism at an Oncologic Drugs Advisory Committee meeting (See “The Pink Sheet” Sept. 7) for taking more than six years to start confirmatory Phase IV studies on Clolar (clofarabine).

Diabetes Trials, Process Are Models for Phase IV

FDA officials at the IOM meeting discussed the new cardiovascular outcomes requirements for diabetes drugs as a model of the type of postmarketing trials that can be expected in the future.

The diabetes guidelines that define the safety trial requirements derived from an open discussion of diabetes safety issues at an advisory committee in July 2007. That meeting presumably sets an early model for the type of Phase IV safety requirement discussions that Jenkins has in mind.

CDER director of medical policy Bob Temple told the IOM meeting that the 1.3 hazard ratio in the diabetes postmarketing outcomes trials “came from experience with the NSAIDs, where everyone was sort of happy.”

With a glancing reference to Cleveland Clinic cardiologist Steven Nissen who initiated the diabetes cardiovascular safety review with a study of Avandia risks, Temple noted that the 1.3 ratio “reflected a proposal from Steve Nissen; so how could we not agree?” Jenkins corrected Temple: “I believe Steve Nissen actually recommended 1.4 and we decided on 1.3.”

Temple reiterated the balance between designing trials to demonstrate safety and maintaining feasible trial requirements.

“You are right,” he noted in response to Jenkins, “the public will have to understand that here is what we know, here is what we have ruled out; here is what we haven’t ruled out.”

Temple also noted that the hazard ratio is not the only measure of risk. “I’m not sure that I can tell you what is an acceptable risk, but I just want to remind everybody that when you put an upper bound on a risk (say 1.3) that is not the only measurement that you are looking at. There is also the point estimate.”

Scott Korn, VP-clinical risk management at Merck Research Labs, told the IOM meeting that the discussions around diabetes safety trials set a reasonable model. “We need to have reasonable expectations for post-approval trials,” Korn said, noting “it is often difficult to prove a negative.”

“What you can often do is instead cap the risk: you can exclude a risk above a certain amount. The example was the diabetes guidance that the FDA issued last year where the community and the agency reached a consensus that we would exclude a relative risk of 1.8 as the upper bound in order to get approval and if we fall within 1.3 and 1.8 then we have to do a post-approval trial to better define that risk.”

The diabetes guidelines accept an element of risk and try to put a cap on it, Korn observed. “That is a realistic assessment. We look forward to having a discussion around that to help define and develop feasible clinical trials that will be informative.”

If advisory committees do become more frequently involved in discussing the design and safety issues for Phase IV trials, that is going to put an extra burden on those groups and could impact their ability to handle the current role in drug approval decisions.

Merck Exec VP-regulatory affairs Peter Honig referred to the challenge that FDA faces in getting advice on outcomes studies from the advisory committee at the IOM meeting. After Jenkins’ announcement of the new use of advisory committees, Honig said: “Hopefully you can field some good cohorts for advisory committee members that will give you thoughtful input.”

MedImmune is poised to be the first manufacturer to collect on government contracts with finished doses of the pandemic flu vaccines. The Centers for Disease Control reported in an update on the pandemic on Sept. 18 that the first deliveries of vaccine at the beginning of October would be the nasal, attenuated live-virus version FluMist.

The AstraZeneca subsidiary received commitments this year from the department of Health & Human Services for about 13% ($151 million) of the total ($1.12 billion) dollars committed by the government for the manufacture of bulk antigen. The first 3.4 million doses of an estimated 40 million doses of FluMist for the U.S. market in the 2009-2010 pandemic effort are now on track for release at the beginning of October, about two weeks ahead of the target date for the first shipments the injectable versions.

Being first is good PR for the product that was once a notable commercial flop when introduced for one flu season as a co-marketed product by Wyeth in 2003. MedImmune has been marketing the product alone. Under AstraZeneca the product recovered to $104 million annual sales in 2008. The pandemic bulk contract alone is more than 45% greater than the previous full year sales.

The product is also getting some good exposure from government officials within the vaccine community and on Capitol Hill.

During a September 21 press briefing on early immunogenicity findings in ongoing trials of the trials of the injectable vaccine formulation in children 10-17 years of age, FDA’s Deputy Commissioner for Science & Public Health Jesse Goodman, MD, digressed to report that “the live attenuated vaccine does not appear to work typically just through inducing an antibody response.”

Broader Response Possible; But Not for Patients With Complications

“One of the reasons” that the intranasal vaccine “has been particularly effective in some instances,” Goodman said, “is that it induces a broader immune response, involving cellular immunity and other factors.” FluMist is recommended for use in children down to age 2 but is not recommended for children with asthma or wheezing.

National Institute for Allergy & Infectious Diseases Director Anthony Fauci, MD, added that “when you look at data from the live attenuated vaccine, you don’t necessarily look at the classic serocon version or levels of titers. It is a different kind of immunological response.”

Fauci and Goodman were reporting on the preliminary childhood vaccination findings from the NIAID tests to suggest that the one-dose regimen of 15 mg of injectable antigen should suffice to create immunity in children above 10 years of age. Fauci reported from the early results of trials started in August “it seems likely that the H1N1 flu vaccine will require just one 15-microgram dose for children 10 to 17 years of age.”

FluMist also got a qualified endorsement during an update on the pandemic response on Sept. 15 by HHS Secretary Kathleen Sebelius to the House Energy &Commerce Committee. Sebelius was pressed by California Democrat Anna Eshoo for information on FluMist and the preferred patient group for use of the product. Noting that MedImmune has a facility in her congressional district, Eshoo asked whether the nasal spray would be “better used for children” and “how might it affect the voluntary compliance” to the pandemic vaccination effort.

Sebelius noted that the limitation against use in young children and individuals with health complications. She added, however, “it certainly is a viable alternative for a lot of the population.”

The introduction of the Senate Finance Committee's health care proposal turns the focus from what the pharmaceutical industry will contribute to reform efforts toward what manufacturers stand to gain.

The pharmaceutical industry could see an increase of approximately $115 billion over 10 years in U.S. drug sales as a direct result of the Senate Finance Committee's health reform legislation - at least by one way of slicing up the numbers used in economic analyses underlying the bill.

That calculation is based on how the Senate Finance Committee explained the rationale for the specific fees due from each health care business sector that stands to benefit from expanded health coverage.

Senate Finance Committee Chairman Max Baucus, D-Mont., unveiled details of the legislation, America's Healthy Futures Act of 2009, in the form of a "chairman's mark" on Sept. 16.

According to Democratic Finance Committee staff, members believe three major industries will experience "significant expansion" in the form of "new customers" that will be created by the committee's health reform bill: insurers, pharmaceutical companies, and hospitals.

Staffers say that they conducted an economic analysis of how much each industry stood to profit from the impact of the committee's health reform legislation over the 10 years.

Market expansion would stem primarily from picking up millions of new customers with drug coverage who previously did not because they were not insured, Medicaid expansions, and a shift toward use of more brand drugs in Medicare Part D because of the diminished deterrent of the self-pay donut hole coverage gap.

The committee agreed to look at recovering "15 to 20 percent" of the estimated new business through the specific industry segment fees. The pharmaceutical industry fee is set at $2.3 billion annually or $23 billion over 10 years.

If that $23 billion fee is calculated from a 20-percent fee assessment, then it suggests that the Finance Committee analysts estimate that pharma's market should grow by $115 billion in new business over the next 10 years as a result of the legislation.

In that vein, the industry would net $35 billion over the same period, or $3.5 billion annually, after subtracting pharma's $80 billion pledge to help pay for health reform.

If the $2.3 billion per year fee is based on an estimate of 15 percent of new business, then that suggests a projection of new business as high as $153 billion for the drug industry over 10 years.

No Simple Answers To Size Of Bounce

After explaining the rough formula for calculating the fees at the unveiling of the bill, the Finance Committee staff cautioned in follow-up comments against trying to calculate the new business figure directly from the percentage fees.

Specifically, the staff said, "in determining allocations, an economic analysis was done on a range of factors, including long-term industry revenues, profitability, benefit from reform, the contribution of government revenues, as well as a number of other factors. The $23 billion fee was a portion of the overall $80 billion contribution agreed to by the pharmaceutical industry, which came about as a result of the analysis and negotiations with the industry. Other contributions focused on the donut hole, as well as increases in rebates to Medicaid," Further, "the fee is not a tax rate on the new business expected to be generated from reform, and the committee believes that the contribution from the industry will outweigh any benefit from expansion."

The staff statement recognizes the political sensitivity of large estimates of the positive impact of new business on different industries. A big new pool of money for an industry could stimulate further attempts to seek payments from that sector to pay for the cost of added coverage and upset some of the fundamental agreements on which the bill is advancing.

People familiar with the Finance Committee drafting process note that pharma's contributions were calculated differently, to take into account the industry's early offer to make a total package of contributions up to $80 billion. The $80 billion represents the total pharma contribution: the fee was added to help reach that commitment.

By comparison, the special fee on medical device manufacturers is higher, $40 billion over 10 years. The medical device industry is smaller than the drug business so it would seem that the fee should be smaller. However, the $40 billion number presumably reflects the total hit to medical devices - half of pharma's overall contribution.

Estimates of new business for pharma resulting from reform legislation run the gamut from no gain to $200 billion over the same period of time.

An analysis of House health reform legislation by Avalere Health, for example, found the changes would have minimal positive impact on the pharmaceutical industry. Working off the House Energy and Commerce Committee bill in mid-summer, Avalere found a 0.1 percent increase in net revenues to the drug industry, disputing estimates that "health reform legislation would generate a windfall of revenues" from the "millions of newly covered patients into the health care system."

Apportioning The Fees To Individual Companies

The chairman's mark would require heads of Medicare, Medicaid, the Department of Veterans Affairs and TRICARE to report domestic sales of branded prescription drugs for each drug manufacturer for the prior calendar year to the Secretary of the Treasury.

The Treasury secretary would then establish individual assessments by determining the relative market share for each company. A company's relative market share would be its total covered U.S. sales from all government programs as a percentage of the total covered U.S. sales from all government programs for all companies.

In determining each company's relative market share, covered domestic sales will be taken into account as follows: 0 percent of sales up to $5 million; 10 percent of sales over $5 million and up to $125 million; 40 percent of sales over $125 million and up to $225 million; 75 percent of sales over $225 million and up to $400 million; and 100 percent of sales over $400 million.

The fee assessed is determined by the firm's market share in the preceding calendar year and would be a surcharge not deductible for U.S. income tax purposes.

Baucus Alone For Now; Hopes For GOP Support

Baucus formally introduced the proposal standing alone in front of a banner that read "Health Care Reform." No other members, Republican or Democrat, were present at the historic unveiling.

"No Republican has offered his or her support at this moment, but I think by the time we get the final passage in this committee it will have bipartisan support," he said.

Baucus has delayed introduction of a formal legislative proposal for months in hopes of putting together a truly bipartisan bill. The committee chairman, along with two fellow Democrats, has been negotiating with three Republicans in an attempt to craft a bill that would be attractive enough to gain some support from the other side of the political aisle. The group of negotiators on the Finance Committee is dubbed the "Gang of Six."

"I've worked very hard to get that bipartisan support and I think we will get it," he continued. "I think that certainly by the time the committee in this room votes on passing health care reform, there will be bipartisan support."

Sen. Olympia Snowe, R-Maine, thought to be Democrats' best shot at gaining Republican support, did offer some hope of bipartisanship: "As one of three Republicans in the Group of Six, I have appreciated the chairman's leadership of the only bipartisan effort in any committee in either the House or Senate, which has laid real and substantial groundwork for bipartisan cooperation during this ongoing process."

She said that this bill was only a "first step in the process" and that members of the Gang of Six will keep meeting in order to craft a bill that she and other Republican members of the committee can support.

"I believe the chairman's legislation moves in the right direction away from a government-run system contained in bills that have passed other Congressional committees, but a number of issues still need to be addressed - including cost assumptions and ultimate affordability to both consumers and the government as well as ensuring appropriate competition in the health insurance exchange," she added.

The Congressional Budget Office scored the Baucus proposal as costing $774 billion over 10 years. However, CBO concluded the bill would reduce the federal deficit by $49 billion over the same period.

While Baucus hopes to get Republicans on board, he made clear that he does not need them.

"I know this bill will pass," asserted Baucus. "The choice now is now is up to those on the other side of the aisle."

Sept. 11 (Bloomberg) -- GlaxoSmithKline Plc, the world’s second-biggest drugmaker, begins a trial in Philadelphia next week in what may be a test case for more than 600 lawsuits over claims its antidepressant drug Paxil causes birth defects.

Patients and their parents claim internal company documents produced for trial show Glaxo failed to warn about the risks of Paxil until forced to do so in 2005 by the U.S. Food and Drug Administration. In a trial set for Sept. 14, Michelle David blames the drug for causing life-threatening heart defects in her son Lyam Kilker, 3.

The London-based company faces two more such trials a month from October through January in state court in Philadelphia. The first group will show both sides how the rest of the lawsuits may fare, said David Logan, dean and professor of law at Roger Williams University in Bristol, Rhode Island.

“These cases are sort of like the canary in the coal mine,” Logan said in a phone interview. “The early cases set the parameters for any global settlement negotiations.”

Paxil, approved by the FDA in 1992, generated about $942 million in sales last year, 2.1 percent of the total for the company. Glaxo has settled other Paxil-related cases, including a suit brought by the New York Attorney General’s office accusing the company of withholding safety data about the antidepressant.

The drugmaker isn’t liable for Lyam’s heart defects and acted responsibly in testing Paxil and updating safety information, Kevin Colgan, a Glaxo spokesman, said by e-mail.

Scientific Evidence

“The scientific evidence simply does not establish that exposure to Paxil during pregnancy caused Lyam Kilker’s condition,” Colgan said. “Very unfortunately, birth defects occur in 3 to 5 percent of all live births, whether or not the mother was taking medication during pregnancy.”

The FDA said in an alert to doctors on Dec. 8, 2005, that preliminary studies suggested Paxil might contribute to heart defects in infants when taken in the first three months of pregnancy. The government asked the company to update the label enclosed with the medicine, changing its birth-defect warning.

The FDA’s action doesn’t prove any connection between Paxil use and birth defects, the company said in court filings.

“Before 2005, more than two decades of studies had found no association between maternal Paxil use and birth defects,” lawyers for Glaxo said July 8 in court papers. “Since 2005, additional studies have been inconclusive with mixed results.”

‘Acted Properly’

“GlaxoSmithKline will show it acted properly and responsibly in conducting its clinical trial program for Paxil, in marketing the medicine, in monitoring its safety once it was approved for use and in updating pregnancy information in the medicine’s label as new information became available,” the company’s Colgan said.

Lawyers for patients claim Glaxo documents show the company knew since 1980 that Paxil could raise the risk of birth defects. They claim Glaxo didn’t sufficiently research the drug before and after it went on the market.

Animal studies didn’t show the drug was safe, company scientist John Baldwin wrote in a March 20, 1980, memo cited in court filings by David’s lawyers.

“There remains the possibility that this compound could be teratogenic at higher dose levels,” he said. A teratogenic agent is one that causes malformations of an embryo or fetus.

Data Destroyed

“In the face of this warning from Baldwin, GSK chose not to perform any additional animal studies to explore the teratogenic effects of Paxil,” the plaintiffs’ lawyers wrote.

The company in 1993 destroyed raw data from animal studies of the drug, and in 1996, 1998 and 2000 it withheld safety reports of adverse outcomes involving mothers who took Paxil, plaintiffs’ attorneys said in court papers Aug. 10, asking the court to allow punitive damages in the case.

The company designed studies to avoid triggering adverse results and stronger warnings, David’s lawyers claim. In 1994, members of the company’s Paxil team supported a low-dose study “as the best way forward and having an acceptably low risk of triggering adverse labeling worldwide,” the lawyers said, quoting minutes of a meeting.

“In 1998, GSK internally concluded that it had received an ‘alarming’ number of abnormal pregnancy adverse events for Paxil and failed to disclose this information to the FDA, physicians or the public,” the lawyers said in the Aug. 10 filing.

Punitive Damages

Judge Sandra M. Moss, who is overseeing the lawsuits in Philadelphia, denied Glaxo’s motion Aug. 17 to bar punitive damages. She said the company can ask again during the trial.

The company knew the drug was more harmful to pregnant women than cocaine, Sean Tracey, a Houston attorney for David, said during a Sept. 3 pretrial hearing. Glaxo aggressively marketed the drug to women of childbearing age, Tracey said.

David said she was prescribed Paxil during her first trimester to treat mild anxiety. Lyam was born with defects including two holes in his heart as a result of taking the drug, she said in court papers. The infant underwent multiple surgeries within six months of his birth, she said.

She said wouldn’t have taken Paxil if she knew of the risk and contends that Glaxo failed to warn her or her doctors.

“All of Ms. David’s physicians who prescribed Paxil just prior to and during her pregnancy with Lyam have testified that had they been warned that Paxil could increase the risk of cardiovascular heart defects, they would not have prescribed it to her,” according to court papers.

No Evidence

The company countered at the Sept. 3 hearing that there is no evidence David was taking Paxil at the time Lyam was conceived, and there is no evidence the mother’s doctors considered company promotional materials when prescribing it.

The FDA in 2005 said an analysis of data on Swedish patients showed there was a 2 percent risk of birth defects in babies whose mothers took Paxil early in the pregnancy, twice as high as the risk to the general population.

Another study showed the risk was 1.5 percent among Paxil users and 1 percent for those on other antidepressants, the FDA said.

The agency said that while the drug generally shouldn’t be used during pregnancy, its benefits may outweigh potential risks for some expectant mothers who aren’t helped by other medications.

Suicide Claims

Glaxo is also fighting lawsuits in the U.S., Canada and the U.K. over claims that Paxil, also known by the generic name paroxetine, causes homicidal and suicidal behavior. The company has settled some suicide claims, though terms of the settlements haven’t been released.

In 2004, the drugmaker agreed to pay the state of New York $2.5 million to resolve claims that officials suppressed research showing Paxil may increase suicide risk in young people. The settlement also required Glaxo to publicly disclose the studies.

In 2001, a jury in Cheyenne, Wyoming ordered Glaxo to pay $6.4 million to the relatives of a man who shot his family to death and then turned the gun on himself after taking Paxil.

The company’s provision for legal and other non-tax disputes as of June 30 was 1.7 billion pounds ($2.8 billion), the company said in a July 22 regulatory filing that didn’t mention the Paxil litigation.

“We do not disclose our legal reserves for any specific litigation matter,” Colgan said.

The case is Kilker v. SmithKline Beecham Corp. dba GlaxoSmithKline, 2007-001813, Court of Common Pleas, Philadelphia County, Pennsylvania.

To contact the reporter on this story: Sophia Pearson in Wilmington, Delaware, at spearson3@bloomberg.net; Margaret Cronin Fisk in Southfield, Michigan, at mcfisk@bloomberg.net.