Last week, the American College of Physicians (ACP), a 129,000-member group of internal medicine physicians, and second-largest doctors group in the US, called for increased FDA authority and  funding to help protect  consumers from the risks of newly-approved prescription drugs.  Their six recommendations were:

1) increased funding for FDA staff and technological capability to keep pace with the increased workload due to the number and scientific complexity of new products submitted for pre-approval, globalization, and emerging safety challenges.

2) increased FDA authority and capacity to regulate drugs manufactured outside the US;

3) expanded FDA authority and involvement in the design of clinical trials to better evaluate safety and efficacy, through longer trials with larger, more representative target populations;

4) a ban on clinical studies of ‘bundled’ drug products that reduce access to drugs;

5) Improvements that increase  reporting of adverse events by doctors and others; and

6) limits on direct-to-consumer advertising in the first 2 years a drug is on the market.  

Increased FDA funding:

The ACP report notes that FDA’s “ability to approve and monitor new drugs has been compromised by chronic underfunding, limited regulatory authority, and insufficient organizational structure.” ACP recommends that FDA funding is increased, to improve their “ability to approve and monitor prescription drugs….”

 Regulating drug manufacturing overseas:

The ACP should be praised for bringing attention to severe under resourcing at FDA, particularly as it affects the Agency’s ability to ensure the safety of drugs manufactured overseas. Today’s globalized pharmaceutical supply chain has rapidly outgrown FDAs capacity, and FDA is not able to inspect foreign sites with any meaningful frequency. A 2008 GAO study found it would take FDA 13 years to inspect each foreign manufacturing establishment once, while domestic sites are inspected on average every 2.7 years.

 ACP points out that a provision for increased foreign inspections were included in a bill (H.R.759) introduced by Reps. Dingell, Pallone and Stupak in January this year. A similar bill (S.882) championed by the late Senator Kennedy and Senator Grassley also seeks to increase foreign site inspections by FDA. Both bills establish new industry user fees to pay for this expanded oversight, but also require annual increases in other appropriations to ensure sustainability. ACP importantly indicates that both types of financial support are needed, and mentions a number of other key provisions in the House bill, including a requirement for dedicated foreign inspection staff.

Facilitating increased physician reporting of adverse events:

The ACP also recommends FDA pursue efforts to “educate physicians on how and when to report an event that is potentially drug-related.” They also proposed streamlining the reporting systems and ensuring anonymity to “facilitate reporting by health professionals.”

DTC advertising of new drugs:

The report acknowledges that direct-to-consumer (DTC) advertising can “dramatically increase [use] of a new drug and … may expose large numbers of people to a drug with undocumented safety concerns.”

The best example of this concerns was seen in the  rapid use of the  pain-killer Vioxx upon hitting the market. The aggressive DTC advertising and other promotional activities  by manufacturer Merck lead to Vioxx’s use by over 20 million consumers, which then lead to  88,000-139,000 cardiac events, and  an estimated 35,000-55,000 deaths.  Adverse reactions and safety concerns arose with the  drugs Zyprexa and Bextra, among many others 

To address this concern, ACP recommended that FDA ‘limit’ the DTC advertising of newly approved prescription drugs, and require that labels and ads indicate that data related to the new drug’s “risks and benefits … are less extensive than those [for older] products…”

 Prohibiting clinical trials of ‘bundled’ products:

In addition, ACP also makes a recommendation that would help FDA avoid placing itself in the position of helping drug manufacturers introduce ‘bundled’ or combination drug products designed to protect a drug from generic competitors. 

For example, the report describes how, in 2005, the drug manufacturer “Pfizer submitted plans to the FDA to begin conducting large trials to test the cholesterol drug torcetrapib in combination with the popular and widely used statin Lipitor.”  By allowing clinical trials of the ‘combination drug’ rather than just torcetrapib alone, approval of the new combination drug product would insulate Lipitor from competition. This then puts FDA, in approving the study design, in the awkward position of helping the drug manufacturer avoid anti-trust prohibitions, the report said.

This concern is similar to the claims in the PAL member lawsuit on the drug Norvir, where drug manufacturer Abbott Labs bundle their HIV protease inhibitor cocktail drug Norvir in a new bundled-product-drug Kaletra, in order to increase market share.

ACP recommends that FDA not approve clinical trials which seem to be designed to ‘bundle’ a new drug with an existing brand name drug, and thus perpetuate the patent-protected sales of the new combination product.

To read the full report, visit http://www.acponline.org/advocacy/where_we_stand/policy/fda.pdf

A major story broke today in the New York Times, Wall Street Journal and Boston Globeabout Pfizer’s (NYSE:PFE) alleged manipulation of studies of its epilepsy drug Neurontin:

See:

• Keith Winstein’s Suit Alleges Pfizer Spun Unfavorable Drug Studies in the WSJ
• Stephanie Saul’s Experts Conclude Pfizer Manipulated Studies in the NY Times).
• Liz Kowalczyk’s E-mails suggest Pfizer tried to suppress study on drug in the Globe

The studies examined whether Neurontin was effective for conditions other than epilepsy. As the NY Times article describes,

Pfizer’s tactics included delaying the publication of studies that had found no evidence the drug worked for some other disorders, “spinning” negative data to place it in a more positive light, and bundling negative findings with positive studies to neutralize the results, according to written reports by the experts, who analyzed the documents at the request of the plaintiffs’ lawyers.

Neurontin has been an extraordinarily profitable drug for Pfizer, and most of the prescriptions written for it were not for epilepsy, but were “off-label” (prescribed for a use not approved by the FDA). In 2004, Pfizer paid $430 million to settle a criminal and civil case brought by federal prosecutors that charged that Warner-Lambert, which Pfizer acquired in 2000, had illegally promoted Neurontin for “off label” purposes in the 90s.

That $430 million settlement reimbursed state and federal health care programs (like Medicaid) that had paid for off-label prescriptions of Neurontin, but did not compensate consumers or “third party payors” (health plans, union benefit funds and others) that had also paid for such prescriptions. A number of class action lawsuits were brought against Pfizer, and they were consolidated in the U.S. District Court for the District of Massachusetts. The ongoing lawsuit is In re Neurontin Marketing and Sales Practices Litigation, MDL #1629, Docket #04-10981.

That case has been pending for several years, with the parties exchanging documents and arguing before the Court about whether a national class of consumers and third party payors can be “certified,” which is the prerequisite to the case going forward as a class action.

The documents that were recently released were part of “expert reports” submitted by the lawyers for the plaintiffs in the case. The reports both contain and analyze documents from Pfizer about its alleged illegal offlabel promotion of Neurontin.

Now that the reports and documents have been filed with the Court, they are a matter of public record. We here at Prescription Access Litigation subscribe to the maxim that “sunlight is the best disinfectant.” We are posting these reports and documents in their entirety so that the public can see them for themselves. They paint an interesting picture.

• Revised Supplemental Declaration of Ilyas J. Rona Filed In Support Of Plaintiffs’ Renewed Motion For Class Certification – this document describes the Exhibits (expert reports and Pfizer documents) that were filed with the Court. (The descriptions below of the Exhibits are taken from this Declaration.)
• Exhibit A: Parke-Davis memorandum from the Neurontin Marketing Team to the Field Sales Colleagues dated November 30, 1998, ―designed to explain why the Neurontin articles are able to be distributed by territory sales managers.
• Exhibit B: A memorandum from Pat Woster, Chair of the Parke-Davis Central Nervous System Specialty Group, to Medical Liaisons and Associate Medical Directors dated May 16, 1999, listing ―Articles for Distribution relating to the indications that are in this case. For example, one article ―supports the use of gabapentin and pregabalin for treatment of neuropathic pain. Other articles concerned ―acute mania,‖ ―Neuropathic pain after anti-HIV gene therapy, and ―bipolar disorder.
• Exhibit C: CME Guidelines for the Distribution of Educational Materials relating to Parke-Davis CME initiative entitled ―Advances in the Preventative Treatment of Migraine. The guidelines recognize ―that perhaps the most powerful means of promotion is direct contact and encourage ―Parke-Davis sales representatives to participate in raising awareness by distributing copies of the information brochure to appropriate physicians in their areas
• Exhibit D: PFIZER_CGROGAN_0022377, which is a Pfizer email from Christine Grogan to Lance Tyler dated April 26, 2001. The email states: ―Our [Review Committee] has allowed [sales] rep distribution of CME program invitations if the accrediting body has sent a written request asking for such support/help.
• Exhibit E: A Pfizer document entitled ―Neurontin Action Plan – POA2 – 2004 relating to Pfizer’s goals, strategies and messages for 2004. Under strategies, the document states: ―No calls on Psychs!!!!
• Exhibit F: Declaration of Meredith Rosenthal: Estimate of Units Paid for by Neurontin Endpayers that Resulted from Alleged Fraudulent Marketing by Defendants dated August 11, 2008
• Exhibit G: Declaration of Raymond S. Hartman dated August 11, 2008
• Exhibit H: Expert Report of Kimberly P. McDonough dated: August 11, 2008
• Exhibit I: Expert Report of Nicholas P. Jewell, Ph.D. dated: July 29, 2008
• Exhibit J: Expert Report of David A. Kessler, M.D. dated July 31, 2008
• Exhibit K: Report on the Use of Neurontin for Bipolar and Other Mood Disorders prepared by Jeffrey S. Barkin, M.D. dated July 25, 2008.
• Exhibit L: Neurontin: Clinical pharmacologic opinion of Dr. Thomas L. Perry dated August 10, 2008. 14.
• Exhibit M: Report on gabapentin (Neurontin®) for migraine prophylaxis: evaluation of efficacy, effectiveness and marketing prepared by d. Douglas C. McCrory, M.D., M.H.Sc.
• Exhibit N: the Expert Report of John Abramson, MD dated: August 11, 2008
• Exhibit O: Expert report entitled “Reporting and other biases in studies of Neurontin for migraine, psychiatric/bipolar disorders, nociceptive pain, and neuropathic pain” prepared by Kay Dickersin, Ph.D., MA
• Exhibit P: the Consultant Report Prepared by: Brian Alldredge, PharmD
• Exhibit Q: A Pfizer memorandum from Hank McCrorie—the former Executive Vice President in charge of US Sales—to all sales representatives informing them that ―a number of decisions have been made relevant to the promotion and marketing of Neurontin…,including the instruction that ―Neurontin detailing responsibility will be limited only to the US RON sales force (approximately 150 representatives). RON representatives will call only on Neurologists for Neurontin.

Note: There is a separate class action lawsuit in Calfornia state court against Pfizer for the same alleged off-label marketing of Neurontin in California, brought by several members of Prescription Access Litigation’s coalition. To read more about that suit, and the underlying allegations (which are the same as in the Massachusetts case), go here.

Readers: It’s a week of all-star guest blog posts here at the Prescription Access Litigation blog, and we’re going overseas. Earlier this week, we brought you Sarah Rimmington of the consumer advocacy group, Essential Action, with a post on “the WHO’s negotiations on R&D and the developing world.

Today we bring you another great post by a Guest Blogger, Sonia Shah. Sonia is the author of “The Body Hunters: Testing New Drugs on the World’s Poorest Patients,” a book exposing the exploitation of patients in developing countries in pharmaceutical clinical trials with little or no oversight. It’s a peek into the all-too-real world that the book and movie The Constant Gardener addresses.

American drugmakers are increasingly turning to developing countries as sites for clinical trials testing new drugs or new uses for old drugs. Unfortunately, the protections in place for patients in many countries are scant, if not absent. Until recently, the Helsinki Declaration provided some protection for such patients — admittedly, it was often inadequate or underenforced, but it was better than nothing. Now the FDA has renounced the Helsinki Declaration, and the consequences for pharma’s “test subjects” are dire. But I’ll let Sonia Shah give you all the details….
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With hardly a word in the mainstream press, the FDA has gutted the rules restraining drug companies from exploiting clinical trial subjects in developing countries.

With 80 percent of clinical trials failing to recruit sufficient numbers of test subjects on deadline, drug companies increasingly export their trials to developing countries, where sick, undertreated patients abound. It’s faster, it’s cheaper, and it’s easier to conduct the placebo-controlled trials that companies and the FDA prefer. There is precious little oversight of these trials.

Unlike for domestic trials, the FDA does not require advance notice before drug companies take their trials outside US borders. And with 90 percent of trials failing to gain FDA approval, a massive number of trials are conducted, fail, and then vanish with no agency review at all—and little public record, if any at all.

Until now, the FDA’s sole requirement for these overseas trials is that they adhere to the Declaration of Helsinki (or local rules, on the off-chance that they are more stringent). Signed by the United States and 34 other countries in 1975, the Declaration of Helsinki consists of several dozen pithy principles to govern ethical research on humans, and is widely considered the gold-standard in research ethics. Crafted and updated by the World Medical Association, a group representing dozens of national physicians’ organizations from around the globe, the Declaration of Helsinki (DOH) urges that participants’ voluntary informed consent be obtained, that independent committees to review and oversee trials be used, that investigators prioritize their subjects’ well-being, that research subjects be assured access to the best health interventions identified in trials, and that their societies enjoy a “reasonable likelihood” of benefiting from the results of trials.

t’s not a perfect document. It’s very short. It’s a little vague. The FDA does not bother to enforce it. Even when they know of infractions—such as in Pfizer’s trial of the antibiotic Trovan in Nigeria, which not only failed to procure informed consent, but didn’t even have an oversight committee in place at the time of the trial—the FDA has done nothing and approved the drug anyway. We know of that particular trial’s violations only because the Washington Post exposed them several years later. In reporting for a book I wrote on clinical trials in developing countries, I similarly found many examples of trials clearly in violation of Helsinki provisions that were nevertheless reviewed and approved by the FDA.

The FDA has been agitating against the DOH since the late 1990s, when the World Medical Association strengthened the document’s restrictions on placebo-controlled trials, which an unlikely alliance of industry, public health and academic researchers angrily challenged. The strengthened DOH, the FDA’s medical director Robert Temple railed, “doesn’t look like a group of suggestions that are worth discussing.” Under pressure from the agency and drug companies, the World Medical Association diluted the objectionable language about placebo trials—cue the increasing vagueness—but by then the FDA was on the warpath. Just as President Bush opted out of international treaties on climate change and anti-ballistic missiles, in 2001, the FDA bucked two decades of its own precedents, and refused to adopt updated versions of the internationally sanctioned Declaration of Helsinki. That done, in 2004, the agency proposed dumping the DOH from its codes altogether, and on April 28 announced the it would indeed be summarily excised starting in October.

In its place, the FDA will incorporate “Good Clinical Practice” rules. Good clinical practice sounds, well, good, but these rules are no replacement for the Declaration of Helsinki. Unlike Helsinki, which describes ethical principles agreed upon by the international medical community, GCP rules are bureaucratic regulations crafted by regulatory authorities and drug industry trade groups, behind closed doors. They offer little by way of ethical precept. There is no injunction, for example, that research subjects be assured access to study drugs after trials end, or that their communities have a reasonable likelihood of enjoying the benefits of the research, principles of justice enshrined in the DOH.

The FDA’s move against the DOH is more than a symbolic change. With drug companies rushing to countries where the domestic regulatory infrastructure is weak at best—India, where Pfizer and GlaxoSmithKline have set up global clinical trial hubs being perhaps the prime example—and the FDA turning a blind eye, the business of protecting impoverished, sick, undertreated patients from exploitative experimentation falls almost entirely upon local people convened by clinics and hospitals to sit on FDA-required ethics committees. Theirs is a nearly impossible job, much of it shrouded in secrecy. Some, from India and South Africa, spoke to me, anonymously. They told me of how their clinics and hospitals desperately need the income drug-industry trials bring in. Of how, often, their bosses sit on the committees with them, pressuring members to approve as many experimental protocols as come in. They are overworked, underpaid, and poorly trained—if trained at all—in the principles of research ethics. Even the most courageous among them find it difficult to challenge problematic experiments and interrupt the flow of industry dollars.

And yet, they do, and when they do, they rely upon the only set of rules that their administrators and drug company clients consider legitimate: those backed by the FDA.

The last-stand oversight of local ethics committees has clearly been insufficient. A growing body of evidence, from anthropological research to case studies, suggests that the consent of trial subjects in many poor countries is uninformed, and worse, non-voluntary. Many clinical-trial companies openly promote the non-voluntariness of trial subjects in developing countries, not as a reason to conduct fewer trials, but to conduct more. (Specifically, they promote the low dropout rates, a telling signal of coercion.) Anecdotal evidence of the abrogation of the principles of justice—the lack of access to study drugs after trials end, the inaccessibility of the benefits of research, whether because of brand-name prices or the irrelevance of the resulting drug—abounds.

That’s how bad it has been with the Declaration of Helsinki on the books. What we don’t know is how many more violations have been averted by the nameless, faceless people sitting on ethics committees in developing countries, relying upon the strictures of the Declaration of Helsinki. There is no way to know how many times they’ve been able to extract guarantees, protections, and promises from industry researchers, or to amend experiments so that subjects’ rights and safety are better protected, thanks to the principles of the DOH.

All we can know is that come October, thanks to the FDA’s scrapping of the gold-standard in research ethics, their already difficult work will be made more so. The vulnerability of research subjects in developing countries—often the poorest, the sickest, those with the fewest options—can only grow more fraught.
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Thank you to Sonia Shah for writing this insightful piece on the FDA’s scrapping of the Helsinki Declaration. To learn more about Sonia’s books and articles, visit her website at soniashah.com

On Friday, we posted a press release from Breast Cancer Action (Breast Cancer Action: Patients Lose, Genentech Wins with FDA’s Avastin Ruling) criticizing the FDA’s approval of Genentech’s [NYSE:DNA] Avastin for treatment of metastatic breast cancer. We noted that it was odd that the FDA approved this drug, given that the Oncologic Drugs Advisory Committee (ODAC) had recommended. Applications for drugs to be approved for new uses are first sent to Advisory Committees comprised of physicians with expertise in that speciality (here, oncology). If the Advisory Committee recommends that the drug not be approved, the FDA usually approves it — and if it advises that it not be approved, then the FDA usually doesn’t. As an article in BioWorld Today (FDA Splits with ODAC, OKs Avastin Use in Breast Cancer) describes, the vote of the ODAC was close, but serious concerns were still raised by it:

The approval came as somewhat of a surprise, considering that the FDA usually follows the advice of its advisory panels. Although the ODAC vote on Avastin in breast cancer had been close, at 5 to 4, the panel had raised concerns about trial design, toxicity and survival data.

Breast Cancer Action raised some serious concerns about the FDA’s accelerated approval of Avastin for metastatic breast cancer in its press release which we posted on Friday. Barbara Brenner, Breast Cancer Action’s Executive Director, raises some additional concerns about the approval — not about the drug itself, but about how the drug was approved, and based on what type of clinical trial. In an email to advocates (reprinted here with her permission), she describes the danger:

I want to give folks some context for what happened here, particularly in light of the recommendation of the ODAC some weeks ago that the drug not be approved at this time. BCA encouraged that outcome. See the first story on the home page at http://www.bcaction.org/ for the history.

What happened today is that the Commissioner of the FDA, Andrew Von Eschenbach caved to enormous pressure from industry. Some of you have seen the Wall Street Journal editorial yesterday saying that it would be a “moral tragedy” if the drug weren’t approved because lives were at stake, even though there is no evidence that the drug improves survival. What we know is that the head of Genentech met with the WSJ editorial board last week. And they’ve been dribbling out little bits of data about other trials that also don’t have survival data.

The FDA Commissioner, as you know, is never bound by an ODAC recommendation. In this case, the Commissioner Von Eschenbach is as tied to industry as the rest of the Bush administration is.

As you can see from Genentech’s press release , we are very sad that that industry’s interests have trumped those of patients in the case of this particular drug, and that they have evidently acceded to a lower standard of drug approval — PFS (progression free survival) — instead of overall survival.

But the standard has been changed in another critically important way as a result of today’s decision. Before today, a drug could not be approved for marketing unless it had been subjected to a drug registration trial with standards set by the FDA. This standard is higher than the standard for classical clinical trials, largely because routine clinical trials often mask the true side effects of drugs or are done in populations that are likely to result in overstated benefit.

The decision made today was on the basis not of a registration trial, but of an NCI-sponsored clinical trial, not designed for drug registration. This means that, in the future, other drugs companies will be able to argue to the FDA (probably successfully) that the FDA drug registration standards don’t have to be met, basing approval on clinical trials will be just fine.

As I sat last week trying to figure out why Genentech had not even mentioned the AVADO trial (the one that was designed as registration trial, the results of which were expected in the first three months of this, and were in fact partially released last week, one week before the decision today) in their Avastin presentation to the ODAC in December, I came to a stunning realization: what Genentech was hoping for was a decision that would permit drugs companies to avoid the rigors of registration trials in the future, and rely on clinical trials that are often controlled by industry. And that is what they got with today’s decision.

The bar has been lowered in more ways than we can count. A very sad day for patients.

The BioWorld Today article described above gives some of the history:

In May 2006, Genentech submitted a supplemental biologics license application to the FDA seeking approval of Avastin in breast cancer. But the FDA raised concerns about the underlying data, which had not come from a traditional double-blind, placebo-controlled, company-sponsored Phase III trial. Instead, the sBLA was based on an open-label study, known as E2100, conducted by the National Institutes of Health-affiliated Eastern Cooperative Oncology Group. In September 2006, the agency delivered a complete response letter asking Genentech to audit the E2100 data in the same manner expected of a company-sponsored trial. (See BioWorld Today, Sept. 12, 2006.)

Genentech did as the FDA asked, resubmitting the revised sBLA in August 2007. But a second setback occurred in December, when ODAC narrowly voted against approval. (See BioWorld Today, Dec. 6, 2007.)

E2100 had randomized 722 previously untreated breast cancer patients to receive Avastin plus paclitaxel chemotherapy or paclitaxel alone. The study met its primary endpoint of improving progression-free survival (PFS): patients receiving Avastin achieved a median PFS of 11.3 months compared to 5.8 months for the control arm. However, there was no statistically significant difference in median overall survival, with the Avastin group surviving 26.5 months and the control group surviving 24.8 months, leading ODAC to debate the clinical merits of PFS.

The panel also raised questions about the design of E2100 once again and voiced concerns about adverse events. Six deaths were found to be ‘definitely or probably’ caused by toxicity related to Avastin, and 71.1 percent of patients in the Avastin arm experienced severe adverse events, compared to 51 percent in the control arm.

But between ODAC’s negative decision and the FDA’s positive one, data from a new Phase III trial became available. Known as AVADO, the trial was sponsored by Roche and properly designed. The randomized, double-blind, placebo-controlled Phase III study compared Avastin plus docetaxel chemotherapy to placebo plus docetaxel in the first-line treatment of 736 patients with locally recurrent or metastatic HER2-negative breast cancer. Avastin was administered at 15 mg/kg or 7.5 mg/kg every three weeks, and both doses resulted in a statistically significant improvement in PFS. [PAL Ed.: But not in overall survival, as Breast Cancer Action also pointed out in the trial upon which the approval was formally based] (See BioWorld Today, Feb. 14, 2008.)

Although the AVADO data were not officially included in the Avastin sBLA, Genentech submitted them to the FDA for consideration. That may have helped to sway the agency’s decision to go ahead and grant accelerated approval.

In its news release, Genentech said that converting its accelerated approval into a full approval will be dependent on an FDA review of the full AVADO data as well as data from a Genentech-sponsored Phase III trial known as RIBBON I. Initial RIBBON I data are expected later this year, while overall survival data from AVADO are expected around mid-2009.Genentech also plans to provide the FDA with data from three additional randomized trials that are either ongoing or planned.

So the question remains: Will FDA’s approval of a new indication based on a trial that was a not traditional double-blind, placebo-controlled, company-sponsored Phase III trial pave the way for the loosening of standards on what data the FDA will accept for approvals? Does the FDA’s overruling of its own advisory committee make it likely that the FDA will ignore its advisory committee recommendations more often? And what does the FDA’s approval of a drug based on a secondary endpoint like progression-free survival when the drug failed to meet the primary endpoint of overall survival bode for the future?

Got thoughts on these questions? Post ‘em in the comments.

The Government Accountability Office released a report today, finding that “in several key areas, FDA rules for drug approval fail to guarantee the safety and effectiveness of drugs for seniors.” Among the problems identified:

• Inclusion of seniors in clinical trials. GAO found that drug manufacturers “generally included elderly persons and reported safety and effectiveness data for elderly persons in clinical trials.” However, in a number of cases, selected drug trials excluded participants on the basis of age, restricting the participation of seniors.
• Inadequate FDA guidance. FDA has failed to clarify important requirements in the drug evaluation process for seniors, resulting in potential information gaps. For example, FDA does not require that medical officers determine whether a sufficient number of seniors participated in drug trials.
• Failure to document safety and effectiveness. According to GAO, one-third of new drug reviews failed to include documentation of FDA medical officers’ review of drug safety and effectiveness data for seniors.

Of these, excluding or failing to recruit adequate numbers of seniors for drug trials is the most troubling. Since the clinical trials are the only data that the FDA has to determine whether a drug is safe and effective for the population that will be using it after approval, it is vitally important that the clinical trial participants be a microcosm of the much larger patient population that is likely to use the drug once it’s approved.

We know that some side effects don’t show up in clinical trials, either because of the smaller number of people taking the drug or because some side effects only surface after patients have used the drug for longer periods. The FDA at times requires drug makers to conduct “post-marketing studies” after the drug has been approved — studies designed to ferret out the drug’s true risks and side effects once the “real world” data from millions of uses are available. Yet last year, the Office of the Inspector General issued a report documenting the incredibly shoddy job the FDA does at following up and making sure that drug companies actually do these studies.

The FDA’s failure to ensure that post-marketing studies are conducted makes it all the more important that clinical trials conducted to get the drug approved accurately reflect the patient population that is likely to take the drug once it’s approved. This is doubly important for seniors, who take more drugs, are likelier to suffer side effects, and far likelier to have other, complicating conditions.

PriceWaterhouseCoopers (PWC) released one of their periodic surveys of perceptions of the pharmaceutical industry, titled “Recapturing the Vision: Restoring Trust in the Pharmaceutical Industry by Translating Expectations into Actions.” The press release reports a number of interesting findings. Perhaps one of the most interesting, however, is this one:

94 percent of consumers and 81 percent of industry stakeholders said that drug companies are too aggressive in promoting unapproved uses of their product. Fewer than half (47 percent) of pharmaceutical company executives agreed.

It’s interesting to note that PWC chooses to characterize this fact in this way — it is true that 47% is fewer than half. It also can be characterized as “nearly half,” as I’ve done above. Isn’t it notable that “almost half” (yet another way to characterize 47%) of pharmaceutical executives think that their industry is too aggressive in promoting offlabel uses? Promoting a prescription drug for a use that is not approved by the FDA (so-called offlabel uses) is illegal, and such illegal offlabel promotion campaigns have gotten drug companies in significant hot water in recent years, resulting in criminal and civil settlements of hundreds of millions of dollars (e.g. $430 million for Neurontin, $704 million for Serostim, etc.)

If almost half of pharmaceutical execs think the industry is too aggressively promoting offlabel uses, it’s very safe to say that the industry is in fact being too aggressive. These executives are perhaps the ones most likely to cast the marketing activities in a positive light, and to downplay or underestimate the prevalence of illegal or improper marketing. So what do we make of the fact that 47% feel this way?

Other findings of the survey that are worthy of comment:

Three out of four (74 percent) consumers underestimate the average financial investment required to research and develop a new drug by more than 50 percent.

[and later in the release] Almost nine out of ten (86 percent) consumers underestimated the cost of bringing a new drug to market. Independent studies place the cost of developing a single marketed pharmaceutical product in excess of $800 million.

This “finding” assumes that the supposed $800 million cost of developing a drug is correct. Author Merrill Goozner dispelled this myth quite handily in his book, The $800 Million Pill: The Truth Behind the Cost of New Drugs. For instance, a good chunk of this $800 Million estimate represents not a true cost of bringing a drug to market, such as clinical trials, but rather the “opportunity cost” of the money invested in doing so. The “opportunity cost” represents what the drug company would have earned if they hadn’t decided to develop the drug, but had instead, for instance, invested that same money in the stock market. There are other components of this $800M figure that are arguably inflated.

So the public may not be that far off in its assessment of the costs of developing a new drug.

Consumers are split between believing that pharmaceutical companies consider important unmet medical needs when deciding to develop a new drug (55 percent) instead of choosing to develop “me-too” and “lifestyle” drugs with the greatest sales potential (45 percent). This compares to 71 percent of industry stakeholders and 91 percent of pharmaceutical executives, respectively, who say health needs are a top priority for pharmaceutical companies.

In this area, it would appear that perhaps both the public and the industry are not accurately perceiving the industry’s priorities. We can assume that the drugs that the industry chooses to seek FDA approval for reflect the strength of their consideration of important unmet medical needs. One need only look at FDA drug approvals in the past ten years to see that the majority of new drugs are in fact “me-too” and “lifestyle” drugs.

62 percent of stakeholders agreed that drug companies often manipulate or suppress negative clinical trial results to maximize sales. Four out of five pharmaceutical executives disagreed.

I wonder why 62% of stakeholders (including physicians, health plans and others) think this? Perhaps the recent suppression of negative clinical trial results (e.g. Vioxx, Paxil, Avandia) has something to do with it? The only surprising thing here is that only 62% believe this. Also conspicuously absent is what percentage of consumers feel this way. It makes one wonder if the percentage of consumers was so high that it was deliberately omitted. There’s no link to the full results from the press release, so I guess we’ll never know.

More than seven in 10 stakeholders (73 percent) agreed that drug companies spend too much money and effort attempting to prevent generic drugs from competing with their branded products. Consumers strongly agreed that drug companies should be working with generic drug manufacturers to make generics available upon expiration of their branded drug’s patent.

The best thing that drug companies could do to “work with” generic drug manufacturers to make generics available is to get out of their way — to stop filing frivolous patent infringement lawsuits and bogus FDA “citizen petitions,” to stop introducing fake “authorized generics” to try to undermine the first generic on the market, to stop introducing “successor” drugs (e.g. Nexium, Clarinex) that offer no advantage over their now-generic predecessors (Prilosec, Claritin).

[O]nly 10 percent of stakeholders and consumers think that direct-to-consumer advertising provides complete and useful information, compared with 40 percent of industry executives. Furthermore, nearly 94 percent of stakeholders agreed that drug companies spend too much money on drug promotion overall, including direct-to-consumer advertising as well as physician education and overall sales force initiatives. Surprisingly, nearly three-quarters of industry executives agreed.

Another notable finding — if nearly three-quarters of industry executives think their industry spends too much on promotion, then why don’t they do something to reduce it? These surveyed executives are not low-level employees in their companies — they’re “executives!” By definition, they’re in positions of leadership. We need more of these executives to stand up and challenge the convential wisdom within their companies and their industry. People within the industry need to shout that underneath all those drug ads and samples, the Pharma Emperor has no clothes.

The New England Journal of Medicine yesterday released a study showing that Avandia, a popular drug for treatment of Diabetes, increases the risk of heart attack by 43%.

This story was widely reported in the mainstream media (see, e.g., the Associated Press story) and pharmaceutical/health care blogs. We can expect much more on this story in the weeks to come.

Annual U.S. sales of Avandia were $2.2 billion in 2006, putting the drug well into the blockbuster category. This does not include sales of Avandamet, which combines Avandia with metformin, another diabetes drug. Either way, this is a very profitable drug for Glaxo Smith Kline, and their stock took a significant and predictable hit yesterday on the news.

This is only the latest in a string of revelations about GSK drugs. PAL members were among those that sued GSK for a variety of alleged illegal activity (see PAL’s pages on the Relafen, Augmentin, and Average Wholesale Price settlements, totalling $174 million).

Several years ago, former NY Attorney General (and now NY Governor) Elliot Spitzer sued GSK for concealing the fact that Paxil increases suicidal thoughts and behavior in depressed children and teens. As part of that settlement, GSK agreed to publish their clinical trials in a publicly available clinical trials registry. (GSK also agreed to pay $63.8 million to parents who purchased Paxil for their children, as part of a consumer class action. In fact, parents who did so can submit claims for reimbursement from that settlement from now until August 31, 2007 – details at www.paxilpediatricsettlement.com.)

In fact, much of the data in the NEJM study came from that registry. This underscores the importance of such registries, and of the necessity of mandating that drug companies register all their clinical trials in such registries. Various federal and state bills have been filed to enact such a mandate. (See the National Conference of State Legislatures for updated info on these bills.)

Given the importance of this information, why don’t more government prosecutions of drug company fraud include provisions requiring the defendant to submit all its trials to these registries? We previously discussed in this blog the question of whether recent US Attorney settlements with drug companies have real and lasting imapct. (See “Do government fraud settlements deter illegal pharma behavior?”)

Finally, this news further demonstrates the inadequacy of the FDA’s oversight of drug safety after a drug has been approved. In 2006, the Office of the Inspector General of HHS issued a report showing that numerous studies of prescription drugs that the FDA required drug makers to conduct after the drug had been approved had apparently not been conducted or even begun, and the FDA took little action to address the shortfall.

The studies that are used to approve a new drug usually involve, at most, a few thousand patients using the drug for short periods. But many side effects and safety issues only emerge after millions of people have taken the drug, and often only after a number of years. “Post-market” studies are essential to identify these problems. The FDA’s failure to ensure that these studies are done (or lack of authority to do anything meaningful when the studies are not done, depending on who you ask) is a huge and gaping hole in the U.S. drug safety system. Patients and doctors rightly want effective treatments to be available as quickly as possible. But that must be balanced with ongoing monitoring of the safety of drugs, to ensure that side effects and problems that only emerge later are detected and acted upon.

Lastly, it is a sobering thought that, had the NY Attorney General not learned of GSK’s deception regarding Paxil, and sued, and required GSK to submit all its trials to a public registry, the information about Avandia might not have been discovered. How many more Avandia users would have had a heart attack as a result? And how many more Avandia and Vioxx disasters are lurking, unknown, in the hidden and unavailable data of drugmakers that are not subject to the kinds of settlement that GSK is?