A magazine ad for Boniva, fronted by actor Sally Field, generated the DDMAC (now the Office of Prescription Drug Promotion, or OPDP) Untitled Letter last year due to following phrase: “After one year on Boniva, 9 out of 10 women stopped and reversed their bone loss.” That didn’t jibe with the scientific data, DDMAC said in the letter, before requesting that all ads containing the phrase be removed from the campaign.

Genentech went a step further. In September of last year, the company began running corrective magazine ads addressing the overstated claim. The corrective ad states that the violative ad “may have given you the wrong impression.” It goes on to state that “Boniva has not been proven to stop and reverse bone loss in 9 out of 10 women and is not a cure for postmenopausal osteoporosis.” The corrective ads will run though April 2012.

Unlike their mild-mannered, Untitled Letter cousins, Warning Letters are considered more severe, and they typically mandate corrective ads to clear up any overstated claims or minimized risk information. Given that Genentech received the former communique and not the latter, it’s notable that the company chose to run corrective ads without a mandate.

After speaking with DDMAC about the Untitled Letter, Genentech worked with the agency to create and then “voluntarily” launch the corrective ads last September, according to Chris Vancheri, director, public affairs, at Genentech.

In a statement, Genentech said that in addition to the corrective advertisements – which are running in several women’s magazines, including Weight Watchers and this month’s WebMD the Magazine – “our clinical specialists have reached out to health care providers” to inform them about the corrective ads, which intend to “clarify the benefits and risks of Boniva in women suffering from post-menopausal osteoporosis.”

Sally Field was the face of Boniva beginning in 2006, but Vancheri says Field is “no longer engaged” on the campaign. GlaxoSmithKline signed a co-promotion deal with Roche on Boniva in 2001, but the companies broke the partnership in 2010.

In response to off-label inquiries about a drug, biopharma companies can use the kind of boilerplate they’ve been inserting on social media sites for years – thanks for your comment, here’s our contact information, call us for more information – but they cannot address the question publicly, where it appears, a privilege many hoped would be included in FDA’s long-promised and long-awaited social media guidelines. Companies must also include a “mechanism for providing readily accessible current FDA-required labeling,” but cannot include a link to anything that could be construed as promotional, like a “product website, product promotional materials, firm websites, or third-party websites.” Guidance on responding to unsolicited requests for off-label information was published in the Federal Register a few days before the end of 2011.

Responding to an unsolicited off-label question/comment is only appropriate when a specific brand is named, and if the question is “broad in nature,” drug companies should “appropriately narrow the question.” FDA recognizes the fact that companies are “capable of responding to requests about their own products in a truthful, non-misleading, and accurate manner,” and that companies probably know more about their own products than other self-appointed responders:

It can be in the best interest of public health for a firm to respond to unsolicited requests for information about off-label uses of the firm’s products that are made in public forums, especially since other responders may not provide or have access to the most accurate and up-to-date medical product information.

Unlike other forum responders, who can comment publicly in response to any question, manufacturers must wait for the original commenter to respond to the boilerplate message with contact information, before providing “any substantive communication about off-label uses for the product, in response to the original unsolicited off-label question,” and that communication must occur “solely between the firm and the individual who made the request…the firm should not make its detailed response with off-label information publicly available within the same forum.”

FDA’s guidance on industries’ social media interaction with patients, at least with respect to off-label inquiries, seems to be: Don’t participate publicly. According to the guidance document, this sentiment reflects a concern that publicly posted off-label information – in response to an unsolicited query – would be available for an indefinite period of time, and would also reach the eyes of readers who have not requested such information. Even if the drug information is accurate when it’s posted, it may not be accurate next month. For viewers who didn’t ask about an off-label use, but are still party to a public response, the information itself, regardless of its scientific merit, “may promote a product for a use or condition for which FDA has not approved or cleared.”

Those companies that would like to respond to an individual with a question, assuming that person has called or emailed the company in response to the provision of contact information – contact info that leads to a firm’s medical or scientific department, not a marketing department, the guidance clearly states – should include the following materials, according to the document:

• FDA—required drug label
• A prominent statement saying the product has not been FDA approved
• A prominent statement disclosing approved indications, if any
• A prominent statement of all important safety info, including box warnings, if any
• A complete list of references for all of the information disseminated in the response (firms should use peer-reviewed articles whenever possible)

Companies should also maintain the following records about off-label responses:

• The nature of the request for information, including the name, address and affiliation of the requestor
• Records regarding the information provided to the requestor
• Any follow-up inquires or questions from the requestor

The guidance is open for comment for 90 days. Here’s the Federal Register entry.

On November 17, FDA’s Risk Communication Advisory Committee (RCAC) will convene to discuss the best ways to take a drug’s complex clinical data, and present it to doctors and patients in an understandable way. The stated goal is to improve healthcare decision-making by clinicians, patients and consumers.

At issue is the implementation of a drug facts box or table, which would appear in a drug’s promotional labeling and print advertising. Research shows that a drug facts box, or a “table quantifying [health] outcomes with and without a drug,” as described by Dartmouth Medical School profs Lisa Schwartz and Steven Woloshin, could do a better job presenting the benefits and risks of a particular medicine, which facilitates a more informed decision about treatment. It would also dramatically change the way drugs are currently promoted, at least in print. (For a facts box mock-up, click here)

Woloshin says he has not looked into broadcast media applications for the facts box, but suggests that certain warnings, such as approval on the basis of a surrogate outcome, or the main efficacy finding for a drug, could be easily inserted into broadcast spots. For broadcast, “we imagine the primary goal would be to point people to a drug [facts] box, either in print or online…we have not tested these ideas, but hope to in the future,” says Woloshin.

On facts boxes in print, however, Woloshin and his colleagues have conducted extensive research, and have published a substantial body of literature. In fact, three years ago, FDA’s RCAC – then chaired by Baruch Fischhoff, of Carnegie Mellon University – gave the facts box a unanimous recommendation. Speaking to PharmExec about the facts box, Fischhoff calls it “a sound design, both analytically and empirically…it follows the theories of risk communication, it has demonstrated efficacy in its field trials, and is clearly much better than what we have out now.”

So what’s the hold-up on implementation, you may be wondering. Unsubstantiated suspicions abound, and a request for comment from HHS – which received a mandate via the Patient Protection and Affordable Care Act (Section 3507) to review the evidence for or against a quantitative summary of a drug’s risk and benefit, “such as a table or drug facts box,” and to make a judgment – went unanswered. A report filed to Congress by HHS in March requested at least three more years for additional research.

“It’s crazy that people – doctors, patients, tax-payers – don’t have ready access to summaries of [a drug’s efficacy and risks] in a way that we’ve shown can help them make better decisions,” says Woloshin. “FDA is supposed to be interested in transparency, getting information out to people in the most transparent form; that’s exactly what the facts boxes are meant to do.” Asked about possible reasons for foot-dragging at HHS, Woloshin says he’s “completely baffled by the delay,” an opinion he made known in the editorial pages of the New York Times last July. Fischhoff agrees: “Given the amount of work that’s gone into the fact box and the evidence that supports it, it’s hard for me to believe that [alternate design studies conducted by HHS/FDA] would justify a delay of a couple of years.”

RCAC is unlikely to make any bold decisions on Thursday; the discussion is primarily geared toward whether or not substantial gaps exist in the literature around a standardized risk/benefit format, and if data exist to shed light on how to select and present information for clinicians, patients and consumers. Interested parties can sit in on the RCAC meeting remotely, here.

In an exhaustive review of the literature on using quantitative summaries for the presentation of drug benefit and risk information – published on August 15^th – FDA admits that “numeric presentation of risk/benefit information appears to have had a positive impact on several outcomes relative to non-numeric presentation,” (non-numeric presentation means using words like “often” or “rare,” in place of numeric statistics). But the report insists that important gaps exist in the literature, such as “insufficiently investigated actual behaviors” versus theoretical behaviors, and a “focus only on risk information rather than on both risk and benefit information.” The report also cites differences in “a person’s numeracy or literacy levels” as a point against standardized, quantitative summaries.

Note: Apologies for the lack of a facts box quiz, alluded to in PharmExec‘s weekly newsletter. The quiz unfortunately died from editorial and technical complications. -BC

In PLIVA v. Mensing, the Court ruled that generic drug companies should comply with federal regulations instead of conflicting state regulations when it comes to updating warning labels. Federal law prohibits generic companies from updating the warning labels, while some states require generic companies to include updated safety information. For pharmaceutical sales representatives, though, all eyes were riveted on the Sorrell v. IMS Health case, which pitted rep free speech vs. physician privacy.

In a 6 to 3 decision, the Court roundly came down on the side of pharmaceutical marketing as predicted during a recent Pharma Faceoff debate on the topic. “The State may not burden the speech of others in order to tilt public debate in a preferred direction,” Justice Anthony Kennedy argued in writing for the majority. “The capacity of technology to find and publish personal information, including records required by the government, presents serious and unresolved issues with respect to personal privacy and the dignity it seeks to secure. In considering how to protect those interests, however, the State cannot engage in content-based discrimination to advance its own side of a debate.”

In essence, the Court dismissed the privacy concerns, and utilizing ample evidence from the Vermont legislature, insisted that the real goal was to decrease the effectiveness of branded pharma sales efforts and increase generic utilization. Kennedy insisted that the case really was about free speech and just because the state of Vermont does not like the marketing practices of pharma doesn’t mean it can place an additional burden on it. The state should instead enter the “marketplace of ideas” and offer its own perspective on equal footing.

The case could be considered something of a landslide. Typically the court breaks down 5 to 4 along ideological lines, but in this case Justice Sotomayor, joined her more conservative colleagues, Alito, Scalia, Thomas and Roberts.

Not surprisingly, PhRMA and the data mining companies crowed over the decision. PhRMA claimed it was “not only a victory for free speech, but also a triumph for patients and future research and development by biopharmaceutical companies. SDI predicted that “existing laws in Maine and New Hampshire also will likely be declared unconstitutional or repealed in light of this Supreme Court decision.”

In dissenting, though, Justice Breyer raised some interesting challenges. Arguing that the state was not counter-detailing as implied in the decision, Breyer worried that the Court was opening up all state and federal regulation that impinges upon speech. “At best the Court opens a Pandora’s Box of First Amendment challenges to many ordinary regulatory practices that may only incidentally affect a commercial message,” he argued. “At worst, it re-awakens… pre-New Deal threat of substituting judicial for democratic decision making where ordinary economic regulation is at issue.”

Since the law’s passage, Vermont has created the nation’s most significant effort to create a universal health program, which only increases the state’s interest in drug marketing and healthcare costs and raising the stakes for the next showdown.

So, the question for pharma is more basic: Will there be a backlash as Frank Pasquale predicted in Pharma Faceoff? Will states like Vermont take a different approach that restricts pharmaceutical marketing in a way that is less likely to draw the ire of the court?

“Today’s decision introduces a critical distinction between brand-name and generic drugs. Consumers of brand-name drugs can sue manufacturers for inadequate warnings; consumers of generic drugs cannot,” writes Sotomayor. “These divergent liability rules threaten to reduce consumer demand for generics, at least among consumers who can afford brand-name drugs.”

In an article published in Pharmaceutical Executive’s May issue, John Brenner, a partner at Pepper Hamilton, suggested that it’s not inconceivable for plaintiffs seeking “failure to warn” protection to take up their grievances with the brand drug manufacturer, the originator of a given drug label. Generics companies must, by law, use a verbatim copy of the original brand drug label, regardless of new risk information or adverse events reports.

Commenting today on the Supreme Court’s decision, Brenner noted that two state courts, an appellate court in California (Conte v. Wyeth, November 2008), and a Vermont District Court (Kellogg v. Wyeth, October 2010), have ruled that brand drug companies could be held liable for the labeling on a generic drug, and therefore be subject to claims. While the California and Vermont decisions don’t necessarily constitute a consensus, Brenner said that “there are 50 states out there, and a lot of them have a great penchant for saying, ‘We really don’t like to leave our injured citizens without a remedy.’”

Writing for the majority, Justice Clarence Thomas acknowledges “the unfortunate hand that federal drug regulation has dealt [the plaintiffs],” leading Brenner to surmise that “there can’t be any question about the fact that the majority knew exactly what it was doing.” In her dissenting opinion, Sotomayor writes that “a drug consumer’s right to compensation for inadequate warnings now turns on the happenstance of whether her pharmacist filled her prescription with a brand-name drug or a generic…if she takes a generic drug, as occurs 75% of the time, she now has no right to sue.” Brenner says Sotomayor may want to check with the plaintiff’s bar about that one. “[Sotomayor] doesn’t know how clever these folks are,” said Brenner.

UPDATE: Brenner points to a statement released yesterday by metoclopramide (the generic form of Wyeth’s Reglan) claimants, including Elizabeth Conte of Conte v. Wyeth, announcing plans to take their cases to the brand manufacturer, in this case, Wyeth (now Pfizer). If generics companies can’t be held liable for what Reglan users consider an insufficient warning label, then Wyeth/Pfizer itself must be liable, according to the statement. “This ruling puts the responsibility back in the lap of brand name manufacturers,” said Michelle Schwartz, a metoclopramide victim who is also a spokesperson for the Reglan Metoclopramide Victims Organization, in the statement.

But the single most effective tool in the Bad Ad program’s toolkit, according to Arnie Friede, principal at Arnold I. Friede & Associates, and a former associate chief counsel at FDA, is fear. Or rather, in terrorem, a “Latin term that lawyers use” to mean frightening someone into compliance, says Friede.

When the program launched, FDA Commissioner Margaret Hamburg sent an explanatory letter to “more than 33,000” physicians, a fraction of the roughly 972,000 physicians in the US. Sales force management and reps themselves will have to decide if they are willing to play Russian roulette with a physician who may or may not be an informer. “FDA is trying to create the perception that the rep doesn’t know if the doctor is or is not a friend,” says Friede. “Accordingly, reps should be on the straight and narrow.” For FDA, the conversation between a rep and a doctor is one of the hardest areas to regulate efficiently, according to Friede. Creating in terrorem means prevention, he says.

Concerns about the Bad Ad program being abused by competing brands seem to be unfounded. According to FDA’s Division of Drug Marketing, Advertising and Communications (DDMAC), only 4% of the complaints that came in since last May were anonymous. Friede says complaining to DDMAC about competing brand messages is not something new, to be facilitated by the Bad Ad program. “There are plenty of channels for competitive complaints with DDMAC,” says Friede. Companies wishing to complain about marketing materials anonymously can simply do it through a law firm, Friede says, adding that “people that live in glass houses shouldn’t throw stones.”

Of the 328 submissions to the Bad Ad program, 188 came from HCPs, 116 from consumers, and 24 were submitted by industry representatives. The program will be expanded this year, according to DDMAC, to include a “web-based continuing education program,” and a new focus on med students and early career HCPs. FDA will also seek collaborations with medical, pharmacy and nursing schools to “enhance student education.”

To expedite distribution, and to make sure educational initiatives – under  Risk Evaluation and Mitigation Strategies (REMS) requirements, and otherwise – are being met, AstraZeneca signed a deal with Biologics, an oncology management company, to distribute vandetanib exclusively through Biologics’ specialty pharmacy. Financial terms of the deal were not disclosed.

Approved in the US on April 6, vandetanib is an orphan drug indicated for the treatment of medullary thyroid cancer that can’t be removed by surgery, or that has spread to other parts of the body. In the US, somewhere between 500 and 1,000 patients, approximately, have this rare form of cancer, according to Dan Duffy, executive VP and general manager, oncology pharmacy services group, at Biologics. FDA puts the number at 1,300 to 2,200 in 2010, according to a release.

Biologics is tasked with managing vandetanib’s REMS requirements (only REMS-certified pharmacists are allowed to dispense the drug) in addition to working with payers and consolidating referral sources. Ten nurse liaisons are “going out to educate the physician and clinical staff about program specifics, how to make it efficient for them, and to ease the administrative burden for the physician,” said Duffy. For patients, the company expedites available copay assistance, with a focus on rapid turn-around times. Without insurance, a 30-day supply of 300 mg vandetanib, taken once daily, costs $10,454.00, according to an employee in Biologics specialty pharmacy. Patients without insurance may be elligible to recieve the drug at no cost, through AstraZeneca’s prescription savings program, according to Laura Woodin, a spokesperson at AstraZeneca. In clinical trials, vandetanib was “shown to affect the electrical activity of the heart, which in some cases can cause irregular heart beats that could lead to death,” hence the REMS, said FDA, in the release.

Woodin said in an email that the company’s exclusive distribution arrangement with Biologics is “a new approach for our US business…vandetanib is also the first treatment that AstraZeneca has developed and brought to market under orphan drug designation in the US.” Woodin said the small patient population for vandetanib was a major factor in signing the exclusive distribution deal. Duffy said the agreement lets AstraZenca “standardize the distribution channel and really control it.”

Vandetanib doesn’t currently have a brand name; AstraZeneca requested Zactima, but FDA did not accept that name, said Woodin. The company is currently in talks with FDA about a new name.

In order to incentivize the formation of ACOs, the CMS guidelines for the Medicare Shared Savings Program would reward ACOs that treat Medicare Part A and Part B beneficiary populations at or under a pre-determined cost benchmark; for those ACOs that keep costs below the benchmark, as much as 60% of the money saved would be distributed back to ACO members. Benchmarks for specific ACOs would be determined by average per capita Medicare Parts A and B expenditures, according to the proposed guidelines. Exceeding the benchmark, however, means being held accountable, or paying the government for overage costs.

Are physicians ready to take on that kind of risk? “Frankly I think that [risk] is one of the things that will limit the number of institutions or organizations that are interested in playing here,” said Dan Mendelson, CEO of Avalere Health, a consulting firm. “If you have excellent data systems, and you understand risk, and you have control over your providers in terms of utilization, you’re probably a managed care company already,” he said. Managed care organizations are not eligible for the Shared Savings Program. Jeremy Lazarus, speaker for the American Medical Association (AMA) House of Delegates, said in a statement that “ACPs offer great promise for improving care coordination and quality while reducing cost, but only if all physicians who wish to are able to lead and participate in them.” A spokesperson for the AMA said more time was needed to digest the guidelines, before making additional comment on whether a critical mass of physicians would join or create ACOs.

Regarding the impact of ACOs on drug sales, Mendelson noted a “broad flexibility for ACOs to introduce concepts like step therapy,” or the practice of beginning treatment with the safest and cheapest drug therapy. With ACOs, the “organization controlling the spend is no longer the physician, it’s now the system,” said Mendelson. “From that perspective, [ACOs] look more like Kaiser [Permanente] than like selling into an oncology practice.”

John Kamp, executive director of the Coalition for Healthcare Communication, said ACOs represent additional pressure toward the use of generics and other cheap alternatives. In order to cope with those pressures, drug marketers will need to become more sophisticated in “talking about the system economics of using specific new drugs, as well as the individual patient outcome,” said Kamp. “The short-term cost pressures are much more acute than long-term cost savings.”

To participate in the Shared Savings Program, an ACO will need at least 5,000 beneficiaries on its roster, healthy and sick, according to the guidelines. “One of the things that emerges here is that if you can enroll patients who do not have multiple sclerosis or cancer or other biotech-targeted conditions, you’re going to do better,” said Mendelson. “There’s an incentive for the selection of healthy patients that the government will need to mitigate over time.” According to the guidelines, ACOs taking steps to avoid “patients at risk in order to reduce the likelihood of increasing costs” will face sanctions, which could include “termination from the program.”

Health providers eligible for participating in the Shared Savings Program include physicians in group practices, networks of individual practices, partnerships or joint venture arrangements between hospitals and physicians, hospitals employing physicians, and “other groups of providers of services and suppliers as the Secretary determines appropriate,” according to the guidelines. ACOs must enter into a three-year agreement with CMS to be eligible for the savings incentives, using one of two proposed models described in the guidelines.

Earlier this week, a federal judge declared the foundation of President Barack Obama’s health care law unconstitutional, ruling that the government cannot require Americans to purchase insurance. The case is expected to end up at the Supreme Court.

US District Judge Henry E. Hudson based his ruling on grounds that the Constitution’s Commerce Clause regulating interstate commercial transactions could not be interpreted to allow the federal government to compel a person’s decision to buy or not to buy a product—in this case, health insurance.

In his order, Hudson said he will allow the law to remain in effect while appeals are heard, meaning there is unlikely to be any immediate impact on other provisions that have already taken effect. The insurance coverage mandate is not scheduled to begin until January 2014.

Hudson is the first federal judge to strike down a key part of the law, which had been upheld by fellow federal judges in Virginia and Michigan. Several other lawsuits have been dismissed and others are pending, including one filed in Florida by 20 states. In practical terms, the decision merely hands action off to the top court, in which the nine Supreme Court justices can decide whether to hear the case or not.

White House health reform director Nancy-Ann DeParle said the administration is encouraged by the two other judges who have upheld the law. She said the Justice Department is reviewing Hudson’s ruling but that implementation of the law will proceed on track.

Regardless, Hudson’s ruling injects another note of uncertainty that will complicate efforts by Pharma and other industries to move beyond the ideology of reform and focus on practical issues linked to implementation of the more than 900 provisions of the bill requiring follow-up regulatory action. At a time when China, other key emerging markets, and the industrialized bloc of nations are all focusing on healthcare as a key strategic sector, this lack of predictability represents a potential strain on US competitiveness. If in the unlikely event that court action scuppers reform, Big Pharma will suffer some unintended consequences, the most important of which is a lower potential customer base—i.e. the currently uninsured—as well as more pressure on the pricing front. Most economic analyses show that the absence of an individual mandate to purchase insurance drives up insurance premiums, raising the visibility of high drug costs and adding to compliance problems among patients.