Pharma Law and Business Roundup for March 2013

Yet another busy month has passed since our last stop here at IPWatchdog. So let’s recap some of the more interesting developments. The last few weeks, in fact, have been bookended by concern over a batch of diabetes drugs and links to pancreatitis, but also pre-cancerous cellular changes in the pancreas.

First, a study in JAMA Internal Medicine indicated the drugs can double the risk of developing pancreatitis, an issue that has plagued these meds for years. Insurance records for more than 2,500 diabetics between 2005 and 2008 were examined and found patients hospitalized with pancreatitis were twice as likely to have taken the drugs than a control group that did not have pancreatitis. The study did not examine other meds, such as Novo Nordisk’s Victoza, that were not available at that time.

The issue raised questions about whether the results might alter treatment practice by physicians. Of course, the drug makers issued statements standing by the safety of their medicines, while acknowledging the risks have been detected in the past. The American Association of Endocrinologists and the American Diabetes Association issued a joint statement noting the analysis was a retrospective study, not a prospective, randomized controlled clinical trial.

And some Wall Street analysts also played down the findings, citing limits on study design and methodology, such as statistically significant and meaningful imbalances favoring the patients in the control group in several characteristics that are known to be important risk factors for acute pancreatitis. And some also noted the lead author has a controversial track record of publishing studies that harped on safety concerns with other widely used medicines.

[Bio-Pharma]

For a moment, it appeared the attention given the study might dissipate. But then the FDA weighed in and announced it is evaluating “unpublished, new findings” by academic researchers that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin mimetics.”

The agency cited patient deaths based on examinations of pancreatic tissue specimens and added the researchers were asked to provide more information on their methodology and provide samples. The drugs in question include Bydureon; Merck’s  Janumet; Victoza; Onglyza, which is marketed by Bristol-Myers (BMY) and AstraZeneca (AZN); and Tradjenta, which is marketed by Eli Lilly (LLY) and Boehringer Ingelheim.

Besides noting that labeling already includes language about the risk of pancreatitis, the FDA added something else: the agency cited the recent published study in statement, suggesting there was, after all, reason to take the findings seriously.

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Meanwhile, the fracas over disclosing clinical trial data continued. AbbVie, the Abbott Laboratories spin off, filed a request for an injunction to prevent the European Medicines Agency from releasing detailed patient-level data from studies concerning its top-selling Humira rheumatoid arthritis treatment.

The filing was made after two Freedom of Information requests were filed with the EMA last year by other drug makers seeking “raw data” on the safety and efficacy of the medication, a multi-billion-dollar seller. In a statement, AbbVie defended its action by saying it seeks to protect “confidential and commercially-sensitive information.”

Abbvie supports “transparency of clinical research and safety information for the benefit of patients and healthcare professionals, (but not) the disclosure of commercially confidential information that does not meaningfully contribute to the scientific review or evaluation of our products.” The US and European industry trade groups filed documents supporting AbbVie.

This happened shortly after Roche announced a new plan to increase access to such information. The drug maker vowed to work with an “independent” group of “recognized experts” to evaluate and approve requests to access patient-level data and will also support the release of case study reports for all of its licensed medicines.

The move came after Roche became embroiled in a row with researchers at the Cochrane Collaboration, who two years ago complained they were repeatedly prevented from gaining access to up-to-date efficacy information for the influenza treatment. More recent attempts to obtain data prompted a response from Roche that critics called stonewalling. Roche then responded with a compromise offer to form a multi-party advisory board for determining which data should be accessed, but that went nowhere.

Now, Roche says that an independent body will assess the validity of requests for data, which will be available in a “secured system.” From there, access to patient data will be available for trials that have been submitted with a regulatory application and will be available after regulatory reviews have been completed in the US and European Union. This process begins this year and Roche says talks are being held with other drug makers “to see if this can be an industry-wide initiative.”

There were caveats. The drug maker will release full case study reports, summaries and safety updates for medicines approved by the European Medicines Agency. But the information will be edited “in line with relevant country or regional laws” in order to ensure patient confidentiality and “to protect legitimate commercial interests, including intellectual property rights.” But starting in April, Roche “will provide any CSR on request that cannot be obtained from the EMA for third-party researchers.”

As for Tamiflu data, Roche said 71 of 74 completed trials are now in the public domain either as a primary publication, secondary publication or on its own rochetrials.com, and arrangements are being made for the remaining three trials to be posted. And Roche is forming what it calls a Multi-party Group for Advice on Science, which will consist of four “renowned” scientists in the field of influenza to review Tamiflu data, identify any unanswered questions and agree on a statistical analysis plan.

There are some murky points. Roche says there will be an agreement, but does not offer specifics concerning parties or substance, yet maintained it will provide access to all requested Tamiflu clinical trial data for the analyses. And four scientists will invite independent experts and third parties to a meeting in June. But three of its panelists have recently been scientific advisors or consultants to Roche, or were grant recipients.

Not surprisingly, the effort was criticized. “Making the results of trials more open will not be – and should not be seen as – a simple process, although it seems a simple statement, aimed at the media, will solve all the problems that have accrued over the last 20 years,” scoffed Carl Heneghan, the director at the Centre for Evidence-Based Medicine at the University of Oxford and one of the Cochrane Collaboration researchers who has tussled with the drug maker.

One drug maker, however, has publicly agreed to make patient-level data and case study reports available. Last year, GlaxoSmithKline disclosed plans to do so after paying a $3 billion settlement to settle civil and criminal charges that included a failure to release trial data. So far, though, Glaxo has not announced a specific start date or released named of independent panelists who are to assist in the effort.

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Although compulsory licensing is hardly a household topic in the US, the issue raises neck hairs in the pharmaceutical industry. So it was worth noting that Indian authorities are considering a proposal to eliminate licenses that would be granted based on the price of a brand-name medicine.

The move came just one year after authorities issued the first compulsory license allowing a generic drug maker to make a copycat version of a patented medicine, and as India’s Intellectual Property Appellate Board was expected to decide an appeal by Bayer, which was fighting the license issued last year for a generic of one of its cancer meds.

The decision last year to issue a license to Natco for a generic version of the Bayer Nexavar cancer drug was a game-changing moment because the Indian market is so large and could set a tone for decisions by other countries.

So India’s Department of Pharmaceuticals issued a new draft guidance saying once patented drugs come under proposed price controls, the costs should be considered reasonable and compulsory licenses should not be issued based on affordability. Instead, a new Committee for Patented Drugs should decide prices based on what is charged in the UK, Canada, France, Australia and New Zealand.

The licensing debate is far from over, though. Just a few days later, the IPAB rejected the Bayer appeal, which the drug maker then promised to fight once more before the Indian High Court in Mumbai.

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In response to the scandal over a fungal meningitis outbreak, the FDA has begun a crackdown on compounding pharmacies and targeting about 30 ‘high risk’ operations in nearly a dozen states and made a point of posting inspections reports were issued for several compounders for a variety of serious manufacturing violations.

Rather than wait for complaints to be filed against compounders, the agency is using a “risk-based model that relies on adverse event reports, historical inspection data, reports of quality problems and public information to identify pharmacies that may pose higher risks and are known to have engaged in sterile compounding.

The FDA has suffered harsh criticism for failing to pursue enforcement action against the New England Compounding Center, which has been linked to 722 cases of fungal meningitis, including 50 deaths. The outbreak, which has been described as one of the worst such public health crises in the US in decades, has prompted lobbying by drug makers to curb compounders and Congressional probes into FDA decision making.

The House Energy and Commerce Committee is leaning on the FDA to disclose documentation concerning its actions toward the NECC. In response, the FDA has begun coordinating its efforts with state board of pharmacy in identifying compounders and making its findings available to all states on its website, since many of the riskier compounding pharmacies ship across state lines.

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This may prove to be Quixotic, but San Francisco officials approved a referendum that will allow residents to decide whether to require city officials to hold talks with drug makers about pricing for ‘essential medicines.’ The measure, which is known as the Prescription Drug Purchasing Initiative and is designed to increase patient access, will appear on ballots this coming November.

The referendum was proposed by the AIDS Healthcare Foundation in response to the prices for certain AIDS medications, but specifically, Stribild, a once-daily combination HIV pill from Gilead Sciences that was approved last summer by the FDA last summer and costs $28,500 annually. AHF targeted San Francisco for its referendum, since the city has a large population of people who are HIV infected and drug prices have a significant impact on its finances.

The city spends over $23 million per year on prescription drugs, including about $3.5 million dollars annually on antiretroviral medications to treat inpatients with HIV and related conditions, according to a notice city officials posted last fall when the petition was approved to gather signatures to place the referendum on the November 2013 ballot.

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In a closely watched decision, a federal appeals court upheld the conviction of a former biotech chief executive, who argued that federal prosecutors violated his First Amendment and commercial speech rights. Scott Harkonen had been convicted of wire fraud for allegedly skewing the results of a clinical trial in a 2002 press release about the effectiveness of a drug.

The former Intermune chief executive issued a release containing results of a clinical trial for a drug called Actimmune. The trial failed, but the press release stated a sub-analysis showed the drug helped patients with a fatal lung disease called idiopathic pulmonary fibrosis, or IPF, live longer. Physicians began writing more prescriptions even though Actimmune was not approved for that disease.

At his trial, federal prosecutors argued Harkonen orchestrated a scheme to widen the market for Actimmune in a way that deceived doctors and investors. And they maintained that he did so by manipulating the interpretation of a sub-group analysis from the clinical trial in order to show the drug offered a significant survival benefit.

The former CEO maintained the case was really about looking beyond strict statistical significance in order to recognize perceived value in scientific debate over study results. And he pointed to the extent to which the feds relied upon the so-called ‘p value,’ a key probability measurement, in arguing that he distorted the results for his own ends.

Harkonen contended the feds overstated reliance on the p-value to discuss the benefits that were parsed from the trial data. And to bolster his argument, he cited a 1902 US Supreme Court case to argue that “federal fraud statutes do not permit the government to prosecute individuals for expressing scientific opinions about which reasonable minds can differ.” But the court noted the evidence supports the finding that he knew the press release was misleading and had intent to defraud.

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Debates over relationships between the pharmaceutical industry and physicians and academics, who make crucial decisions about research and treatment, continues to fester. And a new report found that pharmacy and therapeutic committees that make formulary coverage decisions for Medicare Part D plans have limited oversight of conflicts held by committee members. As a result, the insurers lack the ability to prevent financial interests from influencing coverage decisions.

The committees, which are run by private insurers that contract with the Centers for Medicare & Medicaid Services, have limited definitions of conflicts of interest, which can prevent them from identifying conflicts. And many committees allow members to determine and manage their own conflicts, according to the report, which was issued by the Office of Inspector General at the US Department of Health & Human Services.

Moreover, CMS does not adequately oversee compliance. At least two members on each committee must be independent and free of conflict with insurers, pharmacy benefit managers and drug makers. During 2010, CMS never conducted audits and if the agency had tried to review the information, it would have found the data unusable because of discrepancies, the report stated.

The implications are obvious – there were 31 million beneficiaries who are 65 years and older who were enrolled in Part D plans as of March 2012, according to the report. And with so many seniors using multiple medications for chronic, as well as acute ailments, this means there is little oversight on the decision makers who influence usage.

This was the second time in recent months that concerns were raised about conflicts of interest involving a federal healthcare program. A study in JAMA Internal Medicine found that many of the state Medicaid drug selection committees lack sufficient conflicts policies for adequately protecting the decisions for choosing medicines.

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In another closely watched debate, the Federal Trade Commission filed a brief siding with generic drug makers in dispute with brand-name drug makers. At issue is whether a brand-name drug maker should be required to sell samples of its medicine to an aspiring generic rival when its medicine was approved with a Risk Evaluation and Mitigation Strategy.

In a lawsuit, Actelion Pharmaceuticals filed against two generic drug makers, the company argued that its REMS could be threatened by relinquishing strict control of its medicine and should not be forced to do business with another company if it chooses not to do so. But generic drug makers complain that brand-name drug makers use the strict distribution provisions of the REMS regulation as an excuse not to provide samples needed for bioequivalence testing.

In deciphering the matter, the FTC warned that if the courts uphold Actelion’s argument, it could “pose a significant threat to competition in the pharmaceutical industry.” The agency, which did not take a position on the facts in the case, explained the Hatch-Waxman Act would be incapacitated if generic drug makers are unable to access samples of brand products.

The FTC also maintained that Actelion misinterpreted the FDA Amendments Act, which states that a REMS should not be used to block or delay an Abbreviated New Drug Application and that the FDA has issued letters clarifying that particular brand-name drug makers may sell drugs to generic drug makers for bioequivalence testing without violating a REMS agreement.