2012 was a momentous year for both the regulatory profession and Regulatory Focus. In our first year as an online-only publication, we covered a quickly changing landscape, dealing with topics that spanned the quality of pharmaceutical products, the passage of new legislation, the safety of medical devices, and the legal issues surrounding product regulation and marketing.
So what happened this year in the US? We're glad you asked. The editors and staff of Regulatory Focus have sorted through the more than 1,600 articles we wrote this year to answer a difficult question: What were the top stories of the year?
Based on a number of factors-the impact of the story on the broader public, the staying power of the story, its impact on regulated industry, its precedence and its novelty-we've sorted, cut and condensed the year into a list of the 25 top stories.
Read on for our explanation of each story, including links to some of the most important aspects of each one. Our list of non-US regulatory stories will be coming next week.
 The 50th Anniversary of the Kefauver-Harris Amendments to the FD&C Act
It's not every year the US Food and Drug Administration (FDA) marks a major milestone, and 2012 was one of the biggest: a half century of the regulatory authority FDA uses to assess pharmaceutical products based on their safety and efficacy.
Prior to the passage of the Kefauver-Harris Amendments to the Federal Food, Drug and Cosmetic Act of 1938, FDA was only endowed with the authority to assess the safety of a drug product. The law was also notable for its establishment of current good manufacturing practices (CGMPs) and the practice of postmarketing surveillance-all concepts that the agency has continued to build upon in the last half-century.
 Regulatory Harmonization: GHTF is No More
2012 marked the 20th-and last-year of the Global Harmonization Task Force (GHTF). The consensus-based medical device standards organization was perhaps the most significant effort to date to bring together various regulatory authorities to create uniform definitions, standards and submission criteria for devices.
In November, GHTF Chair Kazunari Asanuma sent out the group's final goodbyes, reminding stakeholders that the organization had accomplished much in its 20 years of service. But the organization is unlikely to be missed too much; the International Medical Device Regulators Forum (IMDRF), the regulators-only (i.e. no industry stakeholders) successor to the GHTF, has announced that it will be maintaining and building upon GHTF's work.
 FDASIA Passed, but These Measures Didn't
One of the most significant pieces of legislation to affect FDA in the last decade was passed into law this year. Known as the FDA Safety and Innovation Act, it was chock full of requirements and measures aimed at a host of different goals. But just as significant as what made it into FDASIA was what didn't make it into the law.
A measure to track and trace pharmaceutical products to cut down on counterfeiting almost made it into the law, but was scrapped at the last minute. Many consumer groups were also pressing to get measures passed that would have required stronger premarket testing requirements for 510(k) substantial equivalence applications, calling the current system rife with "loopholes." The final piece of legislation contained almost nothing to this effect, and unlike the track and trace measures, there don't seem to be any continuing efforts to pass a fix.
A third measure which would have prevented branded manufacturers from preventing potential generic competitors from obtaining copies of their product through the use of Risk Evaluation and Mitigation Strategies (REMS) restrictions also failed to make it through to the final, passed version of the bill.
 Pay for Delay Gets its Date of Reckoning
So-called "pay-for-delay" agreements, under which generic and branded companies settle ongoing patent litigation in return for a quid pro quo (generic companies typically get cash payments and a date by which they can enter the market, while branded companies get more time to market a product without competition), have been under fire by federal regulators for years.
Agencies, and in particular the Federal Trade Commission (FTC), call the deals anti-competitive and allege they harm consumers by keeping the prices of existing medications higher than they would be with competition. Companies, and in particular the generic pharmaceutical industry, argue that the agreements generally settle difficult patent issues quickly and cost-effectively, and in many cases allow consumers to access drugs even more quickly than they would otherwise.
2012 may go down as the year when the courts finally started to see the logic in FTC's arguments. In several cases this year, FTC scored minor and major (though far from unanimous) legal victories. Now, a December announcement by the Supreme Court indicates they are prepared to take up Federal Trade Commission v. Watson Pharmaceuticals and two other cases, potentially setting up a final answer on the issue of whether or not the deals are anti-competitive. Could pay-for-delay be going extinct in the coming year, or is it here to stay?
 The Science of Regulatory Gets a Boost
The term "regulatory science" has been around for years, but 2012 brought a concentrated effort on the part of FDA officials who seemed to be doing everything in their power to use the term and promote it to the public. At various times FDA promoted its effort to advance regulatory science abroad, in the US, in their guidance documents, and with the help of private organizations.
All that talk seems to be bearing fruit for regulators. Regulatory science initiatives have resulted in new chemical testing methods and several initiatives aimed at replacing the use of animals for toxicity testing. This trend looks likely to continue through 2013 and beyond, as several of those initiatives are set to start producing additional regulatory science-based test methods for both pharmaceutical and medical devices products soon.
 Safety of Medical Devices Comes to Forefront, but Doesn't Go Far
Consumer safety advocates pushed hard on the safety of medical devices this year, and essentially got none of what they were asking for. In short, they claimed that several medical devices-vaginal mesh, metal-on-metal hip implants and more-were cleared through the 510(k) process despite serious issues regarding their safety, which were later borne out through consumer use. Had those products been subject to similar testing requirements as higher-risk medical device products now approved through the Premarket Approval (PMA) process, their argument went, such devices would not be harming as many patients.
Proponents bet big on the coming reauthorization of the Medical Device User Fee Act(MDUFA), with Consumers Union taking a particularly prominent role in pushing for reforms.
The problem: Congressmen didn't seem to want to listen, and in many cases advocated for loosening restrictions on devices, arguing that FDA's system of regulation was too onerous relative to the EU's. In the end, little that consumer advocates wanted made it into the final FDASIA legislation, leaving many of their arguments intact but waiting, perhaps, for another opportunity in which to use them.
 The Regulatory Considerations of Killing Someone on Purpose
Most of the time, expansive knowledge of the country's regulatory processes is used to give someone access to a drug, not take access away. And yet that's precisely the tactic increasingly being used-and to fairly good success-by anti-death penalty advocates. Their basic tactics have included arguing that a particular drug was imported illegally, wasn't manufactured per FDA regulations, was stored incorrectly, or simply that regulators lacked the authority to permit its use based upon its safety profile-all in the hopes of making it difficult for state officials to carry out executions using difficult-to-obtain drug products.
The tactics have frequently been sufficient to delay executions, and the trend seems likely to continue, particularly after some justices have called FDA's allowance of the import of death-inducing drugs "callous" and "disappointing."
 Obesity Drugs Finally Find FDA Approval
2012 was a banner year for obesity drugs, which had largely been absent from the market for the last two decades. With the assistance of new risk-based paradigms for controlling their prescription and use, FDA approved products from Vivus (Qsymia, known as Qsiva in the EU) and Arena Pharmaceuticals (Belviq). FDA officials have indicated that the approvals aren't an anomaly, saying they are evaluating the potential of a "special medical use" pathway that could be used to approve additional "socially beneficial" drugs in the future.
 FDA Makes Use of the Animal Rule Pathway
It's been more than a decade since someone spread anthrax through the US postal system. In the panic following the anthrax attacks, FDA passed what it referred to as the Animal Rule, which allowed it to approve anti-pathogenic products based on efficacy testing done in animals instead of humans. The pathway was meant to spur the development of drugs as contingencies (called medical countermeasures) for ailments which don't normally have a market except in exceptional circumstances. 2012 saw both the first pharmaceutical (Johnson & Johnson's levofloxacin) and biologic (GlaxoSmithKline's raxibacumab) approved through the animal rule pathway.
FDA and other agencies also announced additional support measures for the pathway. In June, FDA said it would fund an academic-based training program to develop good laboratory practices for the biosafety-level 4 facilities that typically investigate dangerous pathogens. Then, several weeks later, the Presidential Commission for the Study of Bioethical Issues announced that it would be investigating methods on how to best include the interests of children in the pathway with an emphasis on the potential ethical issues associated with their participation. Could 2013 bring additional Animal Rule-based approvals? At least one thing seems clear: In a dangerous world, the animal rule pathway seems likely to stick around for quite some time.
 The Case-and Potential Precedence-of a Counterfeit Drug
Before 2012, Roche's drug Avastin was perhaps best known for its use in a number of cancer therapies, its questionable use as a breast cancer therapy, and its considerable cost. The year would add another point of notoriety: questionable authenticity.
In several cases throughout the year, FDA would announce that it had been made aware of counterfeit copies of the drug infiltrating the supply chain thanks to doctors who purchased from non-approved suppliers. An investigation by the Wall Street Journal would eventually link most of the supplies to a rogue distributor in Istanbul, Turkey, but the real source of the drugs remains unknown. At issue: with the rise of high-price oncology and orphan drug products, will FDA be able to protect the drug supply from increasing numbers of counterfeiters? 2013 may well determine if this lapse was an anomaly or the start of a growing trend.
 FDA Has Enemies, a List and a Lawsuit
The beginning to a positive story about the FDA typically doesn't involve information alleging that the agency maintained an "enemies list" of journalists and a surveillance operation against its own employees.
And yet that's exactly what FDA was grappling with for most of the year, as story after story broke about information related to a lawsuit filed by a group of former reviewers within FDA's Center for Devices and Radiological Health (CDRH). The reviewers alleged they had suffered repercussions after raising concerns about the safety of certain medical device products, and that FDA had retaliated by monitoring all communications-including personal ones-made from their FDA-issued computers. Worse, they claimed these communications included protected statements to government whistleblowing protection agencies and members of Congress.
Some high-profile voices-notably Sen. Charles Grassley-wound up getting involved, lambasting the agency for its lack of disclosure on the matter and requesting responses from high-ranking FDA officials.
Eventually the New York Times would report that an unsecured trove of documents-nearly 80,000 in all-had inadvertently been released, showing the agency to be extensively involved in monitoring both its employees and its critics. While the case made headlines throughout 2012, it remains in the process of litigation, and may well carry on through 2013 (and beyond, depending on any appeals). [Read more]
 Conflicts of Interest Overshadow Safety Debate
2012 started with a story that held the potential to cast serious doubts on whether the advice FDA receives from its advisory committees-groups of experts convened by FDA when it needs impartial advice on the safety or efficacy of a particular drug-was worth listening to.
Though the committees' recommendations don't carry the force of law, they are often followed by FDA except in rare cases. The problem in at least one case: The members aren't always entirely impartial. The Wall Street Journal reported that an advisory committee charged with reviewing the safety of birth control products marketed by Bayer had several members with direct financial ties to the company, potentially leading to a conflict of interest given the committee's close voting margins. FDA would eventually fire back-forcefully-at critics, but the issue continued to simmer throughout the year. This may well have been the scandal that never erupted in 2012, much to the benefit of FDA.
 Biosimilars Hit the Ground, But not Running
2012 was supposed to be the year biosimilars really got going. Thanks to the US Supreme Court upholding the Patient Protection and Affordable Care Act (PPACA), better known as Obamacare, FDA's newly-won authority to regulate biosimilar products under the new 351(k) pathway was preserved. In January, the agency released three guidance documents detailing the considerations of showing biosimilarity and interchangeability.
And then … not much else happened. Companies, patient groups and other various organizations continue to stake their claims in the dockets of the Federal Register, arguing, for instance, that biosimilar products should be required to have a distinct, non-generic name to distinguish the product from the originator. In a statement at a year-end conference hosted by the RPM Report, FDA officials said that while they had received several investigational new drug applications for biosimilar products, none have yet been accepted by the agency and all are still pending review. Will 2013 be the year these applications finally get their chance to be reviewed, or, as we explored in September, will they be bogged down by complex problems and costly litigation?
 Drug Approvals Hit the Mark Once Again
Pharmaceutical manufacturers went into this year fearing the effects of a patent cliff and billions of dollars in lost sales resulting from the onset of generic competitors. While that certainly happened, their landing was softened by a collective piece of good news: FDA drug approvals are at levels not seen since the mid-1990s.
Depending on which calendar metric you use, FDA either approved 39 drugs this year (calendar year) or 35 (fiscal year ending 31 September)-either one good enough for praise from industry. Going on two-year cumulative approval numbers, FDA had its best two-year stretch (69 drugs approved in all) since 1997-1998, when it also approved 69 new molecular entities, second only to its record-setting 92 drugs approved in the 1996-1997 timeframe. The development should give FDA a powerful tool in its arsenal to silence critics, who have long complained about sluggish approval numbers.
 The Death of Off-Label Marketing Restrictions?
In December, the US 2nd Circuit Court of Appeals reversed a lower court's finding that Alfred Caronia, a pharmaceutical sales representative, had engaged in illegal off-label marketing, marking a potentially groundbreaking legal precedent. The court, arguing in US v. Caronia, found that Caronia had been prosecuted for his speech in aid of pharmaceutical marketing, which they argued is protected under the First Amendment to the Constitution. The decision immediately sparked a firestorm of confusion and derision, with FDA's Bob Temple going as far as to call the decision horrifying.
The number of unanswered questions raised by the decision is considerable: Which marketing practices are now permissible? Is FDA going to practice its enforcement as usual until told otherwise by another court? Will the decision have long-lasting precedence? Will the Supreme Court take it up for review? With this news item coming so close to the end of the year, it seems that answers may not be available for quite some time.
[10-1] Read the top ten regulatory news stories of the year by going [here].
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