Of course, in an ideal world, the regulators should be the only ones sifting through the evidence since that is what they are trained and paid to do. But if the story of Avandia, GlaxoSmithKline’s anti-diabetic drug, tells us anything it is that the verdict of expert advisory committees counts for little once the mere sniff of a safety scandal has got out.

In 2006, just before safety concerns about Avandia were made public, the drug dominated the diabetes market with sales of more than $3 billion, according to EvaluatePharma. In 2007, an advisory committee voted by 22 to one to allow the drug to remain on the market with appropriate warnings. But certain studies showing it raised the risk of a heart attack gained in currency and by 2008, its sales were less than half those of 2006. Other studies did not show this risk but these were not so avidly discussed.

Earlier this month, another FDA advisory committee again ruled in favour of Avandia remaining on the market, albeit with a reduced majority and new warnings. But this considered opinion is unlikely to make doctors rush for their prescription pads. Even if they did, their type-2 diabetic patients are also looking at their options.

Takeda, meanwhile, which makes Actos, Avandia’s main rival, is laughing all the way to the bank. Sales of the drug have risen from $2.8 billion in 2006 to $3.8 billion in 2008, according to EvaluatePharma. Not only has the company benefited from politicians such as Rosa De Lauro, a Democrat from the House of Representatives, screaming that “Avandia is dangerous and should be pulled from the market.” But it has also been gifted a copyline for a direct-to-consumer ad campaign most agencies would die for. The day after the FDA decision, Takeda started running ads that are scheduled to appear in 154 publications over the next few weeks saying: “Actos has been shown to lower blood sugar without increasing your risk of having a heart attack or stroke.”

In the light of such adverse publicity it is hard to see how Avandia can possibly recover. Indeed, all that can be said in favour of the FDA vote is that it should reduce what GSK can expect to pay in lawsuits.

The lesson to be drawn from the Avandia story is that companies should take every step to be seen to be upfront and clean when communicating the risks and benefits of prescription drugs. This has always been the case but it is especially true now that Big Business — be it Big Banking, Big Oil or Big Pharma — is under such intense public scrutiny and when the world has become so much more transparent. Politicians, as we also see from the BP environmental disaster, can score easy points by attacking Big Business. Patients, hearing attacks on Big Pharma drugs, pick up only on the risks, amplifying them further on social media sites. Competitors, meanwhile, can hardly believe their luck, and will understandably exploit the situation to the hilt.

The result should be a compelling argument for Risk Evaluation & Mitigation Strategies, otherwise known as REMS, whereby regulators effectively put more onus on companies for a full appraisal of the risks associated with their drugs. Whether such strategies will work remains to be seen; the truth is that everyone, patients as well as companies, wants drugs presented in the best possible light — until, of course, something goes wrong.

On July 23, sanofi released a statement expressing concern about FDA’s decision to approve a generic version of Lovenox because of the “potential implications for patient safety.” Sanofi said the generic version, manufactured by Momenta Pharmaceuticals (Cambridge, MA) and Novartis’s generic-drug unit, Sandoz (Broomfield, CO), was not subject to the same extensive testing for safety and efficacy that Lovenox has undergone and therefore cannot be considered an equivalent drug. “By nature, Lovenox is a complex biological product and its efficacy and safety profile relies heavily on the strict adherence to the specific processes applied in its manufacturing as well as its traceability from the animal mucosa to the finished product,” according to the company statement.

FDA’s announcement of the drug’s approval acknowledges the challenges in producing the generic version and emphasizes that the appropriate precautions were taken before making its decision. “Before approving generic enoxaparin sodium injection, we expected, among other things, a series of sophisticated analytical tests and a study in healthy volunteers to assure that the drug would be as safe and effective as the brand name product,” said Keith Webber, PhD, deputy director of the FDA’s Office of Pharmaceutical Science. 

Early this week, sanofi filed a lawsuit in the United States District Court for the District of Columbia seeking to overturn FDA’s approval of the generic Lovenox. Momenta Pharmaceuticals released an update on Tuesday that said sanofi’s suit sought a temporary restraining order and preliminary injunction forcing FDA to suspend and withdraw its approval of the abbreviated new drug application filed by Momenta and Sandoz. The court set a date for a hearing on Aug. 17, and in the meantime there are no restrictions on Momenta and Sandoz to market their generic version of enoxaparin sodium injection. The companies say they plan to “vigorously oppose” sanofi’s suit.

In other sanofi news, reports around the web, such as this one from the New York Times, speculate that sanofi is on the verge of making an unsolicited $18-billion bid for Genzyme. The bid represents an offer of roughly $70 per share of the Cambridge, Massachusetts-based biotech firm. Analysts are eagerly awaiting the release of a letter from sanofi detailing its offer for Genzyme. Rumors of the deal have been circulating for several weeks, as PharmTech editor Patricia Van Arnum described in her blog post from early July.

Last week, the Partnership to Improve Patient Care (PIPC), which includes a wide range of healthcare organizations working to support the government’s role in and awareness of CE research, held a forum about delivering patient-centered comparative effectiveness (CE) research. Senator Max Baucus (D-MT) was the forum’s keynote speaker.

“It’s only fitting that patients are at the center of the research we seek to foster in the new law,” the Senator told the audience. “No longer will patients and their doctors have too little information about how different treatments work.”
He went on to describe how today’s doctors and patients have more tests and treatment options to choose from then ever before, but do not necessarily have enough “reliable evidence” to help choose among those options. This is where the new law really comes into play. H.R. 3590 terminated the Coordinating Council for Comparative Effectiveness Research that was established under the 2009 American Recovery and Reinvestment Act of 2009, and instead established a Patient Centered Outcomes Research Institute to commission CE and related drug research. The new center is to be funded for 10 years.

According to Baucus’ statement at the forum, patients will have strong representation on the governing board of the new Institute. Board members are currently being selected through the Government Accountability Office. “The research itself will focus on clinical outcomes in the real world,” said Baucus. “The research will focus on the information that doctors and patients find useful when making decisions about care. The new law requires the Institute to consider subgroups of patients that may experience different effects from the same treatments, if evidence in the field warrants it…. 
And the Institute will operate transparently and within a limited scope. …The Institute will not develop medical guidelines, treatment protocols or coverage recommendations of any sort.”

Overall, explained Baucus, the new Institute will help to strengthen the doctor-patient relationship by providing useful information so that patients can make better-informed decisions about their healthcare.

I look forward to seeing the work that comes out of the Institute and the how that information affects the patient-doctor relationship on a practical level. The fact that average citizens are able to nominate Institute Board members may help increase consumer confidence in the Institute’s work.

See related blog posts

Will Comparative Effectiveness under Healthcare Reform Change Drug Development?

Comparative Effectiveness Versus Personalized Medicine

The inspection report in question contains disturbing observations about J&J’s Lancaster, Pennsylvania, facility, which manufactures over-the-counter products such as Pepcid and Mylanta. If the inspectors’ observations are to be believed, plant managers have been taking a laissez faire approach to the facility’s manufacturing operations. For example, inspectors noted that the plant’s instructions for cleaning and maintaining equipment omitted crucial details about the materials and methods required. Nor did the instructions explain how to disassemble and reassemble equipment to ensure proper cleaning. Inspectors also claimed that the plant’s equipment was not inspected routinely according to written procedures.

This state of affairs opens the door to malfunctions, and FDA officials apparently had a chance to witness several of them. During one packaging operation, a capper machine crashed, a cooling loop failed, and operators observed leaky bottles of product. Yet inspectors said that staff did not conduct quality reviews of products that had been manufactured during equipment failures.

Inspectors did not give the plant’s analytical-testing operations high marks, either. FDA officials said the plant’s laboratory controls did not establish scientifically sound test procedures to ensure that products meet standards of identity, strength, purity, and quality. Inspectors observed as analysts strayed from written test procedures without justification. And when employees took samples of drug products to determine their conformance with specifications, they did not properly identify the samples, according to FDA.

The well-publicized quality problems at its Fort Washington, Pennsylvania, plant apparently haven’t spurred J&J to confirm that its other US manufacturing operations are up to snuff. But the new problems in Lancaster also affect Merck & Co. (Whitehouse Station, NJ), which operates the plant as a joint venture with J&J. I’m sure that Merck does not want its reputation to suffer by association with J&J. If it hasn’t already, Merck will probably lean on its partner to help improve the Lancaster facility. It might take this extra pressure to get J&J to seek and address systemic problems at its manufacturing operations. In the meantime, the public will eye both companies with suspicion.

This is what drug giant AstraZeneca has recently been accused of doing. In June, the European Commission (EC) fined the company €60 million for misusing the patent system and marketing procedures to block or delay the market entry of generic competitors to its ulcer drug Losec from 1993 to 2000.

“It is not for a dominant company but for the legislator to decide which period of protection is adequate,” said Competition Commissioner Neelie Kroes in an EC press statement.

Since then AstraZeneca has unsurprisingly appealed the decision, but only succeeded in reducing the fine to €52.5 million. According to a July statement from the EC, the court rejected the company’s claims that “its conduct constituted normal competition and that it could be explained by errors or unauthorised behavior by AstraZeneca’s patent agents”.

However, the court did disagree with the EC on one issue relating to parallel trade. According to the EC, AstraZeneca had deregistered market authorizations in some EU countries with the intent of blocking or delaying entry by generic firms and parallel traders. At the time, generic products could only be marketed and parallel importers only obtain import licenses if there was an existing reference market authorization for the original product. The court agreed that the purpose of a marketing authorization is not to exclude competitors, but annulled the decision concerning the restrictions on parallel trade in two of the three countries concerned.

Despite this, a memorandum from law firm Skadden, Arps, Slate, Meagher  & Flom LLP believes that the EC is viewing the AstraZeneca judgement as a “victory” and an “enforcement of its sector inquiry and the enforcement agenda derived therefrom.”

The suit was brought by Novartis employees whose primary responsibility is to visit physicians’ offices, drop off drug samples, and deliver scripted messages about the company’s products. Echoing the opinion of much of the pharmaceutical industry, Novartis argued that these workers are outside salespersons and therefore exempt from overtime pay under federal and state law.

The case finally reached the US Court of Appeals for the Second Circuit, which rejected Novartis’s reasoning. The decision might have been influenced by the US Department of Labor, which took the unusual step of filing an amicus appeal brief in support of the sales reps. This decision likely will affect the entire pharmaceutical industry, which faces several similar lawsuits filed by sales reps seeking overtime pay.

At first glance, the decision seems like good news for pharmaceutical sales reps. But the obligation to pay overtime might become another excuse for drug companies to cut their sales forces. In response to the recession, pharmaceutical manufacturers have laid off thousands of reps as a cost-cutting measure. Even without the recession, reps have been on shaky ground as physicians become increasingly unwilling to meet with them. As a result, companies have sought alternative ways of reaching doctors such as e-detailing.

I’m happy to see the Department of Labor and the Second Circuit protect sales reps’ right to fair compensation. On the other hand, I still fear for the reps’ jobs under the current market conditions. Maybe new blockbusters would be the best cure for these workers’ job insecurity.

This morning, however, officials from FDA’s Center for Drug Evaluation and Research Office of Compliance shed some light on the status of Part 11 via a press briefing.

George R. Smith, a project management officer in the Office of Compliance and co-chair of the Part 11 Working Group, described the agency’s plans to carry out inspectional efforts tied to Part 11.  The goal, said Smith, is to carry out focused inspections pertaining to Part 11 regulations on human drugs in an effort to help increase industry understanding of and compliance with Part 11. Enforcement actions will be taken when noncompliant activities are determined, he said.

 To explain what this means for industry, here is a bit more background: Since 2003, according to the Part 11, Electronic Records; Electronic Signatures—Scope and Application guidance, FDA enforced “with discretion” those Part 11 records tied to validation, audit trails, legacy systems, copies, and retention. All predicate rule requirements and other sections pertaining to Part 11 such as controls for closed systems, and authority and device checks, had remained in tact and were deemed somewhat “more” enforceable by the agency. It now looks as though those areas that fall under Part 11 and are deemed enforceable will be  included in inspection reviews.

Smith pointed out during the briefing that Part 11 was originally established to apply to all FDA program areas to permit the widest use of electronic technology.  However, the new requirements led to many industry complaints, including comments that Part 11 would restrict use of technology, increase the cost of compliance to an extent not envisioned by FDA, and discourage innovation in technology, all while having no positive public health impact. This feedback led to the withdrawal in 2003 of the five draft guidance documents tied to Part 11 and to the issuance of the Scope and Application final guidance in August 2003.

At this time, it’s unclear what types of new enforcement actions may be taken by FDA during the planned inspectional activities, which are expected to start “soon” according to an FDA notice on the subject. Ideally, the information gained from the inspectional efforts will be used to further modify Part 11 in the future. The agency is expected to post more details on its website later today, July 8, 2010, and Pharmaceutical Technology will update this blog post as information comes in.

Updated: July 9, 2010 2:20 pm EST

Two days before the hearing, on June 21, FDA launched a database to spark rare-disease drug development, and earlier this week, the agency held a public hearing and webcast to solicit input and ideas regarding the development of medical products for rare diseases.

A bit of background—In 1983, the US adopted the Orphan Drug Act, which created financial incentives, including grants, to developers of drugs for rare disease. There are 6000 rare diseases, defined by the Act as diseases that affect fewer than 200,000 people in the United States. According to this definition, approximately 30 million Americans have a rare disease. Neglected diseases, on the other hand, affect impoverished or disenfranchised populations of the developing world. More than 1 billion people around the world are affected by at least one neglected disease such as TB, leprosy, or malaria.

Since the Orphan Drug Act was passed, 357 drugs and biological products have received orphan-designated market approval. The 2007 FDA Amendments Act gave FDA additional authority to award priority review vouchers to orphan drug applicants. And over the past few years, according to Goodman’s testimony, other regulatory bodies have adopted FDA’s orphan-drug regulatory approaches. Today, orphan-drug applicants are able to file one joint application to FDA and the European Medicines Agency for their new products.

And FDA’s efforts don’t stop there. In February of this year, the agency added a new Associate Director for Rare Diseases to its CDER office to complement the work of FDA’s already existing Office of Orphan Products Development (OOPD). This office is overseeing the new rare-disease database, mentioned above, which includes listings of already approved compounds and products that might help treat rare diseases. These compounds have already receivedorphan-status designation and are market-approved for treatment of other rare diseases.

This coming October, the agency plans to cosponsor the first annual Rare Disease Investigator Training Course in collaboration with NIH and the National Organization for Rare Disorders. FDA and NIH have also partnered to complete a study on the US national policy for rare disease research and related medical product regulation. A report is expected in September before the workshop.

Finally, as part of the 2010 Appropriations Act, FDA is establishing two internal committees to examine rare and neglected diseases. The committees will report to Congress in one year and issue guidance on these diseases, according to Goodman’s testimony.

Considering that 30 million Americans have a rare disease and countless more around the world are in the same situation, or worse, FDA seems to be taking positive steps toward medical research and innovation in this area.

The HHS report noted that 80% of approved marketing applications for drugs and biologics contained data from foreign clinical trials. More than half of clinical-trial subjects and sites were located outside the United States. Western Europe accounted for most foreign clinical-trial subjects and sites. Central and South America had the highest average number of subjects per site. Overall, FDA inspected clinical investigators at only 1.2% of all clinical-trial sites for applications approved in fiscal year 2008. It inspected 1.9% of domestic clinical-trial sites and 0.7% of foreign clinical-trial sites. The report said that challenges to conducting foreign inspections and data limitations inhibit FDA’s ability to monitor clinical trials, which included problems of having early-phase clinical trials being conducted outside the US without investigational new drug (IND) applications.

In its report, HHS recommends that FDA require standardized electronic clinical-trial data, monitor trends in foreign clinical trials not conducted by INDs, and to continue to explore ways to expand its oversight of foreign clinical trials. Such recommendations are reasonable, but they also raise larger policy questions that come into play with the increased globalization of the pharmaceutical industry. That is, given the nature of the products being made and the attendant regulation that is required, should a different model of business practices and regulation apply to pharmaceutical products compared with consumer and industrial products? Should another set of rules of apply?

There is no easy answer to that question as it requires a balance of free-market principles with public regulation. Drug products, unlike consumer and industrial products, require a higher level of regulatory oversight to ensure their safety and quality. Products developed or manufactured outside the US are neither implicitly better or worse than products developed or manufactured in the US. But given the limitations of financial resources and jurisdictional authority of US federal agencies outside the US, is it a prudent course to have clinical development or manufacturing of pharmaceutical products that are targeted for the US market, to be performed outside the US? Is this question an economic debate of free trade versus protectionism or a broader policy matter in ascertaining the relevance of domestic regulation in a global marketplace? Should regulation dictate business practice or business practice dictate regulation?

It seems now that we have a hybrid response. During the past several years, FDA has responded with the opening of offices in China, India, Central America, and South America as a way to increase its oversight of pharmaceutical development and manufacturing outside the US, which is a good move in the interest of public safety. But again, it raises another broader philosophical question: should federal resources be used to indirectly support offshoring functions outside the US? There is an ongoing policy debate as to how to increase the US position in science, technology, engineering, and mathematics (STEM) with initiatives supporting STEM activities in education and suggestions to foster competitiveness in innovation. But in the case of pharmaceutical products, is there a disconnect in federal policy, where on one hand we want to encourage STEM activities domestically, but on another hand are indirectly fostering STEM activities outside the US?

A lot to consider. Admittedly, it is a difficult balance of short-term, long-term, economic, and scientific goals, but perhaps one in which the sum of the parts rather than the individual parts should be considered.

“…We have a shared vision of personalized medicine and the scientific and regulatory structure needed to support its growth,” said Hamburg and Collins. “Together, we have been focusing on the best ways to develop new therapies and optimize prescribing by steering patients to the right drug at the right dose at the right time. We recognize that myriad obstacles must be overcome to achieve these goals.”

To that end, Hamburg and Collins said in their commentary that the NIH and FDA will invest in advancing translational and regulatory science, better define regulatory pathways for coordinated approval of codeveloped diagnostics and therapeutics, develop risk-based approaches in reviewing diagnostics to assess their validity and clinical value, and make information about those tests more readily available.

They cited data that showed that only about 10% of labels for FDA-approved drugs contain pharmacogenomic information, underscoring the deficiencies in information for advancing personalized medicine “There has been an explosion in the number of validated markers but relatively little independent analysis of the validity of the test used to identify them in biologic specimens,” they said.

To fill this information void, NIH, with advice from FDA, other Department of Health and Human Services agencies, and other stakeholders, is creating a voluntary genetic testing registry as a single public source of information on the more than 2000 genetic tests that are available through clinical laboratories. The registry will include information such as whether a test has been approved by FDA and data on genetic variants.

NIH and FDA also pointed to other efforts, such as a recent NIH-FDA collaboration on regulatory and translational science, announced in February 2010, which includes joint funding for regulatory sciences. They also pointed to NIH-supported research centers, the NIH Therapeutics for Rare and Neglected Diseases Program, the NIH Clinical and Translational Sciences Award Program, FDA’s efforts under its Critical Path Initiative to improve evaluation tools such as biomarkers and assays, and FDA’s Voluntary Genomic Data Submission Program (a forum under which companies can discuss genomic information with FDA separate from the product-review process) as ways in which policymakers are facilitating the advancement of personalized medicine.

Such collaboration is important, but the key question going forward is whether it will be enough to advance a promising but still unknown field. In their concluding comments, Collins and Hamburg likened the government’s efforts to building “a national highway system for personalized medicine.” Let’s hope that we are going down the right road.