It’s no surprise, then, that the prospect of a new treatment for people with medically refractory epilepsy would be greeted with great enthusiasm. As an adjunct to AEDs, the responsive neurostimulator system, or RNS, under development by Mountain View, Calif.-based NeuroPace, is designed to detect abnormal electrical brain activity and deliver electrical stimulation to regulate brain activity before a seizure develops. The RNS could become the first electrical stimulation device approved by the FDA in epilepsy since vagus nerve stimulation was green-lighted in 1997.

But the results of the Feb. 22 FDA adcom meeting evaluating the NeuroPace RNS raise troubling questions about regulatory decisions in epilepsy care. As reported in Medical Device Daily, the FDA briefing documents submitted for the Neurological Devices Panel of the Medical Devices Advisory Committee meeting indicated that a pre-specified statistical analysis plan of NeuroPace’s prospective, randomized, double-blind, sham-stimulation-controlled pivotal study called for the use of a generalized estimating equation (GEE) model and required that superiority be demonstrated based on a reduction in the frequency of total disabling seizures during the blinded evaluation periods (BEP).

However, neither the study protocol nor the statistical analysis plan “explicitly stated” which of two methods would be used to estimate standard error, producing what the FDA called “distinctly different p-values” for the primary efficacy endpoint. The agency and sponsor concurred that an alternative model was needed, agreeing to use the Poisson regression model. Although the FDA recommended that monthly seizure counts be used, NeuroPace chose the daily model, with the expectation that many seizure-free days would occur in the treatment group and there would not be a clinically meaningful way to group data.

That premise seemed reasonable, since seizure activity can vary from day to day. However, the observed variability in the study exceeded the expected variability in daily seizure counts following a Poisson distribution. NeuroPace then made ad hoc modifications, reverting to monthly seizure counts along with the use of a negative binomial distribution to analyze the returns. According to the FDA, NeuroPace had to add an adjustment for clinical co-variates along with the other modifications to achieve statistical significance for the primary efficacy endpoint.

With these modifications, the pivotal study showed a statistically significant 37.9 percent reduction in seizure frequency in the treatment group compared to a 17.3 percent reduction in the control group during the three-month BEP. Long-term results showed median seizure frequency reductions of 44 percent and 53 percent, respectively, at one and two years post-implant.

Statistical Qualms Bubble Up

In its briefing docs, the FDA argued that some alternative post-hoc GEE models did not achieve statistical significance, none of the pre-specified secondary endpoints achieved statistical significance and no observed data analyses achieved statistical significance. Moreover, response to the device varied by the number of seizures seen at baseline, and findings from the treatment arm may have benefited from two patients on the sham arm with a different response pattern than others in the trial.

Despite these statistical qualms, 12 of 13 adcom members agreed there was “reasonable assurance” that the NeuroPace RNS system is effective for patients meeting the criteria for the proposed indication: adults with partial onset seizures from no more than two foci who are refractory to two or more AEDs. One panelist – a statistician – abstained. The panel voted unanimously that the system is safe, and 11 members concurred that the RNS benefits outweighed the risks, with two abstentions.

I understand the genuine desire to offer hope to epilepsy patients with uncontrolled seizures. My husband developed epilepsy at age 15 a year after a serious head injury, and he is not seizure-free after 40 years on various combinations of AEDs and a left temporal lobectomy.

But should the FDA permit statistical manipulation in epilepsy that would likely raise eyebrows in other indications? At BioWorld Today, I write about the development of drug therapies designed to treat individuals with cancer, hemophilia, multiple sclerosis, Alzheimer’s disease and many other poorly treated diseases. I understand the desire to bring new treatment options to patients with agonizing conditions. I really do.

I also see countless drugs rejected by the FDA when efficacy is not assured, even when safety is unquestioned. And, compared to medical management, the implantation of a deep brain stimulator is not inherently safe. Up to one in five patients could be expected to have a serious adverse event related to implantation and related medical procedures, according to the FDA’s own risk/benefit analysis of the RNS. Shouldn’t the burden of proof for such a device be even higher than that of a drug?

Above All, Demonstrate Efficacy

With respect to epilepsy, quality of life implications often are cited as a compelling reason for drug or device approval, with patients seemingly willing to accept a higher risk threshold in return for the prospect of improved seizure control. In my view, that premise should be predicated on demonstrated efficacy. In the real world, physicians are quick to suggest new treatments, and patients often are desperate. Few have the benefit of advocates with neurological expertise who can provide an unvarnished appraisal of a newly approved therapy. I wake up every morning with someone who has run the epilepsy treadmill, trying therapies touted for their efficacy that proved futile, and worse.

The NeuroPace RNS may, indeed, help some epilepsy patients, which would be a terrific outcome for the developer and the epilepsy community, alike. However, that claim seems far from proven, which should give the FDA pause in approving its usage without additional study. Individuals with epilepsy deserve treatments that offer true hope, not outcomes derived on the basis of statistical tinkering.

Editor’s note: To read more about Marie and Chuck Powers’ experiences with epilepsy and an unusual condition that surfaced after a temporal lobectomy ‑ prosopagnosia ‑ visit her personal blog, About Face.

Although Omontys is not a biosimilar, the unexpected postmarketing reports of serious hypersensitivity reactions linked to the erythropoiesis-stimulating agent (ESA) served as a reminder of the variability of biologics, their sensitivity to minute manufacturing changes and the difficulty of catching a rare safety signal in the full-blown biologic development process – let alone an abbreviated biosimilar path. It also evoked memories of a similar incident a number of years ago in which an increase in pure red-cell aplasia linked to Eprex, another ESA, was attributed to a change in rubber stoppers in the drug vials.

Both incidents should give the FDA pause about its approach to biosimilar approval. Because of the variability of biologics, biotechs and patient advocacy groups have urged the agency to require safety data for biosimilars. While the agency maintains that patient safety is its primary concern with any drug, it insists that since the reference biologic has demonstrated safety and efficacy, all a biosimilar must do is demonstrate similarity to the reference drug. The goal is not to require redundant clinical trials that would be expensive, unnecessary and unethical, according to the agency.

In light of the Omontys and Eprex recalls, the FDA, at the least, should require that marketed biologics and biosimilars have packaging identical to that used in clinical trials and be manufactured at the same facility, under the same processes, as that of the trial drug.

Neither the FDA nor most biotechs want the biosimilar path to fail. But they understand the complexities of making biologics, and they know that one disaster now could doom or indefinitely delay the new approval path.

Unfortunately, people not so familiar with the differences between biologics and small molecule drugs, which are far less complex than biologics, too often equate biosimilars with generics. Since generics are unquestionably accepted as equivalent to small molecule reference drugs, they can be substituted automatically for the brand drug at the pharmacy. Thus, they account for about 80 percent of the prescription drugs dispensed in the U.S. Many generics advocates envision the same success for biosimilars – if the FDA would just start approving them.

Yet even generics have had equivalency problems. Last year, the FDA found that a generic bupropion, approved based on extrapolated data, wasn’t comparable to GlaxoSmithKline plc’s antidepressant Wellbutrin XL 300 mg (bupropion). That incident raised questions about the use of extrapolated data for both generics and biosimilars.

Other generic equivalency issues were raised last year in a Government Accountability Office (GAO) report, which questioned the substitution of generics for some indications. The GAO cited a study that found patients on selective serotonin reuptake inhibitors (SSRIs) who switched to cheaper substitutes mid-treatment averaged $881 more in total health care costs than those who stayed on the more expensive brand SSRI due to a higher rate of hospitalizations and emergency room visits.

Another study referenced in the GAO report looked at the annual health care costs for kidney transplant patients treated with narrow therapeutic index immunosuppressants. Researchers found that patients on the generic needed higher doses of the drug or an additional immunosuppressant to maintain their new kidneys as compared with those on the brand drug.

Such issues could be magnified for biosimilars, given all that scientists don’t know yet about biologics. That, coupled with the public’s tendency to consider biosimilars as just more generics, should set off other alarms for makers of reference biologics. Some courts – most recently, the Alabama Supreme Court – have held brand drugmakers liable for adverse events caused by generics, which share the same labeling as the brand drug. Recognizing all that can go wrong in the manufacture of a biologic, makers of a reference biologic don’t want to be on the legal hook for a biosimilar that a judge or jury mistakenly equates with a generic.

Editor’s note: Need more information about biosimilars? Check out The Biosimilars Game: A Scorecard for Opportunities, Threats and Critical Strategies, a new report by BioWorld Data. Call for details (800) 477-6307.

More specifically, it involves Bob Miller, 54, who is on a hunger strike. Miller stopped eating about the same time my obituary showed up, in protest of the FDA’s refusal to approve Ampligen (rintatolimod), the Toll like receptor 3 modulator for CFS that was given an unfavorable review by the FDA’s advisory panel in December, which I covered.

I talked with Miller by phone Tuesday. He lives in Reno, Nevada, because that’s the headquarters of the Ampligen trials. Miller sounded weak but determined. He choked a few times, when the subjects of his wife and twin sons, age 12, came up.

An Email Doppelganger

OK, let me get the obituary thing out of the way. Like most people with a handful of things going on at once – and like a lot of people who are simply self-absorbed – I’ve put my name in a Google alert, because I want to know if somebody online mentions me or one of my projects.

You’ve probably guessed the next part.

Delivered via Google alert, the obituary had everything spelled right (no “U” in my last name, like a lot of people tend to add. Not related to that guy!), but it got the age wrong (58, nope. One more year to go, why rush things?).

Of course, I’ve gotten Google-alert obituaries of “myself” before. I always read them, if only to find out what this other guy with my name was like, and at what age he died. Sometimes, I try to imagine myself into deceased person’s life. This latest one had been a coal miner in Kentucky for 15 years.

By Another Name, the ‘Gom-Boo’

Nobody knows what causes CFS, so I asked Miller, who’s been sick for 30 years, how his disease first manifested. He said he developed flu-like systems that would not go away. His co-workers passed it off as what they called the “gom-boo,” the name for any of a number of infections they picked up in the moist, black-dusty, oxygen-deprived environment where they worked.

Miller was a coal miner in those days, he said.

I registered the coincidence mentally, and went on with the interview. Heard how Miller, after the coal-mine job ended because of his absenteeism, could not hold down employment. How he became bedridden. How 17 years passed before he saw a doctor who diagnosed his CFS.

‘The FDA Has the Power’

Gone are the days when CFS was considered a “fake” disease, masking laziness or a person’s failure to take vitamins. I knew the horrid roster of CFS symptoms. Here’s how they are expressed by Wikipedia and others: post-exertional malaise; unrefreshing sleep; widespread muscle and joint pain; sore throat; headaches of a type not previously experienced; cognitive difficulties; chronic, often severe, mental and physical exhaustion; muscle weakness; increased sensitivity to light, sounds and smells; orthostatic intolerance; digestive disturbances; depression; and cardiac and respiratory problems.

At the FDA advisory panel meeting, a parade of people testified about CFS, and the dire need for a drug like Ampligen that seems to work. Except that there aren’t any drugs like Ampligen.

“The FDA has the power to be able to do this,” Miller said. “The company is willing to sit down with the FDA, sit down with anybody, and trying to figure out how to move this forward, without the drug company going away,” since it lacks the money for much more clinical work, which the agency wants.

Against the Odds

As the interview came to close, after I thanked Miller for talking, he asked, “What was your name, again?”

I told him. There was a two-second pause. Quietly, Miller said, “I knew a Randy Osborne when I worked in the coal mine.”

The same one, it turned out. Miller had not seen him in years.

And so I ended up breaking the news of my namesake’s death to his previous co-worker and, likely, friend. (It’s not easy to work in a coal mine, I would imagine, without becoming friends.) I broke the news to a man who may die himself, as a result of his hunger strike. He’s already been given saline for kidney problems caused by the fast, but has vowed not to take food until Ampligen moves forward, for the sake of himself and as many as a million other patients in the U.S.

I told my girlfriend about the interview, and the identical names, and the coal-mine connection. “What are the odds?” she asked. Over the past few days, I’ve been thinking about other odds. Of Ampligen finding its way to patients, somehow. Of Miller making his point, before time runs out.

The article “Biotech Firms, Billions at Risk, Lobby States to Limit Generics” slams biotechs for encouraging states to adopt legislation limiting the automatic substitution of biosimilars, which the Times repeatedly called “generics.” As BioWorld Today reported, most of the bills being considered by states would require physician notification of what was substituted, enhanced recordkeeping and an opportunity for doctors (and, in some states, patients) to decline a substitute. They also would restrict automatic substitution to interchangeable biologics.

The recommendations are not out of line. When prescribing a small-molecule drug, doctors can specify no generics. Why should it be any different with biosimilars? The FDA, after all, has made it clear that biosimilars are NOT generics. Although highly similar to a reference biologic, biosimilars are not always interchangeable.

For one thing, biosimilars may have minor differences from the reference biologic, so they may not be approved for all the indications of the originator drug. They shouldn’t be used off-label for those unapproved indications, Sherman said. Her worst nightmare would be for a formulary, seeing a big price difference, to treat biosimilars as it would a generic and switch everyone from the reference biologic to the biosimilar, regardless of the indication.

To be deemed interchangeable, and thus eligible for automatic substitution, under the unique two-sided approach laid out by Congress, a follow-on biologic (FOB) must demonstrate biosimilarity and then interchangeability, which means it produces the same clinical results as the reference drug in any given patient. While the FDA has yet to draft guidance on interchangeability, it has said switching trials will be necessary. The questions of how many, how extensive and how long must still be answered.

As part of its challenge in educating the public, the FDA will need to make it crystal clear which biosimilars are interchangeable and which indications have been approved for a specific biosimilar, Sherman said. The agency’s challenge is heightened by groups wanting to rush the regulatory process, so they can realize what they expect to be big savings. (In reality, biosimilars are likely to offer a 20 percent to 30 percent savings rather than the 50 percent to 90 percent discount seen with generics.)

Among regulators, the newness of the biosimilar field has led to a cautious, go-slow approach in the U.S. and other markets. Recognizing the potential to increase access to biologics, regulators want to avoid a disaster that could cancel the game.

Thus, Japan requires doctors to submit biweekly reports for every patient receiving a biosimilar for the first six months following approval. And in India, biosimilar sponsors must submit periodic safety update reports every six months for the first two years and then once a year for the following two years.

While the FDA can’t require physicians to submit reports, it is concerned about safety. Biosimilar data packets won’t reveal very rare signals, Sherman noted, so pharmacovigilance will be needed. “Patient safety is our paramount concern,” she said. When an adverse event occurs, the agency needs to know which product caused the problem.

That’s where the states come in. Since they regulate pharmacy licensing within their borders, a state can require pharmacies to notify physicians when a substitution has been made and keep records of the FOB that was dispensed. It’s all about safety.

The Times suggested that Amgen Inc. and Genentech Inc. are pushing for the state legislation – not because of safety concerns – but to protect their brand biologics from competition. What the article ignored is that Amgen, at least, is developing a biosimilar pipeline along with its partner Actavis Inc. And the Thousand Oaks, Calif., biotech has been successfully competing with numerous biosimilars in Europe and other countries for several years.

Editor’s note: Need more information about biosimilars? Check out The Biosimilars Game: A Scorecard for Opportunities, Threats and Critical Strategies, a new report by BioWorld Data. Call for details (800) 477-6307.

Even though I’ve been covering biosimilars for BioWorld for a few years now, I was surprised at the impact these follow-on biologics (FOBs) are having throughout the world, given that the European Union (EU) is continuing its two-year approval slump and no biosimilar candidates have stepped up to bat yet in Canada or the U.S.

Some of my surprise undoubtedly stems from a lifetime of watching the home teams play. With that caveat in mind, I’ll share a few of the stats that had me doing a bit of a double-take:

• The number of EU and U.S. clinical trials for biosimilars being conducted by foreign companies that have never played in highly regulated markets before;
• That Malaysia adopted a biosimilar regulatory path, based on that of the EU, a year before the World Health Organization released its guidelines and nearly two years before Congress cleared the way for a U.S. path. But countries like China, Israel and Russia have yet to draft a biosimilar rulebook;
• That Australia, Brazil, Japan, Malaysia and South Korea have all approved at least one official biosimilar, while the FDA is still waiting for its first application. In all fairness, most of these countries had their regulatory path in place at least a year before the FDA had the authority to lay out its ground rules. However, Brazil, which has approved two biosimilars since 2010, got into the game the same year as the FDA;
• The emergence of the MENA region (the Middle East and North Africa) as a growing market for biosimilars and other drugs;
• That Cuba is a major dealmaker and biosimilar partner in several emerging markets;
• The diversity of the players, especially since some of the most ambitious ones on the global field are not the major league biopharma teams. For instance, Geneva-based BioXpress Therapeutics SA is working on a pipeline of 18 biosimilars, including 16 monoclonal antibodies (MAbs), and Sapporo, Japan’s Gene Techno Science Co. Ltd. has nine biosimilars in development, including six MAbs, plus a biosimilar filgrastim awaiting Japanese approval;
• The position biosimilars and other FOBs play in helping many emerging markets break into the biologics field. That’s especially true in South Korea, which is looking to become a world leader in biosimilar development. Thanks to a package of financial and institutional aids for biologic testing and production facilities it provided a few years ago, the South Korean government expects that, by 2015, the country’s new biosimilar sector will have created 120,000 jobs, contributed $2 billion to the gross domestic product and generated $1 billion in exports. By 2020, South Korea predicts biosimilars made in that country will account for more than one-fifth of the global market.

Another statistic that caught my attention is the sheer number of biosimilars being developed worldwide. As of December, the FDA had received 50 requests for initial biosimilar discussion meetings, referencing a total of 12 biologics. But globally, more than 276 biosimilars are in the pipeline, referencing 19 MAbs, as well as other biologics such as epoetin, etanercept, filgrastim, insulin and interferon. (That’s not counting all the companies that haven’t fully disclosed their pipelines.)

In other words, while biosimilars may still be in the sandlot in the U.S., they’re already headed toward a world series elsewhere.

The year also saw lawmakers get into the bipartisan spirit, passing both FDASIA and the JOBS Act. As we head into 2013, it will be interesting to see how those regulatory additions – such as the GAIN legislation aimed at giving antibiotic developers a leg up and the provision allowing for small firms to consider going public as an emerging growth company – may affect the industry.

But first, let’s take a look at some of the notable stories and trends in biopharma over the past 12 months.

Obesity Drugs Score Approvals. Finally!

After striking out at the FDA over the past two years, two of the big three obesity drugs won approval in 2012. Vivus Inc.’s Qsymia (phentermine/topiramate) and Arena Pharmaceuticals Inc.’s Belviq (lorcaserin) hit the market. It’s too early to judge market uptake – though analysts have been monitoring Qsymia’s launch on a weekly basis – but the approvals are at the very least a sign that the FDA is considering obesity a serious health concern and those first two nods could pave the way for more obesity drug approvals in the future.

While Qsymia and Belviq topped the most exciting approvals in 2012, according to BioWorld’s informal poll, the year was full of other FDA nods. Irritable bowel syndrome drug Linzess came in second in the BioWorld poll, followed by cystic fibrosis drug Kalydeco, prostate cancer treatment Xtandi and recently approved medullary thyroid cancer drug Cometriq. But plenty of other drugs easily could have made the list – Stribald, formerly known as Btripla, for HIV; Bydureon’s hard-won approval in Type II diabetes; Erivedge, the first hedgehog inhibitor to reach market; Aubagio for multiple sclerosis; cancer drug Kyprolis; Lucentis’ approval as the first new drug for diabetic macular edema in more than 50 years; and Ariad Pharmaceuticals Inc.’s Iclusig (which, at three months ahead of its PDUFA date, came in just under the wire to make the 2012 list.)

Glybera Celebrates Victory at Long Last

But no approval in 2012 proved a bigger triumph than Glybera, the first gene therapy to (finally) gain approval. After some back and forth at the European Medicines Agency (EMA) and its Committee for Medicinal Products for Human Use (CHMP), the CHMP awarded a positive recommendation in July, followed by the EMA’s official stamp of approval in November. It wasn’t easy; the drawn-out process drove developer Amsterdam Molecular Therapeutics into bankruptcy, forcing it to divest Glybera into newly formed private company uniQure BV. But the approval marks not only a big win for the gene therapy space, it also signals a change in the at least European regulators assess clinical benefit in rare diseases, given that application for Glybera included data from a mere 27 patients. The advent of gene therapy, a one-off treatment vs. the typical daily or weekly administration, in the marketplace also stands to change reimbursement policies in order to accommodate those types of long-term treatment options.

HCV’s ‘Nuc’lear Fallout

At last year’s JP Morgan conference, Bristol-Myers Squibb Co.’s execs couldn’t help gloating over their $2.5 billion acquisition of Inhibitex Inc. After all, it was hardly the whopping $11 billion Gilead Sciences Inc. paid for fellow hepatitis C virus (HCV) drug developer Pharmasset Inc., a price many analysts at the time considered much too high, particularly considering the growing competition to get an all-oral HCV regimen to market.

But a big mushroom cloud appeared over the space during the summer, and when the dust settled, BMS was pretty much out of the picture, having discontinued its nucleoside HCV drug due to toxicity issues. The news also affected other “nuc” programs, most notably Idenix Pharmaceuticals Inc.’s IDX19368, which was placed on clinical hold. Meanwhile, positive data just keep coming for Gilead, which is entering 2013 easily poised as one the lead contenders for an all-oral regimen.

New Battle Lines Drawn in Amyloid-beta/Tau Debate

The HCV space was advancing like gangbusters, but other areas were not so fortunate in 2012. With all the Phase III readouts, drugs targeting Alzheimer’s disease could have been the year’s top success story; Instead, detractors of the amyloid-beta theory gained ammunition in the ongoing amyloid-beta-vs.-tau battle. First, there was the Phase III implosion of bapineuzumab – the headline in BioWorld Today said it all: “J&J-Pfizer’s Alzheimer’s Drug Crashes, Burns in Phase III.” That news was promptly followed by the Phase III miss of Eli Lilly and Co.’s solanezumab, though Lilly isn’t ready to admit defeat yet. Those failures, however, came as no surprise to those who fall on the tau tangle side of the Alzheimer’s argument. TauRx Therapeutics Inc.’s Claude Wischik even told BioWorld in November that it never made “any sense to us that people think going after amyloid” would make a dent in the disease. TauRx is putting the tau theory to the test, getting ready to launch a Phase III program testing tau aggregation inhibitor LMTX, though we likely won’t see any data before 2015.

In the meantime, the case for amyloid-beta seems to be taking its cues from Monty Python – it’s not dead yet. A November talk at the National Institutes of Health had Harvard University’s Jie Shen discussing early stage research concluding that amyloid-beta definitely has “something to do with the pathogenesis of Alzheimer’s disease.” So it looks like the debate is destined to go on to see whether amyloid-beta, tau or a newer Alzheimer’s target might become the Holy Grail in biopharma’s ongoing efforts to treat the devastating neurodegenerative disease.

‘It’s the [Patent] Cliffs of Insanity!’

While politicians spent the last few months of the year sounding off about the so-called fiscal cliff, big pharma finally found itself standing at the edge of its own sheer drop in 2012, staring down into the abyss of lost profits. After years of predictions from industry experts, pharma firms finally started to feel the initial impact as once-blockbuster products began smashing upon the rocks. Pfizer Inc., for instance, saw a 19 percent cut in first-quarter profits stemming from the patent expiration for top-selling cholesterol drug Lipitor and in September saw its credit rating downgraded by Fitch. And it wasn’t alone. AstraZeneca plc’s CEO David Brennan stepped down in April amid shareholder pressure as the London-based big pharma reported staggering drops in sales thanks to generic competition to products such as Nexium (esomeprazole) and Merrem (meropenem). And, on the eve of reporting its third-quarter earnings, Eli Lilly and Co. saw its own ratings lowered by Fitch, which called Lilly’s looming patent cliff “the steepest in the industry,” citing potential losses of antidepressant Cymbalta (duloxetine) and Type I diabetes drug Humalog (lispro) coming next year.

The good news is that, as the threats to its bottom line materialized, big pharma seemed much more willing to try new strategies. The past year saw the industry employ some new and interesting approaches to ramping up drug development – the launch of Transcelerate BioPharma Inc. is a good example, along with the rise in academic partnerships such as GSK’s December deal with MD Anderson. Perhaps if big pharmas can find more ways to foster innovation, they won’t end up in the Pit of Despair.

And, in the ‘Don’t Count Your Chickens’ Column . . .

If you’re going to present stellar clinical data, you’d better make sure those results are accurate. Vertex Pharmaceuticals Inc. learned that lesson in May when it revealed that its previously reported Phase II results for the cystic fibrosis combination of Kalydeco plus VX-809 were a little off the mark: Instead of 46 percent of patients showing improved lung function, the actual results were 35 percent. That 11 percent disparity sent shares of Vertex sinking 10 percent that day.

But that turned out to be nothing compared to Peregrine Pharmaceuticals Inc.’s gaffe a few months later. In what has to be the Biggest Oops for 2012, execs of the Tustin, Calif.-based firm found themselves choking down a few mouthfuls of crow after they had to return to investors with the admission that the survival data from the much-lauded Phase IIb lung cancer trial of bavituximab might not have been so impressive after all. The company cited “major discrepancies” in the findings, which it attributed to an independent third party contracted to code and distribute investigational drug product. Peregrine launched an investigation to determine the extent of the data disparity and, while that investigation is still ongoing, the company’s shares – and perhaps, credibility – have yet to fully recover. To add insult to injury, Peregrine shortly after received a default notice for the $15 million in initial funding under a $30 million term loan, due to the data discrepancies, though the company managed to scrape together $14.3 million in an at-market agreement to replace that funding.

The lesson? Make sure you’ve got your ducks in a row to avoid a data discrepancy debacle like Peregrine’s.

Let’s hope everyone heeds that advice in 2013.

From all of us at BioWorld, thanks for reading, and have a happy new year!

While the OPDP’s move is a welcome step in shutting down Burzynski’s clinical trial pyramid scheme, in which, according to some patient fundraising blogs, trial participants pay more than $100,000 to become guinea pigs for antineoplaston therapy, the letter provides little clarity regarding what is or is not a promotional claim.

The letter specifies, “This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.”

However, some of the so-called violations strongly resemble claims made in countless biotech and pharma press releases posted on company websites.

For example, “ANP was well tolerated with easy manageable side effects of fatigue, skin rash, and electrolyte abnormalities and no chronic toxicities . . . These results compared favorably to radiation therapy and chemotherapy (Mandell, et al. 1999, 7 percent overall survival at 2 years and 0 percent at 5 years), but should be confirmed in phase III trials scheduled to begin in 2009.”

On the face of it, that statement seems identical to hundreds of statements made every day by other companies, so what distinguishes Burzynski’s regulation-violating promotion from permitted “exchange of scientific information?”

Clarity is on Hold

Crystal clarity on that question may be a long time coming. The biopharma community has been clamoring for the FDA’s guidance on a related question – how to use social media – for nearly two years, and the agency has answered with silence – a silence set to continue for another two-year period, under the new FDA Safety and Innovation Act.

That silence has led to a “gotcha mentality” that uses enforcement, rather than guidance, to communicate policy.

For companies that want to avoid running into trouble with their public communications, warning letters such as the Untitled Letter issued to the Burzynski Clinic are some of the only clues available as to what the regulations allow and do not allow.

Stephen King, a public affairs specialist for the FDA’s Center for Drug Evaluation and Research, offered a statement that provided a few more hints on the Burzynski case.

“The FDA takes seriously its role in assuring Americans the drugs they use are safe and effective and manufactured according to current good manufacturing practices (cGMP). The agency also seeks to ensure patients who are participating in clinical trials and expanded access programs are appropriately protected,” King said. “To date, no randomized, controlled trials showing the effectiveness of antineoplastons have been published in peer-reviewed scientific journals nor have all of the trials needed to approve antineoplastons as a treatment for cancer been conducted.”

So far, so good. But again the FDA’s communication falls short of total clarity as to why certain claims violate regulations and others don’t. In the Burzynski case, the clinic’s lack of evidence to back up its claims, and track record of plundering its patients’ retirement funds may contribute to the OPDP’s actions, but nothing in the OPDP letter actually cites false claims or misunderstanding by patients. “The totality of these claims suggest that Antineoplastons, investigational new drugs, are safe and/or effective for the treatment of various types of brain tumors indicated above, when they have not been approved for these uses,” the letter states, suggesting that the only and entire violation by the Burzynski clinic is that it said the words “safe and effective” before the drugs had been approved ‑ words which are ubiquitous in drug company statements regarding clinical trials of unapproved drugs.

“The promotion of investigational new drugs is prohibited by law and the agency is concerned BRI’s promotional claims will mislead patients about the safety and efficacy of unapproved antineoplastons,” said King, providing few hints as to how other companies should modify their language regarding safety and efficacy of their own unapproved drugs.

OPDP instructed the Burzynski Clinic to immediately cease dissemination of “violative promotional materials” for antineoplastons and to submit a written response by Nov. 1.

A company spokesman for the Burzynski Clinic, Azad Rastegar, told BioWorld, “Yes, we have received a letter from the FDA. While we don’t think we have done anything wrong, we have complied with their requests.”

A hunter walks into a bar and says, “Did you hear the one about the FDA?”

“You mean the time it shot itself in the foot?” the bartender responds.

“The left foot or the right foot?” another hunter asks, wiping the beer froth from his mouth.

“What difference does that make?” the first hunter asks.

“I want to know if it’s the one I’ve heard before. Or if this is a new one.”

The first rule of thumb for hunters is to know what they’re doing. Otherwise, they might shoot themselves in the foot – or worse. The second is to get a valid hunting license. The third is to make sure they don’t target animals that aren’t in season.

The FDA broke those rules when it set out to track down a few scientists who it claimed had gone rogue by sharing concerns about device approvals with members of Congress and the White House. The agency tried to get a license. “No way,” it was told by the Office of Inspector General. “That dog just won’t hunt.”

The FDA, being the FDA, decided it didn’t need a license. It loaded its guns, set its snares and hired a document-hunting outfitter to help it bag its trophies. The agency reportedly gave the guide a list of the targeted species and provided scents to sniff out along the document trail. Those smells led to the media and a few hound dog congressmen and their staffs – species that should be on every federal agency’s “do not hunt” list.

The hunters at the FDA justified their poaching by saying the scientists were fair game because they were leaking information, some of which could be proprietary. Those leaks could damage the agency, its mission and its reputation, they reasoned.

Intent on catching the big game and defending its unlicensed hunt, the FDA forgot to set the safety on its weapons. As a result, the outfitter tripped and misfired, publicly posting a database with the contents of all the document tracking, including the proprietary stuff and the scents used to mark the trail. The shot hit the FDA square in the mouth and left a gaping, oozing wound in its reputation.

Now, the FDA’s the prey. And these days, it’s looking a lot like a limping deer caught in the intensely hot headlights of Congress and the media.

Since we made a weekend beeline from BIO 2012 to return to all corners of the globe, I offer some new words to kick off the bio-summer season of 2012:

ATTQK nations: Argentina, Turkey, Thailand, Qatar and South Korea, which are in attack mode to build their biopharma markets, following in the BRIC footsteps. (See BRIC to CRIB)

BRIC to CRIB: Finally, rather than retiring the emerging markets acronym BRIC, I’m renaming it CRIB nations to better reflect their biotech maturity status. BRIC is more appropriately reserved to denote the developed biopharma foundation nations. (Found-nations?) Hey, there’s a bonus buzzword!

FDA as a verb: To stall, meander, show indecision: “I get the feeling my parents are trying to FDA me on my request to move back home.”

HiBi: High-tech social media platforms in biotech applications: (“It’s going to be a quick “Hello/goodbye” for social media as a practicable HiBi platform in drug development if official guidance isn’t delivered soon.”

Irregulatory: Dysfunction at the regulatory level: “Irregulatory activity occurs with regularity with the ongoing implementation of a biosimilars pathway.”

M&A-rriage: Wholly(-owned) matrimony of two disparate species for the love of money: “Do you, large molecule, take this pharma . . .

Pharmeleon: Small-molecule company that is metamorphosing into a biotech entity (as in specialty pharma, biopharma, health care company). See any big pharma for examples.

Pop a capital: Invest in an R&D company. “The angel investor has decided to pop a capital in your assets.”

R&DAR (RADAR): Research and development, approval, reimbursement: “You need bio-r&dar to succeed in the new millennium drug development market.”

Reg-leg: A regulatory and legislative situation: “The drugmaker got into a reg-leg mess, running afoul of the EMA and sued by the brand maker.”

SoMe: My acronym for social media, which concurrently denotes that self-absorbed, so-into-me aspect that thumbtalkers can exude.

Unnovation: Inability to perform in the clinic: “Big pharma’s patent cliff worries were exacerbated by its unnovation tendencies.”

Be among the first to use these, but use them with haste, for they have mandatory expiration dates!

It started off innocently enough, as I passed by the New York pavilion – “Whadda you lookin’ at? Take a friggin’ ink pen and move on! I’m workin’ here! You’re blocking the aisle – I got customers.”

On to the California booth . . . “Trade your business card for a free sample? It’s the legal medi-juana right here. All you have to do is say the magic word: glaucoma! And chase it with our patented CIRM stem cell martini!”

The China pavilion was easy to spot, as it keeps getting bigger every day – by about an 8 percent growth rate! Its emergence was pushing the Japan pavilion just enough to put their backs against the East wall and the Europe exhibition area into the general vicinity of the toilet. And if the conference exhibition hall doesn’t close precisely on time at noon Thursday, China’s spread could even start shanghaiing the U.S. state pavilions. All this respect without a single company in top 50 biopharma list?

The reimbursement lobbyists, drunk with power, had just taken over Regulatory Row and evicted the FDA from its booth, when I overheard this FDA conversation:

“Let’s set up over there – in the vacant obesity market space. I don’t believe they will be coming this year, since we burst their bottom line bubble.

“Dr. Labyrinthine, would you get together with Dr. N. Terminable and Dr. Persnickety to draw up a guideline to facilitate the pathway to the new location? We may have to petition BIO to extend the conference another few weeks while we meticulously plot the most efficacious course of action.”

People were looking for the Amgen booth, but there was just an empty space on the exhibition floor where it was the day before. No, it wasn’t the bio-rapture – Novartis had just pulled off the most bullish takeover in history, acquiring Amgen in the middle of the convention, and having the Teamsters move Amgen’s booth inside theirs.

Then, exactly 200 years to the June 18 declaration that made the War of 1812 official – all Bio-Hell broke loose as Revolutionary War II was ignited . . . Novartis’ bold move had lit the biopharma fuse. The Big Pharma Immortals had had enough of playing nice and finally turned on one another in a donnybrook the likes that hadn’t been seen in Boston since the 2004 Red Sox-Yankees American League Championship Series.

They flooded BIO’s registration booth with emergency registrations for all their lawyers, black ops fixers, etc., assembling the strike teams to battle outright for supremacy in ruling the new millennium biopharma world. BIO, of course, set a new attendance record that would easily offset the damages to the convention center.

The regulatory overlords tried to stop the madness, but it was only then they finally realized “because I said so” and “I’ll think about it” were no longer effective weapons.

Well, this started the Great Biopharma War of 2012. By the time the large molecule dust had settled, there were only 13 colonies, errr, booths left. Into the broken concrete floor, they staked RXBIG battle flags that bore the rugged symbol monickers of JNJ, PFE, ABT, AZN, LLY, GSK, BMS, RHHBY,  NVS, SNY, MRK, TEVA and TKPHF. Rebels such as Bayer, Novo Nordisk and Boehringer Ingelheim went underground until they could breach the $15 billion-plus large-cap war chest list).

The rebels tried to take the Underground Biopartnering Railroad to seek asylum behind the BRIC Wall, but were met at its perimeter by government forces, armed with compulsory licenses, in litigation formation, under a sign that read “Bring us your tired (personnel), your (cash-)poor (R&D) – but be prepared to leave your IP at the border!”

Meanwhile, the Immortals began negotiations to explore the benefits of merging into one international corporate behemoth, named BioPharMonster Inc., that would hold the health of all humanity hostage.

The Pharma Un-Civil War was a reality, as the seductive forces of biotechnology had done what the competition, regulation and consumer frustration had been unable to do for more than a century: unhinge pharma’s cool.

The floor space (as well as the market space) had been pharma-fied, but there was a small skirmish that was still garnering attention, as several generics makers were mounting a nominal attack on the big pharmas from the rear, with the cry, “Give me biosimilars or give me death!”

In the end, Pfizer, patently fighting off a $10 billion bad mood, still emerged as the revenue victor despite the offensive charge financed by Novartis’ cache of 15 approvals in 2011.

Roche’s booth was afire, but Roche just unshackled Genentech in the clinic by commissioning its biotech enforcer to run amok: “We’ll need to replenish our arsenal and war chest, so, “Genentech, SMASH!”

Wake up, Michael – it was only an allegory! Still, I dread sleeping tonight, lest I suffer a relapse in the forecasted heat wave that starts tomorrow!

No litigation allowed – it’s only a dream, right?