Michelle Hoffman, editorial director of Pharmaceutical Technology.

Michelle Hoffman

I have no doubt of Congress's good intentions. They want to protect us from predatory lenders, from the overwrought claims of advertisers, from harmful ingredients in our foods and drugs, but also increasingly, from ourselves. I'm thinking specifically of the bill passed by the Senate on June 11, 2009, that mandates cigarette manufacturers to disclose the ingredients in tobacco products and gives the US Food and Drug Adminstration the authority to oversee these products. While I am in no way advocating the use of tobacco, I also wonder what, ultimately, such a bill will accomplish.   

I could understand the need for some kind of regulation if cigarette manufacturers were still allowed to make claims that cigarette smoking were healthful—all the while knowing that it was not. But those days are long past. I refuse to believe that anyone over age 18—the age at which one can legally purchase tobacco products—is unaware of the health risks associated with tobacco use. If not, I'd be happy to tell them: The use of tobacco significantly increases your risk for heart and lung disease. And although I think full disclosure is important—tell smokers about all of the ingredients in their cigarettes—I'd be very surprised if such disclosures will dramatically decrease the number of people who smoke.  Short of making tobacco use illegal, there is little the government can do to prevent its use. Those who choose to smoke do so in spite of the known risks. There will always be people willing to take those risks. 

And that brings me to my next point. At the same time our representatives are protecting us from our own bad behavior, they're protecting us from paying for it, too. In discussions of how to subsidize a national healthcare policy, there appears to be no notion that people who knowingly engage in risky health behaviors—and are therefore more likely to require expensive healthcare—should bear a greater share of the health insurance cost. Instead, we get bizarre proposals, such as the one made by US Rep. Charles Rangel (D-NY), chairman of the House Ways and Means Committee, that would prevent drug companies from claiming  a tax deduction on their advertising expenses. Rangel estimates this act would generate some $37 billion in savings, which could be applied to healthcare, according to a July 16 report on Bloomberg.com. 

Companies—in all industries—pay no taxes on money spent for advertising. Advertising costs are considered to be business expenses and are subtracted from revenues before taxes are calculated. Only profits are taxed, notes Clark Rector, a spokesperson for the American Advertising Federation in Washington, DC.  

The Rangel proposal would in fact tax the money drug manufacturers spend on advertising, but would not impose similar taxes on companies operating in any other industry. That tax may be discriminatory to drugmakers and may violate the First Amendment (a position on which both the conservative DC-based Washington Legal Foundation and the more liberal American Civil Liberties Union agree, notes Rector). But the bill proposal has me wondering why Rangel would single out drug advertising? Is the notion that the revamped healthcare policy would enable more Americans to buy drugs and would boost drugmakers' profits—a circumstance for which drugmakers alone ought to pay?  

 paying for healthcare are those who, by their risky behavior, may require more and more expensive use of the healthcare system—people like tobacco users. Put together, I see a policy that coddles risk-takers while requiring the government (not the individual) to restrict risky behavior, and at the same time, creating a moral hazard by protecting risk-takers from the expenses generated by their bad choices. 

A good society should alert people of potential dangers. Should that society also absolve risk-takers of any responsibility or requirement to bear the economic consequences of their choice to disregard those dangers?  

Articles

Is it good policy to pay for bad behavior?

The Good Society

A while ago, I got into a verbal skirmish with an investment banker. His bank invited and then disinvited me to a reception they were holding in conjunction with a conference I was attending. When I commented on the gaucheness of the disinvitation, the banker made an appeal to our shared difficulty in managing lists. But I was having none of it. The Bernie Madoff scandal had just hit the news, and we were starting to learn the scale of our national economic crisis, precipitated in part by something called "credit default swaps," an invention of investment bankers. So, I replied that as an editor, my mistakes appeared in print, in public, and were acknowledged and corrected in the same way. And as a holier-than-thou cherry on my supercilious cake, I added that it would be nice if all businesses—say hedge funds and investment banks, for example—operated with that level of transparency.  

But what happens when publications take advantage of that presumed transparency to dupe readers and boost advertising revenues? That's what seems to have happened at Elsevier. According to late April reports in 

, the publisher issued in the early 2000s the 

Australasian Journal of Bone and Joint Medicine

, an ersatz medical journal that purported to publish reports about the successful clinical use of particular drugs—all of which were manufactured by Merck (Whitehouse Station, NJ). According to allegations, the journal was actually publishing reports written by Merck. In short, Elsevier was publishing advertisements and passing them off as objective, peer-reviewed articles. 

article, acknowledging the practice and noting that the company has "affirmed our business practices as they relate to what defines a journal and the proper use of disclosure language with our employees to ensure this does not happen again."

Interestingly, not all in the pharmaceutical community feels there was any wrongdoing. One response to a post in the blog, "ADventures in Ethics and Science," suggested that Elsevier's only transgression was that it did not make it clear enough that the journal was sponsored by Merck. Another comment writer says: 

I know all the medical blogs are going after Merck, but I think a more reasoned discussion is necessary. Merck has to advertise, and it has to be creative to get a message across. I think that there is an urban myth that physicians should learn about new drugs or indications or whatever by some pure, academic, non-monetary format. It doesn't happen. Physicians are seeing hundreds of patients, trying to pay their bills in a managed care environment, and there are thousands of medical products companies trying to tell them they need this or that. Sometimes, you just have to do something innovative to get the message across.

I agree that physicians are busy with patients and paperwork, but that's why they rely on medical journals—and their expert peer-reviewers—to provide an objective, uninterested assessment of the clinical uses of medications. To publish ersatz journal articles is not a clever marketing ploy; it is a deliberate attempt to make physicians use a drug that they think has been fully and objectively determined to be the best treatment for a particular medical condition, when in fact it may not have been. 

The journal's practice came to light during a civil suit against Merck by a patient who claimed to have suffered a heart attack while on Merck's drug Vioxx (rofecoxib), 

 reported. Was the patient's health compromised by Elsevier's deception? That's unknowable. But it might have been. And other patients may have received less than optimal care because their physicians were misled by articles they read in the fake journal. 

For those of us involved in publishing, this incident should remind us that we are not impartial observers and chroniclers of the drug-making process, but very much a part of it. By subjecting the articles we publish to rigorous peer-review, we are trying to promote the best practices in the discovery, development, and manufacture of drugs and, thus, bear some responsibility for the public's safety.  

Peer-review is a very important quality control. Journals that merely pretend to conduct peer-review pervert the enterprise as much as accountants who, by producing phony financial statements, enable money managers to perpetrate Ponzi schemes masquerading as hedge funds.  

Misleading the public about their investments-be it money or medicine-is unacceptable.

Truth and Transparency

It's become an embarrassment of riches. New, robust cell lines now churn out therapeutic monoclonal antibodies (mAbs) in quantities so high, biopharmaceutical manufacturers are having a hard time purifying the drugs with state-of-the-art tools and techniques. The bottleneck, many claim, arises because, simply put: downstream processing technologies have not kept pace with improvements in upstream production technologies. 

(ILLUSTRATION BY M. MCEVOY. IMAGES: YAMADA TARO, JOEL SARTORE, IMAGE SOURCE/GETTY IMAGES)			

"Since the introduction of monoclonal antibodies, upstream productivity has increased about 1000-fold," says Uwe Gottschalk, group vice-president for purification technologies at Sartorius Stedim Biotech in Gottingen, Germany. "Downstream technologies have improved only about 10-fold when we compare the productivity of critical steps such as chromatography. There is a gap, and it's widening. If we keep the existing strategies and technologies, then there is little chance of closing the gap," says Gottschalk, who edited the recently published book, Process Scale Purification of Antibodies.   

In the current paradigm, therapeutic mAbs are produced by mammalian cells. These cells are maintained in large bioreactors—vats that can hold tens of thousands of liters. The cells are suspended in a culture medium, essentially a nutritive broth, and genetically engineered to produce therapeutic mAbs. The cells generally secrete the antibody products into the medium, along with the molecular waste of cellular metabolism. Many cells—sometimes as many as 50%—die in the bioreactor during the course of production, and these dead cells often split, or lyse open, and spill their contents into the medium. These contents include bits of the fatty cell membrane, cellular proteins, virus particles that may have infected the cell or were suspended in the medium, and the nucleic acids DNA and RNA, which, in this context, are also considered waste products. Purification, therefore, has two goals.  

The first goal is to retain product, and this is accomplished in the "capture" phase of purification. The second goal is to discard contaminants, achieved during the "polishing" phase. Before either of these phases is initiated, however, the contents of the bioreactor are "clarified," usually by centrifugation, followed by filtration. The idea is to remove particles, including the remaining and now unwanted intact cells. Centrifugation separates out components by weight, so the intact cells fall to the bottom of the centrifuge tube, leaving the lighter components—including the antibody product—suspended in the fluid on top of the centrifuge tube. The solid matter is discarded, and the supernatant is then filtered to remove any remaining particulate matter. Capture and polishing then follow. Of these two phases, capture has received the most the attention in terms of technical innovation and cost reduction.  

The current wisdom posits that high-yield bioreactors are producing so much material that biopharmaceutical manufacturers are having a hard time purifying it all. But not all manufacturers are experiencing the bottleneck, or at least not as severely as others. Manufacturers producing very large quantities of blockbuster drugs, at quantities that can exceed one metric ton per year, in fixed facilities may feel the problem more acutely than others. For them, the problem boils down to this: A manufacturer may have two options to deal with the bottleneck. Either it acquires additional purification equipment, or purifies the product  in batches. But producers using dedicated, fixed facilities may simply not have the space to accommodate additional equipment. For them, the best option might be to purify the product in batches. Three to five batches may be necessary to purify all of the protein product now produced by today's high-yield cell-culture systems. 

Figure 1: The major steps in monoclonal antibody purification. (FIGURE IS COURTESY OF THE AUTHOR, ADAPTED FROM SOURCE 4)			

Gunter Jagschies, senior director of strategic customer relations at GE Healthcare BioSciences in Uppsala, Sweden, is less swayed by stories of bottlenecks. "You hear these stories, and at the same time, they seem to come down to existing installations built with too small downstream processing equipment to accommodate very much higher productivity upstream. This is not so much a problem of the technology but more of the ability to predict what would happen with cell culture," he says. Jagschies points to case studies that indicate that 10 metric tons of product—roughly 10 times today's highest production levels—can be made with existing technologies. The problem, as he sees it, has to do with the rate at which high-yield supernatants can be run through a column.  

"You have to process monoclonal antibodies quickly," says Jagschies. "There are problems maintaining the antibodies' stability in liquid." The protein product is vulnerable to enzymatic degradation by proteases, with the result that the composition of a batch at the end of an 18-hour holding period may differ from the starting composition. Theoretically, product yields could become so high as to require several days to purify the contents of just one bioreactor. "But no one is there yet. Current [purification] technologies can handle a batch in 12 to 18 hours," Jagschies says. 

Ironically, the purification problem may be more acute for contract manufacturers and niche manufacturers, who are producing the smallest product quantities. Current blockbusters—Genentech's anticancer drug Rituxan (rituximab), for example, or Abbott's arthritis drug Humira (adalimumab)—enjoy billion-dollar sales because they address diseases with large patient populations. But the day of the blockbuster may be over—even for the relatively new mAb drugs.  

In coming years, niche drugs for relatively rare conditions, or targeted therapeutics that are effective for subpopulations of patients suffering from fairly common conditions such as arthritis, will require much smaller production batches to serve the reduced markets. But smaller batches may mean very expensive purification equipment that is not used to its maximal capacity or for its total life span, which raises the the cost per use of such equipment. Even producers of blockbusters are looking for lower-cost options as pressure increases on them to lower drug prices, and as they stare down the specter of competition from follow-on biologics. In fact, cost considerations have been as much of a driver of innovation as the high product yields. 

Of the steps in mAb purification, the capture step receives the most attention, possibly because it's so important in trapping the product, but also possibly because of the expense associated with it. Standard protocol relies heavily on the affinity of human antibodies for a compound called Protein A. 

In the early years of antibody purification, manufacturers relied on "natural" Protein A; that is, the protein as it was isolated from the cell walls of the bacterium 

. These days, most commercially available Protein A has been genetically engineered and molecularly cloned. As used in a chromatography column, Protein A is part of a resin. Resins from different vendors differ markedly to respond to the distinctive needs of their customers, but they all share some common features. In general, this resin consists of some kind of porous bead inside of which is a gelatinous matrix to which the Protein A is chemically affixed. The antibody product is poured through the chromatography column, diffuses inside the beads and through the gelatinous matrix where it finds and binds to Protein A. Almost all of the contaminants, most of which do not have an affinity for Protein A or the resin components, exit the column. In subsequent steps, buffers are run through the column to release the antibody product from Protein A, and the now somewhat purified product is collected and shunted into subsequent "polishing" steps. 

Protein A is so efficient at attracting and binding the antibody product that, says Henrik Ihre, product manager for Protein A and program manager for mAb products at GE Healthcare BioSciences, "you go from 1% to above 98% purity in one chromatographic step." And while some companies have tried to engineer more antibody-binding sites onto Protein A, nature it seems, has produced the best overall variant of the molecule.  

"Nature has engineered Protein A to be pretty efficient and robust," marvels Laura Whitehouse Pew, vice-president of market development at Massachusetts-based Repligen. Repligen produces the recombinant Protein A that other manufacturers immobilize in their resins. 

So if they can't improve upon nature with regard to the affinity of Protein A for antibodies, many resin manufacturers have tried to improve the durability of the resin to increase its lifetime and, thus, lower its cost per use. Ian Sellick, director of marketing at Pall Life Sciences in New York, says that a chromatography column can cost as much as $5 million to pack and is good for up to approximately 200 purification cycles. To increase durability, commercial vendors such as GE have developed Protein A variants that can hold up for more purification cycles. Resins frequently degrade during the harsh cleaning protocol in between cycles. Cleaning makes use of very caustic chemicals such as sodium hydroxide—lye—which decouples Protein A from the matrix. The Protein A in GE's MabSelectSure resins has been genetically engineered to resist such cleansing-induced decoupling. As a result, the resins may be usable for more than 300 cycles, thus reducing the cost of use per cycle.  

Other companies are offering somewhat more rigid matrixes, with the hope of  reducing the compressibility of the matrix and increasing flow-through rates. For example, DSM (Heerlen, The Netherlands) developed EBA resins. These Protein-A-based resins, developed in partnership with the Danish firm Upfront, use tungsten carbide particles. According to DSM literature, the added weight allows fluids to flow through the column at increased rates, with the aim of accelerating processing times. Pall, too, offers a zirconium-based resin.  

Pall, in an attempt to reduce resin costs, is offering a product that uses a synthetic substitute to Protein A. According to Sellick, Pall's "gel-in-a-shell" resin is reconfigured to offer the same level of separation at a rate that's faster and which holds up better during sodium-hydroxide cleaning than traditional Protein A-based resins. To cap it all off, Pall's Hypercel product line is a quarter the price of some of the traditional Protein A-based resins. Sellick adds that Pall's new resin can withstand between 100 and 200 purification cycles.  

Pall is not the only manufacturer exploring the use of synthetic capture chemistries, or ligands. BAC (Naarden, The Netherlands), for example, produces affinity ligands which are derived from Llama antibodies. One of their products is marketed 

 GE as IgSelect, a complementary product to Protein A-based resins. 

Manufacturers stress that different resins offer biopharmaceutical manufacturers a range of options so they can match their chromatography solution to their particular equipment needs and to the exigencies of their particular monoclonal product. But as much as manufacturers may differ on their choice of resins, they all seem to have converged on the use of disposables. Every provider of chromatography resin offers disposable options. In many cases, this means that biopharmaceutical manufacturers have the choice of purchasing prepacked, disposable columns.  

Vendors note that the disposable option eliminates the enormous upfront capital expenditure related to the purchase of stainless-steel chromatography equipment. Disposables also eliminate the time and expense related to packing the column initially. Most of these disposable columns can be used through several purification cycles—somewhere in the neighborhood of 10 to 20 cycles. The disposable option may be especially good for smaller batches of niche products, early-stage process development, contract manufacturers who have to produce many different products in the same facility, or for any manufacturer who—for whatever reason—does not need to run hundreds of purification cycles.  

Millipore (Billerica, MA) has gone the furthest with a disposable gambit. At the Interphex 2009 show in March, the company unveiled its suite of Mobius products. The Mobius line (marketed as Mobius Flex Ready Solutions) is made up of two components. The first is a metal cart, approximately the size and shape of your average New York City hotdog vendor's stand. Into these can be inserted the entire disposable purification train, with all of the bags and hoses already attached. (Disposable trains for other aspects of biopharmaceutical processing are also available to work in concert with the Mobius carts.)  

The truly intrepid biopharmaceutical manufacturers may move away from column-chromatographic solutions entirely. In an attempt to reduce the footprint of the purification apparatus as well as costs, some vendors are developing membrane-based purification devices. Lisa Crossley, president and CEO of the Canadian firm Natrix Separations, described in January at the Biomanufacturing Summit in San Diego, CA, organized by WTG, a novel capture membrane the company has developed. Unlike other membrane-based capture technologies that put the affinity chemistry on the membrane's surface only, Natrix's membrane offers a more dimensional structure. The apparatus is composed of a support membrane that houses a porous hydrogel to which is affixed either Protein-A or synthetic ligands, depending on the customer's needs. It is available in both multicycle and single-use, disposable formats.  

The dimensionality of the Natrix product is intended to increase the binding surface area, diffusion rates, and flow rates, all while reducing the equipment's footprint, and significantly reducing operating costs, Crossley says. In addition, the membranes can be used for simultaneous clarification and capture, eliminating the need for separate harvest and primary purification steps. "There's a big cost savings in combining two steps in one," Crossley says.  

The Natrix membranes offer such an impressive combination of attributes that one person attending Crossley's San Diego presentation exclaimed that Natrix had delivered the "Holy Grail" of mAb purification. Others in the industry are not quite as moved. The pharmaceutical industry is slow to adopt any technology that might engender regulatory scrutiny, and so may take a "wait-and-see" stance on this and other technological developments. Furthermore, skeptics point out that the Natrix technology's robustness has not yet been proved for full commercial-scale use. To date, the technology has been used for commercial-scale manufacturing of nutraceuticals and veterinary vaccines in North America and Europe, but is still in the preclinical stage for biopharmaceutical applications. 

Pressure toward greater efficiency and lower cost may, surprisingly, drive the industry back to the future as they explore alternative technologies, notes Sartorius's Gottschalk. "Because of the expense, many other industries don't use chromatography at all," he says. He points to technologies used to purify components from blood plasma. Typically, these manufacturers precipitate the desired products out of the plasma, a technique that Gottschalk offers might be adapted to mAb purification in the years ahead.  

Jagschies, on the other hand, is dubious that chromatography will disappear. "Right now, the world leader in plasma-derived biopharmaceuticals, CSL from Australia, has put chromatography in place pretty much everywhere," he says. "This will not change back, not in my time at work for sure." Several players, notes Pall's Sellick, are also exploring fractionation and crystallization.   

Gottschalk doesn't stop there, though. He is looking at ways to improve purification beyond the capture step. "We need to shift our focus from product capture, where yields are increasing, to contaminant removal," he says. He suggests that it may be possible to remove more impurities—nucleic acids, for example—in the early clarification steps, thereby reducing the burden on the capture materials and possibly reducing the number of polishing steps required as well.  

Millipore has also been considering ways to beef up impurity removal. For example, the company is specifically honing in on ways to improve the efficiency and lower costs of some initial clarification steps. Following centrifugation and before capture, the contents of a bioreactor go through depth-filtration.  

"People argue that the current template [for this stage] is not broken, so why fix it?" asks Fred Mann, program manager for Downstream Process Solutions at Millipore. "But you can refine it, improve productivity, and make the process more robust," he says. As a result, Millipore has restructured its depth filters to incorporate a medium specifically designed for high-titer feedstock filtration, which, he says, will allow customers to run more liters of feedstock through the filters. In addition, the filters are self-contained and installed into hardware with no product contact rather than in stainless-steel housings that require hoists and cranes for assembly. The filtration system, which Millipore markets under the name MilliStak? Pod, reduces the need for cleaning and cleaning validation of the filtration assembly between runs, is safer for operators, and reduces labor costs, says Mann. 

Other polishing steps include rounds—typically two—of ion-exchange chromatography. The material is put through a cation exchange column to remove positively-charged host cell proteins and high-molecular-weight impurities such as protein aggregates. Following that is an anion-exchange step, where negatively charged contaminants, including retroviruses, parvoviruses, host-cell protein, and residual DNA, are removed. In the final steps, the product is run through filters and irradiation to remove any remaining virus particles. After that, the now-pure mAb product is put into the formulation buffer. 

Gottschalk is convinced that the ion-exchange steps present the greatest opportunity for improving the downstream paradigm. He notes that when run in "flow-through," it becomes possible to replace a 100-L column with a (disposable) 1-L anion-exchange membrane, thus reducing the requirement for space, among other things. As for cost? "In the worst case, the costs are equivalent for membranes. Since so much cost is in fixed assets, virtually all processes benefit significantly from disposable strategies in polishing," he says. 

Overall, Gottschalk predicts that cost and efficiency considerations will force a whole new process to emerge for mAb purification. "The paradigm will shift," he says. "And whatever it will be, I predict we'll see it within the next 5 to 10 years." 

 1. F. Detmers, P. Hermans, and M. Ten Hafft, "Affinity Chromatography Based upon Unique Single Chain Antibodies," 

 2. G. Jagschies, "Where Is Biopharmaceutical Manufacturing Heading?," 

 3. L. Giovannoni, M. Ventani, and U. Gottschalk, "Antibody Purification Using Membrane Adsorbers," 

 4. U. Gottschalk, Ed., Process Scale Purification of Antibodies (John Wiley & Sons, 2009).  

 5.  U. Gottschalk, "Downstream Processing of Monoclonal Antibodies: From High Dilution to High Purity," 

 6.  M. Rios, "Eluting Possibilities with Mixed-Mode Chromatography," 

Manufacturers of therapeutic monoclonal antibodies consider new paradigms in purification technologies.

Easing the Bottleneck

Imagine that you're standing in a train station, and two trains are waiting to leave on adjacent tracks That's how I picture the Obama administration's policies that will affect the pharma industry going forward. One is the cost-containment track. The second is the science-innovation track, powered by the economic stimulus package. These tracks seem to be running parallel to each other with little hope of crossing down the line. 

The cost-containment track has been built by legislative initiatives and key healthcare post nominations. First, there was the Mar. 2 nomination of Kathleen Sebelius for secretary of the Department of Health and Human Services, a move that President Obama described as advancing "Healthcare reform that reduces costs while expanding coverage," according to a White House press release. 

Then there was the Mar. 14 nomination of Margaret Hamburg for Food and Drug Administration commissioner, along with the expectation that Joshua Sharfstein will be chosen as deputy director. Sharfstein was a former staffer for Rep. Henry Waxman (D-CA), the chairman of the House Energy and Commerce Committee who recently introduced a bill to establish  a regulatory pathway for follow-on biologics. This move is a potentially significant cost-containment initiative in its own right and has received strong support from Obama. 

Finally, the economic stimulus package passed in February includes $1.1 billion to "compare drugs, medical devices, surgery and other ways of treating specific conditions." Many see this as another measure for the government to contain drug costs. "Supporters of the research hope it will eventually save money by discouraging the use of costly, ineffective treatments," notes a Feb. 11 

The second, science-innovation track is tied to the stimulus package, which contained some $10 billion for the National Institutes of Health (NIH). With a prestimulus budget of more than $30 billion, NIH is now the largest supporter of basic biomedical research in the United States.  

And when he signed the executive order reversing the ban on federal funding for embryonic stem-cell research, President Obama said, "Medical miracles do not happen simply by accident. They result from painstaking and costly research ... and from a government willing to support that work" (a full 

). The president has noted the importance of scientific innovation in driving America's future economy on several occasions—a position I agree with. 

The problem is while we're spending money to drive novel discoveries at the basic science level—discoveries that will form the foundation for novel medicines of the future—we're also limiting the money available to take those discoveries out of the laboratory and put them into the clinic. That money traditionally comes from profits earned by drug companies and is often plowed back into the commercial development of promising drug candidates.   

 found that, on average, it costs $1.2 billion to bring a promising biotechnology drug into market. Their research also indicates that approximately half of that money—about $615 million—is spent on preclinical development. Let's assume that most of that funding is covered by the innovation budget, largely through NIH support. Where is the additional $600 million or so supposed to come from? How is the drug to move through development and into the marketplace? 

In years past, this money has come from a combination of private and public equity markets, along with partnerships from large pharmaceutical companies. In this economic environment, support from the equity markets is simply not forthcoming. So, what about the pharmaceutical companies? They, too, have reduced their appetite for risk, using cash to purchase better-established pipelines through large-scale mergers (think Pfizer's acquisition of Wyeth, and Merck's acquisition of Schering-Plough) rather than in-license less developed—but more innovative—drugs in progress. Limiting what these companies can charge for the drugs that do make it to market will only decrease their taste for investing in early-stage drugs. 

As I said, each track on its own is justifiable and reasonable. But stimulating innovation on one track and containing costs on another can only serve to widen the distance between the two important initiatives. A truly coherent health and science policy has to find ways to bring these two tracks closer for the health and well-being of the economy, the pharmaceutical industry, and, oh, yes, people.  

Obama's cost-containment and science-innovation initiatives need to overlap.

Parallel Tracks

Scientists studying epilepsy have traditionally focused on the comings and goings of ions through molecular channels in nerve cells, and many current antiseizure therapies seek to modulate that dynamic. However, some people don't respond to channel-based therapies, causing scientists to look further for other molecular activities to target therapeutically in epilepsy management. A recent report suggests they may have found one. A paper published in 

points to a possible inflammatory interaction between white blood cells and blood-vessel walls that appears to damage the barrier that prevents unwanted substances from flowing into or out of the brain, the so-called blood–brain barrier. The researchers found an increase in "sticky" adhesion molecules on both  white blood cells and on the cells lining the blood vessels in the brain of mice in whom epileptic-like seizures had been induced. This interaction, they proposed, might be therapeutically blocked by monoclonal antibodies, thus reducing the severity and incidence of seizures.  

P.F. Pabene et al., "A Role for Leukocyte–Endothelial Adhesion Mechanisms in Epilepsy," 

Scientists studying epilepsy have traditionally focused on the comings and goings of ions through molecular channels in nerve cells, and many current antiseizure therapies seek to modulate that dynamic.

Coming Down the Pike: Treating Epilepsy

Amid the rush of reports about new appointees to the Obama administration, one appointment stands out for the lack of discussion around it: FDA commissioner. A blasé attitude toward the appointment of a commissioner to lead the US Food and Drug Administration seems to have become something of a tradition among modern administrations. For most of its recent history, FDA has been led by temporary acting directors who lack the mandate to overhaul the agency. I am disappointed that there has not been any public acknowledgment of high-level discussions around this appointment and hope that the next appointment will not once again be an afterthought. 

Many will argue that in light of the current financial crisis, the new administration has the more immediate problem of putting in place a competent team of financial experts. Of course, that's a priority. However, the appointment of FDA commissioner might loom a little larger in that equation if one considers that the products regulated by FDA account for approximately 25% of the US economy. So there is more at stake in the way FDA is managed than the mere health of the American people and the safety of the country's food and drugs; part of the US economy's health is also dependent on this appointment. 

The selection of a new commissioner also will address a growing philosophical issue at FDA: What, exactly, is the agency supposed to be? Some observers are asking whether food and drugs ought to be regulated by separate agencies (see Jill Wechsler's January column). And with the growth of the pharmaceutical industry overseas, FDA is not just for domestic use anymore. Already, the agency has set up outposts in Asia to inspect facilities producing drugs for US domestic consumption. There is also discussion about whether FDA should monitor the supply chain of ingredients used in overseas manufacture of drugs destined for the US. Finaly, there remains the question of whether FDA exists to speed drugs through the approval process or to take a longer time and avoid all possible risks once a drug enters the market (of course, FDA's regulations have expanded to include postmarket monitoring.)  

The argument that favors rapid approval allows potentially life-extending and life-saving medicines to enter the market early, where they might improve the lives of thousands who have no other treatment option. A slower review, on the other hand, might delay the release of important drugs, but also might identify potential side effects in drugs before they can do harm to the general population.  

Mandates under the Prescription Drug User Fee Act (PDUFA) favor speedy review, but some well-publicized drug failures put pressure on FDA to move more slowly before releasing drugs to market. It is interesting that in a recent performance report to Congress, FDA noted at least 21 instances since 2007 in which the agency took longer to approve a drug than is specified by the Act. Some reviews ran as much as seven months beyond the 6-to-10 month review period prescribed by PDUFA. It may be that the agency is merely understaffed and therefore needed more time to review applications (there were slightly more applications for new molecular entities and biopharmaceutical products than there have been in years past). Or, the delays may signal that FDA is giving greater scrutiny to drugs than can be accomplished within PDUFA timelines. If the latter reason pertains, it should serve as a rebuttal to critics who maintain that FDA is in the pocket of drug companies that provide PDUFA fees.  

None of these issues will go away by ignoring them—not if history is any guide. In fact, it seems that the role of FDA continues to expand beyond premarket approval of drugs and beyond US borders. As these new roles pile on, the question of what the agency will be to whom only becomes more acute. So, when the new commissioner is chosen, we can only hope it is done purposefully and with a full understanding of all of the implications that appointment carries.  

A. Maurer, "BIO President Sees Biotech Industry Challenges for NewAdministration," 

http://www.techjournalsouth.com/news/article.html?item_id=6747

A. Goldhammer, "Selecting the next FDA Commissioner," 

 A. von Eschenbach, "Performance Report to the President and the Congress for the Prescription Drug User Fee Act," 

http://www.fda.gov/ope/pdufa/report2007/PDUFAFY2007perf.html

FDA's role should not be overlooked as it has been in years past.