Michelle Hoffman, editorial director of Pharmaceutical Technology.

Michelle Hoffman

Now that the Obama administration is about to take office, you can feel the release of all that pent-up energy and frustration that has been building among researchers and drug developers working with human embryonic stem cells. For nearly 15 years (federal funding restrictions have been in place since 1994, during the Clinton administration, and became even more restrictive during President Bush's tenure), these scientists have said that the single most important factor in advancing stem-cell research—and possibly even therapies—would be  "a new administration." 

Indeed, President-elect  Obama  has stated publicly that his administration would relax regulations governing federal spending on embryonic stem-cell research. For example, in a statement received by the group Science Debate 2008 in August from the Obama campaign, and quoted by 

) then Senator Obama said, "I strongly support expanding research on stem cells. I believe that the restrictions that President Bush has placed on funding of human embryonic stem cell research have handcuffed our scientists and hindered our ability to compete with other nations. As president, I will lift the current administration's ban on federal funding of research on embryonic stem cell lines created after Aug. 9, 2001 through executive order, and I will ensure that all research on stem cells is conducted ethically and with rigorous oversight." 

An unscientific survey of press releases, product announcements, and exhibits suggests to me that drug companies, equipment vendors, and outsourcing providers are getting ready to scale up their stem-cell research and manufacturing capabilities. In fact, I will share with you my hunch that the growth area in pharma discovery over the next year or two will be in the area of stem-cell-related therapies (and associated equipment, technologies, and services). Another piece of evidence that this may be the case has more sinister undertones: the rise in stem-cell-related scams. 

In soap operas, any time a promising young ingénue comes into town, you can be sure that an evil twin is sure to follow. So, too, I'm afraid, with a promising new drug or therapy. Think back to the days when the class antidepressants known as the selective serotonin reuptake inhibitors (SSRI), such as Prozac, came onto the market. It didn't take long for "alternative" SSRI-type products to follow. And I don't think I have to tell anyone with an email account, how many alternative erectile dysfunction remedies are available "without a prescription." I'm guessing my Spam filter has thousands in it right now—1110, to be exact (OK, maybe some of those are alerting me to the 60 million Euros I won in the European lottery). The point is: You know that a phenomenon may be in the offing when the snake-oil salesmen show up. 

A study conducted by Darren Lau and colleagues at the University of Alberta in Edmonton, Canada, and published in 

 (DOI 10.1016/j.stem.2008.11.001; Vol. 3, Dec. 4, 2008, pp. 591-594), examined direct-to-consumer (DTC) websites advertising stem-cell based therapies. They concluded, "The direct-to-consumer portrayal of stem-cell medicine is optimistic and unsupported by published evidence." The websites, the authors said, overrepresented the benefits and underrepresented the risks of therapies for, sadly, conditions such as Parkinson's and Alzheimers that have not been amenable to other forms of treatment. Sadder still, at an average cost of $21,500, these therapies exploit patients' pocketbooks as well as their hopes. The authors caution patients to be wary of claims made by DTC stem-cell clinics advertising on the Internet. They also call for more research to either substantiate clinics' claims or to "develop stem cell therapies that actually work."  

Now that we're entering a New Year, with a new administration that has a new attitude toward stem cells, US-based scientists can get back to the business of finding just such therapies. In the meantime, 

Speaking of new beginnings in the New Year, I'd like to call your attention to "Insider Solutions," a new quarterly column debuting in this issue. In it, editorial board member and pharmaceutical consultant Susan J. Schniepp offers practical insights for dealing with common compendial and regulatory issues. I'd also like to thank all of our columnists, authors, reviewers, and board members for their continued efforts on our behalf. And to you, the readers, I wish the very best for 2009. 

Articles

The incoming administration has renewed hope for stem cells, but less adequate copycats may follow.

A New Start for New Cells

I was in Asia last week, learning what I could about the evolving pharmaceutical industry there. In one country, the industry is growing with a keen eye toward the export market. In this country, standards, practices, machinery, raw materials, and packaging materials are all GMP-compliant and strive to meet the most stringent international quality standards. 

The other country couldn't be more different. There, equipment manufacturers are happy if their products are good enough. The government in this country issues new guidances at roughly five-year intervals. They are still developing their regulations and are aware of international quality standards, but feel no compunction (as far as I could tell) to conform to them. 

One country is building on inventions and lessons learned by more established pharmaceutical practitioners. The other country is developing its industry from the ground up, almost as though no other country has developed these systems and practices before.  

The curious thing is that both of these countries reside in the same geographic space: China. On one hand, there's a cadre of pharmaceutical companies eager and able to produce high-quality  goods to sell to Europe and North America. These companies are aware of quality standards, but to meet them, must purchase their manufacturing equipment and supplies externally—from vendors in the West whose goods are GMP-compliant. 

As far as I could tell, Chinese manufactured equipment and supplies for use in the domestic Chinese market do not meet international quality standards. It is quite common for larger Chinese pharmaceutical companies to maintain two types of manufacturing plants: one with GMP-compliant equipment, supplies, and ingredients for export, and a second with Chinese produced, non-GMP-compliant materials for the domestic market. 

The language barrier made it difficult to be precise about what people were telling me, and of course, I had only the briefest exposure to the Chinese industry, but I thought I could discern several reasons for the existing situation. For one thing, Chinese consumers are not yet demanding higher quality goods. In addition, the cost structure frustrates efforts toward improving the quality of goods for the domestic market. As one manufacturer explained, to make a profit, it has to keep down its cost of goods—so low in fact that it can't afford GMP-compliant  equipment and supplies. In conrast, because they can make greater profits in the developed nations, Chinese manufacturers can afford to purchase high-quality equipment and raw materials. 

Until the Chinese government mandates quality from all domestic producers, those who want to produce higher quality drugs operate at a disadvantage vis à vis  their lower-cost, lower-quality competitors. If I understood correctly, it would be economic suicide for Chinese companies to produce GMP-compliant drugs for domestic use. It seems that the lack of government mandates for high-quality drugs actually discourages companies that want to produce better quality products. 

Countries with well-developed pharmaceutical industries have done the work and research to determine what those standards ought to be. By not adopting agreed upon international standards, the Chinese government makes it more difficult for their manufacturers to compete globally. What does it say about the government's regard for the safety of its own people that it adopts lower standards for its domestic market than for the export market?  

Several people who have experience working within the Chinese market suggested that the Chinese have a centuries-long history of maintaining a fierce independence from outside influences. I'm sure many of you are familiar with the story, likely apocryphal, about the Chinese mariners who discovered the New World before Columbus and Erikson. Supposedly, the sailors landed in the New World, looked around, decided there wasn't much to interest them, and went home. Perhaps the Chinese simply feel the same about the Western pharmaceutical industry. 

China's quality approach to domestic versus exported products seems to be a lose-lose situation.

A Tale of Two Pharmaceutical Industries

It's been a few days since the Dow fell below 10,000 points, and as I write this, the Index is threatening to dip below 8000. Even though the economic turmoil has its origins in the financial and banking sectors, there may just be an object lesson in it all for the pharmaceutical industry. 

This situation, we are told, started with something called "subprime." As I understand it, subprime loans are those given to people who are not ideal borrowers based on their poor credit history (i.e., defaulting on past loans). Why all of a sudden were they given these loans? It appears that Congress, in an attempt to make homeownership possible for more people, allowed lending institutions to relax standards so that previously unqualified borrowers could qualify.  

In some cases, unethical lenders compounded the risk by deceiving financially naïve buyers into taking on more debt than they could pay back. These risky subprime loans were packaged and sold to supposedly sophisticated investment banks, who intended to sell the loans to someone else—the public—in the form of securities (which could now be more aptly named "insecurities"). But suddenly that wasn't possible. 

Declines in the housing market made the newly purchased houses less valuable than the dollar amount of the loans themselves. So the loan-based securities were suddenly very unattractive, and investment banks were left holding the subprime bag.  

The problem is that these banks borrowed money themselves to buy loans. When the mortgage-backed securities wouldn't sell, the investment banks had to default on their loans. Some of those loans were insured, so insurance agencies such as AIG were also financially imperiled by having to pay the banks for the defaulted loans. (Fortunately, the government bailed out AIG, whose executives promptly spent almost a half-a-million dollars on spa treatments, thus demonstrating the kind of fiscal responsibility that made it seem like a good idea to insure high-risk loans in the first place. It seems they were happy to take the lucrative premiums, believing it was highly unlikely that they'd ever have to pay anything out. But I digress.)  

I wonder whether the investment banks knew they were buying low-quality loans? At the core of this crisis lies a low-quality product—the subprime mortgages—sold and resold to unsuspecting buyers. The consequences for the companies involved in the production, sale, and resale of this shoddy merchandise are bankruptcy and ruin. The consequences for the executives of those companies, however, seem to be anything but. I'm not the only one to note in horror that CEOs and other top managers of companies driven to ruin have been awarded, or should I say rewarded with, enormously generous severance packages.  

There's an adage in business that you get the behavior you reward. So what does it say about the value of quality when executives who allowed their companies to produce, sell, or buy (for resale) the very lowest quality goods available get paid for it? Nowhere, it seems, are there incentives to produce quality goods or disincentives for moving shoddy goods. But shouldn't firms—and more specifically—executives at firms be held responsible for the quality of the goods they produce and/or sell? Now that we've seen the results, might we think differently about executive accountability? 

's editorial board got me thinking about this when he shared a rumor (as yet unsubstantiated) that the European Medicines Agency (EMEA) is considering punishing executives in pharmaceutical firms if their product fails to meet quality standards. Wouldn't it be interesting if corporate heads were held accountable for the quality of the goods manufactured by their companies? Pay raises could be tied, in part, to the quality of their company's products. Conversely, corporate heads could take a pay cut or pay fines when quality dips. 

If corporate officers were held responsible for outcomes, as determined by product quality, we may be able to reduce the burden on oversight agencies such as EMEA and FDA to monitor the integrity of the supply chain and finished products. There's one more possible consequence of such a system. Producing quality products may just be good for business.  

Pharma companies could benefit from the lessons learned in this fall's financial crisis.

Quality Counts

The analogy is often made comparing proteins with machines. It's an apt analogy, and like a bent or twisted machine, a misshapen protein is unable to function properly. Proteins are long chains of amino acids, folded into a certain configuration that allows them to perform a mechanical function. When they're folded incorrectly, they perform that function poorly or not at all, and that malfunction can lead to disease.

In humans, for example, misfolded proteins lay at the heart of diseases such as phenylketonuria (PKU) and cystic fibrosis. Many of these diseases have genetic origins, and much research has focused on correcting the gene. An alternative approach may be to look for an agent that can restore a protein to its proper shape. This approach might, in theory, also restore the protein's function. 

Indeed, in nature, molecules called "chaperones" facilitate correct protein folding. Angel Pey and colleagues at the University of Bergen in Norway, the Universidad de Zaragoza in Spain, the Biocomputation and Complex Systems Physics Institute also in Zaragoza, and the University of Zurich in Switzerland, tested a panel of chemicals to see whether any would act like chaperones and restore the shape and function of  the protein phenylalanine hydroxylase (PAH), the protein when misfolded leads to PKU.  

, the team reports that several chemicals showed evidence of improving activity in animal models. It remains to be seen whether these particular compounds can be developed into drugs. But the larger message for drug developers is that it may be worthwhile to look for drugs with chaperone-like activity when trying to reverse the symptoms of genetically determined diseases. 

: A.L. Pey et al., "Identification of Pharmacological Chaperones as Potential Therapeutic Agents to Treat Phenylketonuria," 

Molecules called "chaperones" facilitate correct protein folding.

Coming Down the Pike: Chaperones

 has been trying for months to get the attention of the presidential candidates to learn their plans for the agencies that will affect the pharmaceutical industry in the coming years. I'm sorry to report that, in spite of my incessant queries (some may call it nagging), I've heard nothing from either campaign. But the project got me thinking about how—or even whether—the political stripe of the president affects the institutions that have an impact on the pharmaceutical industry. So, I took a look backward for any related trends, making a few assumptions along the way. So 

 what follows is a very unscientific survey.  

One assumption stems from an observation I've made that there's a difference in the expectations and political preferences between the business interests and the scientific/research interests within industry. Executives seem to be concerned that a Democratic administration would impose price controls, which could drive down profits. Researchers, on the other hand, think Democrats would increase budgets for research grants, from which they and academic collaborators would benefit. Price controls are a new issue for the drug industry, so we can only wait and see what happens. 

We can, however, look at how the budget for the National Institutes of Health (NIH) has fared since 1980 (see Figure 1). Note that the data set is limited in that there's been only one Democratic administration in that time. Also, correlation does not equal causation, and past performance is no predictor of the future. In an attempt to eliminate the effects of inflation, I expressed the budget as a percentage of the gross domestic product (GDP).  

It seems the data both support and refute the common wisdom. NIH's budget remains essentially flat through the Republican administrations of Ronald Reagan and George H. W. Bush. It starts to rise during the first half of the Democratic Clinton administration, but doesn't really take off until the latter half of that administration and into—and this surprised me—the first half of the Republican administration of George W. Bush. During the second half of the G.W. Bush administration, the budget drops precipitately, seeming to reverse all the gains of the first half of that administration. Current levels are estimated to drop to 2001 funding levels. 

How does NIH funding relate to the pharma industry? Here, I made a huge conceptual leap and thought that more research dollars should, in theory, translate into a greater number of FDA approvals for new molecular entities (NMEs). The average number of NMEs during the Reagan/Bush years was 22 per year; during the Clinton years, 32; and during the G.W. Bush years, 23. It would seem, based on these very unscientific calculations, that the pharma industry fares slightly better during Democratic than Republican administrations. But we have to consider the fate of the US Food and Drug Administration. Again, I expressed the government's appropriations for FDA (not including user fees) as a percentage of GDP (see Figure 2). 

 The budget remained essentially flat during the Reagan/Bush years, experienced a slight rise during the Clinton administration, and just this past year, experienced something of a spike. However, when you consider how miniscule the range is, one has to conclude the FDA budget remains flat no matter who's occupying the White House. Maybe the candidates already know this and that's why they aren't responding to our requests for their policies. Still, Senator McCain, Senator Obama, if you want to tell us directly, we're listening.  

Can previous trends of Democratic and Republican administrations predict industry's future?

The Past as Prologue

Lately, I've noticed an unusual new piece of hardware in many public restrooms. It's a large metal hook-like thing nailed to the inside of the door. As I understand the instructions, you're supposed to hook your arm in it and pull the door open. I think the idea is to spare people from having to touch the doorknob with their hands on their way out so as not to come into contact with other people's infectious germs. (The principle, I guess, is that one's arm is less susceptible to infection than one's hand.) 

Sometimes, instead of this hook (I don't know whether it has an official name yet: A description of the device came up in a Google search for "sanitary door opener," as did mentions of animal-operated door openers—the animals use their snouts, much more sanitary than peoples' hands, no doubt; and foot pedals that open lavatory doors), there is a box of tissue papers by the door that people can use to cover the (supposedly) contaminated doorknob as they grasp it with their hands. In the absence of either accessory, I have seen people use toilet paper or paper towels to cover the doorknob.  

The use of paper towels seems to have come first, but very occasionally, and now come specialized devices—sanitary door openers. So, I guess it's a widespread practice reflecting a widespread concern. But where did this concern come from? Why? And why now? 

Well, for one thing, there seem to be more ads on TV designed to make us afraid of the germs "lurking" in our kitchens and bathrooms at home. I don't know whether this is a symptom or a cause of the same phenomenon that put sanitary door openers in restrooms, but the ads are not only more abundant, they're more urgent than I remember them being at any other time in my own (rather long and comprehensive) TV-watching career. 

As much as it would be easy to say that this fear of contracting something—no one knows what—from doorknobs and kitchen sponges is an advertising ploy to sell paper towels, antibacterial soap, and sanitary door-opening paraphernalia, I suspect something else is operating here. For those of us who grew up in the years after the polio vaccine was widely available and after small pox and malaria had been eliminated in the developing world, there was nothing you could catch, it seemed, that couldn't be cured in a few days with an antibiotic. Medicine may not have cured cancer, but plagues and scourges that decimated whole populations in the past had become mere inconveniences, thanks to modern antibiotics and vaccines. 

Then came AIDS, an infectious disease that could kill people and for which no "cure" or preventive vaccine has to date been found (although there now exist very effective treatments that allow people [who can afford the drugs] to live a relatively normal, disease-free life). Close on the heels of AIDS followed reports of Ebola, Hantavirus, and more recently, SARS, and avian flu (the human version being called, quite ominously, pandemic flu). Add to that, the emergence of antibiotic-resistant tuberculosis, antibiotic resistance in general, and the re-emergence of smallpox, and I find myself wondering whether all the alarm stems from the dual fears of contagions that arise seemingly from out of nowhere, and a lack of public confidence in the medical and pharmaceutical establishments to vanquish them. 

This past week, a stomach ailment that in its severest form gives rise to symptoms that mimic acute appendicitis seems to be sweeping through my office. The causative agent is probably a virus, but no one knows for sure. And when colleagues talk about it, I think I detect a slight note of fear and insecurity that perhaps this is another one of those scourges that we can't so easily wash our hands of. 

Are hypersanitation trends a result of scaremongering or a lack of faith in medicine?