Cash Crash

Think you're the only one stashing your financial statements in a filing cabinet without first opening them?  How do you think biotechnology companies feel?  Today's New York Times ran a story by Andrew Pollack ("Broader Financial Turmoil Threatens Biotech's Innovation and Cash") describing the impact of the economic downturn on the biotechnology sector. Among the observations:

- Of 344 companies that NASDAQ is considering de-listing because share prices have fallen to less than a dollar, 25% are biotechnology companies.

- 113 biotech companies now have less than a year's cash at current spending rates. This is up from 68 in the first quarter.

- One company with major problems is DeCode- the Icelandic genetic research company. This might have particular symbolic significance, given the company's profile.

- companies are being pressured by investors to cut their research and focus energy on lead products only.

The article goes on to explain that the main problem for biotech companies is NOT credit (apparently, even banks considered most biotech's too risky to lend to). Instead, the problem is an epidemic of risk aversion among investors, and hedge funds selling biotech stocks to recoup losses elsewhere in their portfolios. The article does note that companies like Amgen, which have widely used products, are thriving compared with the general market. As for the others, one analyst, Andrew Baum, describes the sector as a plane "for which the financial crisis just tipped the nose straight down." The implications for translational research are obvious. (photo credit: Hawk914, Koga's Zero- 1942, 2007)

The Future of Pharmaceutical Regulation

The October 2008 issue of Nature Reviews--Drug Discovery contains a very informative perspective piece on how drug regulators negotiate uncertainty, risk, and benefit when making approval decisions ("Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma"). I have long argued that novel biologics like gene transfer will require creative approaches from regulators, because on the one hand many types of adverse events might be latent and unpredictable, while on the other hand, many novel biologics will target highly morbid or lethal conditions like primary immunodeficiencies.

The authors (Hans-Georg Eichler et al) are all employees of drug regulatory agencies in Europe. Not surprisingly, then, the article is balanced and presents drug agencies as making appropriate trade-offs between patient access and public safety. The article studiously avoids any criticism of pharmaceutical companies. And it makes some questionable claims. For example, in several passages it suggests that drug regulation is increasingly "risk averse" (it seems to me the opposite, but who knows?). Another is that the article contains ample evidence that premature approval has had important costs in terms of health and economics. Nowhere does it provide clear evidence or anecdotes that delay of approval, or restrictive evidentiary standards have had important public health or economic impacts (it might, but if you are going to suggest that the balance is appropriately struck, one needs a clear picture of the benefit side of the equation).

The article contains a number of observations and policy approaches that cry out for careful ethical analysis. Here are two:

1- Drug regulatory agencies accept greater uncertainty about safety and efficacy when new drugs address serious, unmet health needs. Thus, new cancer drugs can be approved on a weaker evidentiary base than new acid reflux drugs (in several instances, new drugs were approved on the basis of uncontrolled, surrogate endpoints (e.g. gefitinib). Why should evidentiary standards be relaxed in this way? And to what degree? If the disease is serious enough and standard care non-existent, then what is the basis for any drug regulation?

2- The article states that "rare drug reactions will continue to be identified only after wider use in the market," and that more sophisticated approaches to drug safety will increasingly "blur the line between pre-marketing and post-marketing activities." How will this affect ethics review and oversight? How will privacy protections be maintained in this gulf-stream of flowing health data? How will trial registries absorb and respond to post-marketing studies?

This article contains multitudes– I highly recommend it to anyone interested, as I am, in the problem of uncertainty, risk, and drug regulation (photo credit: Alincolnt, schedule 5, 2006)

Cancer, Low and Middle-Income Countries, and Translational Research

In the October 20, 2008 issue of Journal of Clinical Oncology, oncologist Zeba Aziz describes morning rounds in a cancer ward in Lahore, Pakistan. The first patient earns $20 a month and requires a combination therapy costing $10K. In the second case, a father can only pay 15% of the treatment needed by his daughter. The third case involves a single mother, who showed a significant tumor response on the first cycle of treatment but can not afford subsequent rounds.

According to Aziz, only 2% of Pakistan's population has health insurance; 95% earn $30-100 / month. Aziz's hospital serves 10K cancer patients annually, and has a medicines budget of around $80K each year. Treatments that wipe out the immune system are especially tricky, because medicines for infection might not be affordable.

Low and middle-income countries (LMICs) are undergoing an epidemiological transition in which chronic diseases replace infection as the main drivers of mortality. According to Franco Cavalli ("The World Cancer Declaration: A Roadmap for Change," Lancet Oncology, September 2008), cancer kills more people worldwide than AIDS, tuberculosis, and malaria combined. Cavalli describes a "World Cancer Declaration" issued by the Geneva based International Union Against Cancer that calls for improvements in the prevention, detection, reporting, and treatment of cancer in LMICs.

But a serious response to cancer in LMICs will require changes in translational research as well. Clearly, the vast majority of cancer treatment research is directed toward markets in high-income countries. These treatments have properties– costs, side-effect profiles, demand for ancillary services– that make their application in LMIC populations improbable. If, as argued by many commentators, we in HICs have a duty to persons in LMICs, translational researchers and funding agencies should give some thought and effort to the development and testing of treatments that, while perhaps not adding as many weeks of extra median survival, are deployable in settings like Aziz's clinic. (photo credit: CasaDeQueso 2008)

From Bench to Ringside: The Presidential Debate

Last night, Obama and McCain confronted each other in the final Presidential debate. A flagging economy and two wars have left little room in the two campaigns for discussion of science, policy, and human research. Yet last night's debate touched on two themes: embryonic stem cell (hES) research, and biomedical research funding.

Obama accused McCain of opposing embryonic stem cell research. From what I can tell, McCain actually supported the use of embryonic tissue for research and opposed Bush's ban and vetoes. But the logic of McCain's attacks on Obama, of late, are that personal associations tell us something about who a person is and where they stand. And McCain pals around with embryo research opponents like his running mate.

Contrast the two candidates' statements on hES research from Sciencedebate 2008– a group that invited McCain and Obama to declare positions on various science policy issues. McCain stated "While I support federal funding for embryonic stem cell research, I believe clear lines should be drawn...."  The remainder of his response qualifies his support.  On his own website, McCain stops short of declaring support–or opposition– for hES research, and talks more about what he would oppose than what he would support.  Obama's support is more full-throated at Sciencedebate 2008: "As president, I will lift the current administration's ban on federal funding of research on embryonic stem cell lines... embryonic stem cells remain the 'gold standard,' and studies of all types of stem cells should continue in parallel for the foreseeable future."

Elsewhere at Sciencedebate 2008, Obama's campaign singled out gene transfer in a statement on genetics: "As a result [of safety issues involving 'gene therapy'], the NIH established the Recombinant DNA Advisory Committee.... Until we are equipped to ascertain the safety of such methods, I will continue to support the activities and recommendations of the Recombinant DNA Advisory Committee." [Note: Harold Varmus chairs a science advisory committee for the Obama campaign. Varmus reorganized RAC when he was the director of the NIH under the Clinton administration]

What about research-- specifically translational research?  Just as they do for Joe the plumber, both candidates support NIH research. According to a report in Science ("Scientists Strive for a Seat at the Table of Each Campaign," Jeffrey Mervis, 26 Sept), Obama pledged to double the NIH budget in five years. Elsewhere, his campaign said 10 years. Maybe the latter figure is inflation adjusted? Obama's statement on Science and Innovation singles out "rapid translation of medical research."

I am not aware of any clear statements on translational research from McCain, though he favors greater funding for NIH, and based on his debate and website, he seems to have a soft spot for autism research. As on other issues, McCain is less willing to commit to a timetable on NIH budget doubling. (photo credit: Thomas Hawk, Wordle of McCain and Obama convention speeches, 2008)

Northward Migration?

"Since 2005, we've started seeing the big 20 pharma corporations making investments [in gene therapy]," says a deputy head in European Medicine Agency (EMEA) in the October 2008 issue of Nature Biotechnology ("Ark floats gene therapy's boat, for now," by Randy Osborne). "When you want to know what season is there and when the weather will change, you have to see which birds are flying."

All this should be very encouraging for the field. Yet the story also describes the many travails of companies seeking regulatory approval for their gene transfer products. One is Introgen, which sought approval for its adenovirus-p53 cancer product Advexin. FDA returned Introgen's submission with a "refuse to file" letter indicating that the materials were incomplete. The study on which this filing was based was presented at the American Society of Gene Therapy meeting last Spring. As I indicated in my June 10 posting, a major concern with this study was that its efficacy claims were based on a subgroup analysis of genetic profiles. Others, like TheStreet.com columnist Adam Feuerstein, have been far less guarded in their assessment of Advexin; Feuerstein called Introgen "a living textbook for what investors need to be wary of when considering a biotech investment."

The second product profiled in the Nature Biotechnology story is Ark's Cerepro, which uses herpes simplex virus vectors to deliver a gene, thymidine kinase, to the tumor bed of patients with malignant glioma (a highly aggressive form of brain cancer); the gene then converts a pro-drug, ganciclovir, into a toxin that kills tumor tissue. Ark is reportedly planning to file a license application to EMEA. Preliminary data in a randomized controlled trial against standard of care vs. standard of care + Cerepro indicate a median extension of survival by 42 days (with serious side effects).

One last product profiled briefly is Amsterdam Molecular Therapeutic's product, Glybera, for a very rare genetic disease lipoprotein lipase deficiency. Amsterdam intends to file for licensure "later this year."

The fortunes of clinical gene transfer might indeed be flying North. But with some lead products showing such incremental gains in survival and dependence on combination with standard care, clinical application seems less likely to arrive with a bang than with a modest honk.  (photo credit: denis collette, 2007)

The Problem with Models

Chicago in plastic and balsa. If only animal models were as convincing as the one pictured above from the Museum of Science and Industry. 

The August 7 issue of Nature ran a fascinating feature on how many scientists are reassessing the value of animal models used in neurodegenerative preclinical research ("Standard Model," by Jim Schnabel).

The story centers on the striking failure to translate promising preclinical findings to treatments for various neurodegenerative diseases. In one instance, a highly promising drug, minocycline, actually worsened symptoms in patients with ALS. In other instances, impressive results in mice have not been reproducible. According to the article, a cluster of patient advocacy groups, including organizations like Prize4Life and a non-profit biotechnology company ALS TDI, are spearheading a critical look at standard preclinical models and methodologies.

Much of the report is about limitations of mouse models. Scientists from the Jackson Laboratories (perhaps the world's largest supplier of research mice) warn that many mouse strains are genetically heterogenous; others develop new mutations on breeding. Other problems described in the article: infections that spread in mouse colonies, problems matching sex or litter membership in experimental and control groups, and small sample sizes. The result is Metallica-like levels of noise in preclinical studies. Combined with nonpublication of negative studies, and the result is many false positives.

The article bristles with interesting tidbits. One that struck me is the organizational challenges of changing the culture of model system use. According to the article, many academic researchers and grant referees have yet to warm to criticisms of models, and some scientists and advocates are asking for leadership from the NIH. Another striking point in the piece-alluded to in the article's closing-is a fragmentation of animal models that mirrors personalized medicine.

"Drugs into bodies." That's the mantra of translational research. It is an understandable sentiment, but also pernicious if it means more poorly conceived experiments on dying patients. What is needed is a way to make animal models- and guidelines pertaining to them- as alluring as supermodels. (photo credit: Celikens 2008)

STAIRing at Method in Preclinical Studies

Medical research, we all know, is highly prone to bias. Researchers are, after all, human in their tendencies to mix desire with assessment. So too are trial participants. Since the late 1950s, epidemiologists have introduced a number of practices to clinical research designed to reduce or eliminate sources of bias, including randomization of patients, masking (or "blinding") of volunteers and physician-investigators, and statistical analysis.

In past entries, I have rallied for extending such methodological rigor to preclinical research. This has three defenses. First, phase 1 human trials predicated on weak preclinical evidence are insufficiently valuable to justify their execution. Second, methodologically weak preclinical research is an abuse of animals. Third, publication of methodologically weak studies is a form of "publication pollution."

Two recent publications underscore the need for greater rigor in preclinical studies. The first is a paper in the journal Stroke (published online August 14, 2008; also reprinted in Journal of Cerebral Blood Flow and Metabolism). Many of the paper's authors have doggedly pursued the cause of preclinical methodological rigor in stroke research by publishing a series of meta-analyses of preclinical studies in stroke. In this article, Malcolm Macleod and co-authors outline eight practices that journal editors and referees should look for in reviewing preclinical studies. Many are urged by STAIR (Stroke Therapy Academic Industry Roundtable)– a consortium organized in 1999 to strengthen the quality of stroke research.

Their recommendations are:

1- Animals (precise species, strain, and details should be provided)

2- Sample-size calculation

3- Inclusion and exclusion criteria for animals

4- Randomization of animals

5- Allocation concealment

6- Reporting of animals concealed from analysis

7- Masked outcome assessment

8- Reporting interest conflicts and funding

There's an interesting, implicit claim in this paper: journal editors and referees partly bear the blame for poor methodological quality in preclinical research. In my next post, I will turn to a related news article about preclinical studies in Amyotrophic Lateral Sclerosis. (photo credit: 4BlueEyes, 2006)