Toxic Waste?

Before testing new drugs in human beings, drug developers must first perform a series of safety tests in animals. Unfortunately, these preclinical toxicology studies are typically protected as trade secrets. In fact, many countries have laws that specifically bar drug regulators from releasing preclinical toxicology data submitted by drug developers.

Unless you take the extreme view that animal experimentation raises no ethical concerns, this represents a terrible waste of animals and a failure of researchers to enable the sacrifice of animals to enrich the bank of human knowledge. As an afterthought, it's worth mentioning that this also comes with certain opportunity costs for human beings, since such nondisclosure potentially 1-frustrates efforts by researchers to improve their knowledge about drug safety, 2- results in duplicative expenditure of human resources.

It needn't be this way, and the field of gene transfer shows one modest way toxicology data could be published and pooled. Since it was established, the National Gene Vector Laboratories, at Indiana University, have invited gene transfer researchers to submit summary data on toxicology studies to their database (the laboratory recently was eliminated and replaced with the National Gene Vector Biorepository-- NGVB for short). As described by NGVB director Ken Cornetta and project coordinator Lorraine Matheson in Molecular Therapy (April 2009), the database is intended to provide a resource for researchers so that they can cross-reference toxicology experiments in their FDA filings and avoid duplicative studies. The authors also envision the database as a resource for grant reviewers.

The database contains 27 toxicology studies in all. This number seems small when you consider the volume of gene transfer studies pursued since the database was established. The fact that every institution that has contributed to the database is a nonprofit suggests that the private sector has not taken an interest in this worthy resource. One question I have is how many private companies have used data contained in this databank in their FDA filings (this should be easy to determine).

These questions aside, other fields should create similar resources to pool data and create opportunities for data linkage. I would go so far as to say that ethics policies should require that, at a minimum, such summary data be published on a public database. The failure to do so seem a toxic waste for animals, scientists, funders, and patients alike.  (photo credit: drp, Waste Not, 2004)

The Biotechnology of Neglect

What can the biotechnology industry do for neglected diseases (infectious diseases that, because they primarily afflict low-income countries, are not heavily researched in the public or private sector)? Biotechnology enthusiasts might answer "everything," ignoring the dearth of research and development incentives for small biotechnology firms, much less the major challenges presented by the manufacture, distribution, purchase, and administration of biotechnology products. Critics might answer "nothing," drawing attention to the existing availability of simple, low cost interventions against diarrheal diseases, tuberculosis, etc..

A recent article puts forward a series of proposals on the biotechnology sector and neglected disease. In the April 2009 issue of Nature Biotechnology (Leveraging biotech's drug discovery expertise for neglected diseases), authors Joanna Lowell and Christopher Earl (of BIO Ventures for Global Health) argue that biotechnology companies can play a "pivotal role" in developing small-molecule drugs against neglected diseases. Noting that many neglected diseases involve drug targets that are similar to those for high-income country diseases, Lowell and Earl suggest that companies can simultaneously advance their primary objectives while supporting development of drugs for neglected diseases.  

They offer several reasons why biotechnology companies might do so. First is "the chance to prove technology platforms."  Companies might "leverage" philanthropic support to test biologic pathways of relevance to drugs targeting more affluent markets (I will note, without comment, that such a proposal would need to think through justice concerns). Second is employee morale: initiating such research is an important way of attracting and retaining talented and idealistic scientists. Third is "sustaining underutilized discovery platforms." Once companies have discovered a lead compound, drug discovery platforms can potentially languish.  Using this dormant capacity helps companies maintain their drug discovery platforms so that they will be available in the future.

I leave it to readers to decide the soundness of the proposals. On the one hand, the idea that biotechnology companies can derive benefits from pursuing neglected disease research seems plausible, as does the notion that the biotechnology sector has much to offer low-income countries (curiously, the article centers on small molecule drugs rather than vaccines). The authors cite a number of examples to support their claims, and BIO Ventures for Global Health has received a "seal of approval" (e.g. generous funding) from the Bill and Melinda Gates Foundation.

On the other hand, are struggling biotechnologies likely to embrace this-- especially given today's credit markets? One can be forgiven for wondering whether this is merely a PR ploy for a biotechnology industry that has sought contentious policies like strong intellectual property protections.  BIO Ventures for Global Health is, after all, an arm of the biotechnology trade association, BIO.  (photo credit: ViaMoi, Neglect, 2007)

Guinea Pig Nation?

Here is an irresistible news headline: "Public Policy That Makes Test Subjects of Us All."(New York Times, April 6, 2009). Then you open to the story only to discover, to your disappointment, that the piece is written by John Tierney, probably the most uninformed and underqualified members of the NYTimes staff.

His argument is ridiculous: that the New York City mayor's initiative to "pressure" the food industry to cut salt amounts to a big experiment that would normally have to undergo IRB review and informed consent (never mind that the initiative is not an experiment designed to further knowledge.  Never mind that the initiative is not aimed at generalizable knowledge, or that public health initiatives grounded in a state-based interest that are enacted by elected leaders have the "consent of the governed").

But in the most recent issue of JAMA, a news story (Bridget M. Kuehn, "Rare Neurological Condition Linked to Newer Monoclonal Antibody Biologics," April 8, 2009) reminds us that, in some small sense, licensure of novel biologics makes guinea pigs of us all.  The report describes how FDA recently issued an advisory on the psoriasis drug efalizumab after reports emerged that it may be associated with a risk of developing a rare and fatal brainwasting disease (progressive multifocal leukoencephalopathy, or PML).  FDA had previously issued warnings on two similar, immunomodulating drugs, and established a restricted distribution system for a third (natalizumab-- for multiple sclerosis).

In the case of natalizumab, cases of PML occurred in pre-marketing clinical trials.  For the other drugs, knowledge of the risk emerged only after drug licensing.  Risk of PML was totally unexpected, and is a reminder of the high degree of uncertainty surrounding interventions directed at the immune system.  

Premarketing clinical trials are statistically powered only to detect common, "signature" adverse events.  As we move into an era of biologics-based pharmaceuticals (and accelerated approval), expect that many adverse events will only be discovered once a drug is in widespread use.  Robust systems of pharmacovigilence will be especially critical (photo credit: Peter Guthrie, 2006).