[Insight-developers] Open Source Clinical Trials // Open Source Biology

[Lorensen, William E (Research)]

The second two articles have some interesting ideas about extending the open
source model to other areas.



-----Original Message-----
From: Vannier, Michael [mailto:mvannier at RADIOLOGY.BSD.UCHICAGO.EDU]
Sent: Wednesday, June 16, 2004 9:03 AM
To: ARCHIVE-COMM-L at LIST.NIH.GOV
Subject: Full Drug-Trial Disclosure // Open Source Clinical Trials //
Open Source Biology


Medical Journals Weigh Plan for Full Drug-Trial Disclosure
By BARRY MEIER http://www.nytimes.com/2004/06/15/business/15drug.html
http://www.icmje.org/

New York Times, June 15, 2004

n organization of top medical journals is considering a proposal that
would require drug makers to register clinical trials at their start in
a public database in order for results, whether successful or not, to be
later considered for publication, according to three people working with
the group.

Pharmaceutical companies are not generally required now to disclose
results of a trial or even whether one was conducted. Some academic
researchers have long argued that fuller registries of drug trials are
needed because companies, as well as medical journals and scientists,
tend to spotlight only trials that show positive results.

The plan, if adopted by the organization, the International Committee of
Medical Journal Editors, is likely to put pressure on pharmaceutical
makers to disclose more about the trials they run. The group includes 12
major medical journals like The Journal of the American Medical
Association, The New England Journal of Medicine, The Lancet and The
Annals of Internal Medicine.

The recent discussion among the journal editors about a trial registry
comes amid public controversy about clinical trial data after the
disclosures that the results of antidepressant tests in children were
not adequately publicized.

Because the medical journals in the group are prestigious, and
publication of the results of a clinical trial in them carries much
weight, companies frequently use articles from them as marketing tools
to persuade doctors to prescribe a drug. If the International Committee
of Medical Journal Editors adopts the proposal for a registry, drug
companies not wanting to participate could still seek to have their
research published in other less-prominent medical journals, but the
research might not get as much attention from physicians.

A spokesman for the Pharmaceutical Research and Manufacturers
Association of America, a group representing drug makers, said it was
not aware of the proposal being considered by medical journal editors to
require registration of trials, so it could not comment on it. In the
past, the group has not supported a registry, although a few companies
have adopted a registry.

Many drug companies without registries have noted that they voluntarily
disclose the results of all clinical trials they conduct, either at
scientific conferences or through publications.

But critics say that there is no central registry where clinical trials
and their results are available, making it difficult for researchers to
track all studies that have been done on a single drug.

Ideally, advocates of clinical trial registries say, such databases
would show when a trial was started, list its objectives and then update
that information with the trial's results or the reason it was
terminated.

A proposal to mandate trial registration as a prerequisite for
publication was discussed last week at a meeting of the journal editors'
group, said the three people working with the organization who insisted
on anonymity because, they said, the proposal was still under discussion
and because the group was not planning to announce any change unless it
was adopted.

A decision could come in the summer, one person said.

In a related development, policy makers at the American Medical
Association, which represents many of the nation's doctors, are expected
to vote as early as today on a proposal that would urge the government
to create a public registry of clinical trials and their results, a
spokesman for the A.M.A. said.

Yesterday, GlaxoSmithKline, the manufacturer of the antidepressant
Paxil, released on its company Web site the reports of clinical tests of
that drug in children and adolescents suffering from psychological
conditions including depression.

The action follows a civil lawsuit filed this month by the New York
State attorney general, Eliot Spitzer, that accused the company of
misleading doctors by publicizing a favorable study of Paxil for
pediatric depression while playing down other trials that showed the
drug did not work better than a placebo.

GlaxoSmithKline officials have denied that they selectively disclosed
trial findings.

Regulators in this country and elsewhere are now scrambling to review
unpublished test data on Paxil and several other popular antidepressants
to see if the drugs pose dangers.

In a statement issued yesterday, Mr. Spitzer said that the company's
actions had not resolved his lawsuit but called it a positive move.
"This is a positive first step toward changing a dangerous industry
practice," he said.

A decision by the International Committee of Medical Journal Editors to
consider for publication only clinical trials that have been registered
from the start would be the organization's latest effort to push for
greater disclosure of data.

Two years ago, the group published a joint editorial calling on
companies to provide university researchers with a greater role in
designing trials and access to the analysis of results. That same
editorial also pointed to the fact that the results of some trials were
never published.

"The results of the unfinished trial may be buried rather than published
if they are unfavorable to the sponsor's product," the editorial stated.
"Such issues are not theoretical. There have been a number of recent
public examples of such problems, and we suspect that many more go
unreported."

But some academic researchers have also argued that medical journals are
themselves part of the problem, even if unwittingly so. A growing number
of studies have found that clinical trials published in leading medical
journals tend to show positive results about the drug or medical devices
being tested, a phenomenon referred to as publication bias.

As a result, those researchers say, physicians who rely on medical
journals for information about drugs and medical devices may get an
incomplete view of their effectiveness or safety because they may be
unaware of other less favorable or inconclusive studies.

In an interview this month, Dr. Alan Goldhammer, associate vice
president for regulatory affairs for the Pharmaceutical Research and
Manufacturers Association of America, said that to date the organization
had not supported the idea of a public registry for clinical trials. He
said the association might reconsider its stance in light of the
antidepressant controversy.

Another trade group, the Association of the British Pharmaceutical
Industry, recommended to its members last year that they voluntarily
create trial registries. A spokesman for the group said recently that 8
of its 80 members had created such databases.


----------------

An open-source shot in the arm?

Jun 10th 2004
>From The Economist print edition
http://www.economist.com/displaystory.cfm?story_id=2724420

Medicine: The open-source model is a good way to produce software, as
the example of Linux shows. Could the same collaborative approach now
revitalise medical research too?

CAN goodwill, aggregated over the internet, produce good medicine? The
current approach to drug discovery works up to a point, but it is far
from perfect. It is costly to develop medicines and get regulatory
approval. The patent system can foreclose new uses or enhancements by
outside researchers. And there has to be a consumer willing (or able) to
pay for the resulting drugs, in order to justify the cost of drug
development. Pharmaceutical companies have little incentive to develop
treatments for diseases that particularly afflict the poor, for example,
since the people who need such treatments most may not be able to afford
them.

It is in this environment that a number of medical biologists, lawyers,
entrepreneurs and health-care activists have sought improvements. They
have suggested borrowing the "open-source" approach that has proven so
successful in another area of technology, namely software development.
This is a decentralised form of production in which the underlying
programming instructions, or "source code", for a given piece of
software are made freely available. Anyone can look at it, modify it, or
improve it, provided they agree to share their modifications under the
same terms. Volunteers collaborating in this way over the internet have
produced some impressive software: the best-known example is the Linux
operating system. So why not apply the open-source model to drug
development too?

Source for the goose
In fact, open-source approaches have emerged in biotechnology already.
The international effort to sequence the human genome, for instance,
resembled an open-source initiative. It placed all the resulting data
into the public domain rather than allow any participant to patent any
of the results. Open source is also flourishing in bioinformatics, the
field in which biology meets information technology. This involves
performing biological research using supercomputers rather than
test-tubes. Within the bioinformatics community, software code and
databases are often swapped on "you share, I share" terms, for the
greater good of all. Evidently the open-source approach works in
biological-research tools and pre-competitive platform technologies. The
question now is whether it will work further downstream, closer to the
patient, where the development costs are greater and the potential
benefits more direct.

Open-source research could indeed, it seems, open up two areas in
particular. The first is that of non-patentable compounds and drugs
whose patents have expired. These receive very little attention from
researchers, because there would be no way to protect (and so profit
from) any discovery that was made about their effectiveness. To give an
oft-quoted example, if aspirin cured cancer, no company would bother to
do the trials to prove it, or go through the rigmarole of regulatory
approval, since it could not patent the discovery. (In fact, it might be
possible to apply for a process patent that covers a new method of
treatment, but the broader point still stands.) Lots of potentially
useful drugs could be sitting under researchers' noses.

The second area where open source might be able to help would be in
developing treatments for diseases that afflict small numbers of people,
such as Parkinson's disease, or are found mainly in poor countries, such
as malaria. In such cases, there simply is not a large enough market of
paying customers to justify the enormous expense of developing a new
drug. America's Orphan Drug Act, which provides financial incentives to
develop drugs for small numbers of patients, is one approach. But there
is still plenty of room for improvement-which is where the open-source
approach might have a valuable role to play.

In a paper presented this week in San Francisco at BIO 2004, the
Biotechnology Industry Organisation's annual conference
http://www.bio.org/events/2004/, Stephen Maurer, Arti Rai and Andrej
Sali-two lawyers and a computational biologist, respectively-called for
an open-source approach to invent drugs to fight tropical diseases. It
would work like this: a website they call the Tropical Disease
Initiative would allow biologists and chemists to volunteer their
expertise on certain areas of a specific disease. They would examine and
annotate shared databases, and perform experiments. The results would be
fully transparent and discussed in chat rooms. The authors expect that
the research, at least initially, would be mainly computational, not
carried out in "wet" laboratories.

"We are so used to patents that we forgot ways to discover drugs in the
public domain, and we need to rediscover them"

The difference between this proposal and earlier open-source approaches
in biomedical research is that where before scientists swapped software,
here they would collaborate on the data. And where projects such as the
mapping of the human genome relied on massive top-down government
involvement, this proposal would, like an open-source software project,
be the result of bottom-up self-organisation among researchers
themselves. That said, the authors acknowledge that a government or
grant-giving charity would probably have to provide the initial funds.

Moreover, the results of the research would not be made available under
an open-source licence of the kind that governs software projects.
Instead, the final development of drug candidates would be awarded to a
laboratory based on competitive bids. The drug itself would go in the
public domain, for generic manufacturers to produce. This, the authors
state, would achieve the goal of getting new medicines to those who need
them, at the lowest possible price. "We are so used to patents that we
forgot ways to discover drugs in the public domain, and we need to
rediscover them," says Mr Maurer, of the Goldman School of Public Policy
at the University of California in Berkeley.

This is just one of many attempts to extend elements of the open-source
software-development model to drug research. Yochai Benkler, a law
professor at Yale, imagines test-tube and animal studies organised in
this manner, exploiting the "excess capacity" of graduate students and
university labs, much as students and academics also contribute to
open-source software development.

Trial and error
Eric von Hippel, a professor at the Massachusetts Institute of
Technology's Sloan School of Management, is investigating how secondary
uses for drugs are discovered, with a view to harnessing doctors and
patients to record data. Many medications are approved for one purpose,
but are regularly prescribed for another, "off-label" use. In many
instances, new uses for a drug are discovered only after it is on the
market, when a sort of natural experimentation takes place. For
instance, Botox was approved in America for treating eye-muscle
disorders, and only later found to remove wrinkles. In Europe and
America, as many as half of all drug prescriptions for certain diseases
fall into this category. The drugs often do not go through the formal
process for other uses because the cost of regulatory approval is so
high.

This is a problem for a number of reasons. First, it means that drug
companies are prohibited from advertising the medications based on these
additional uses, so some patients may not get the treatment that would
benefit them. Next, insurance companies in America usually only cover
on-label use. And the effectiveness of the treatment is not formally
evaluated. Dr von Hippel's idea is to decentralise the process of
obtaining data on the off-label use, by collaborating with volunteer
doctors and patients. By defraying costs in this way, it might then be
possible to obtain regulatory approval. It is, in effect, an open-source
clinical trial. Because the drug has already been approved, it has
passed first-phase tests for safety. These do not have to be repeated.
Second and third-phase drug-approvals test for efficacy and
side-effects-and these are the very areas where getting formal approval
for off-label use is sensible.

Meanwhile, not far from Dr von Hippel at MIT, thousands of fruit flies
are being decapitated. Peter Lansbury, the head of a research lab at
Harvard Medical School, avows that they are treated with chloroform, so
"they don't feel a thing". The fruit flies have Parkinson's disease, and
Dr Lansbury's research is examining the therapeutic effect of a thousand
approved drugs, on which the patent has expired in most cases. Might one
of them turn out to be an effective treatment?

This sort of research is unusual because there is no working hypothesis
to prove and no way to profit if the project is successful. It has
simply never been studied before, and should be, says Dr Lansbury, who
is the co-founder of the Laboratory for Drug Discovery in
Neurodegeneration. The laboratory has around 25 researchers and an
annual budget of $2.5m to work on neurodegenerative diseases, such as
Parkinson's or Huntington's, to which the major commercial drug
companies devote few resources because their potential market is small.

Dr Lansbury refers to the work as "not-for-profit drug discovery", but
he sees direct parallels with the open-source approach. For one thing,
his group places much of its data in the public domain. Secondly, though
the research is mainly happening among different research labs within
the confines of Harvard at the moment, the goal is to involve other
scientists around the world. Only through this sort of collaborative,
distributed approach will treatments be found for these diseases, he
says. As for the intellectual property that may be created, the goal is
to use patents only to license treatments cheaply to pharmaceutical
companies to ensure a supply of drugs at low cost. But the most
important thing is to discover the drugs in the first place-something
commercial drug-development seems unable to do.

"What does it mean to apply the term 'open source' in fields outside
software development, which do not use 'source code' as a term of art?"

There are a number of other similarities between biomedical research and
open-source software development. First, both fields attract the same
sort of people. Biology, like software, relies on teams of volunteers,
notably graduate students and young professionals, who have an incentive
to get involved because it will enhance their professional reputations
or establish expertise. Both medical biologists and computer scientists
aim to improve people's lives and make the world a better place. And as
the human-genome project showed, both cultures respond strongly to grand
projects, not just financial incentives-possibly because they are
generally highly paid to begin with.

That said, the dissimilarities are profound. The financial needs and
time to complete projects are wildly different. A new piece of software
can be thrown together in days or weeks, and rarely more than a few
months. The barriers to entry are low: many pieces of software begin
life in an enthusiast's bedroom or garage. Pharmaceutical research, in
contrast, is measured in years, fails more often than it succeeds, and
requires hard-core credentials and in many cases expensive equipment,
not just hard work.

Moreover, the computational portion of the drug-discovery
process-typified as upstream, far from the patient, at the early-stage
level, where profits are thinner-is not the costly bit. Rather, it is
the less computer-intensive things such as toiling in wet laboratories,
performing clinical trials and navigating the regulatory-approval
process where one finds the bulk of the cost of bringing a drug to
market. The closer to the patient one goes, the tougher it is to imagine
open-source processes making a significant impact.

The application of the open-source approach to drug development may
prove to be more useful as an analogy than an application, notes Janet
Hope, a lawyer completing a doctorate on "open-source biotechnology" at
the Australian National University, in Canberra. One reason is that
different intellectual property rights apply, and are protected
differently. Software usually falls under copyright, which arises
automatically and without cost to the author. Biomedical discoveries are
generally protected by an entirely different legal regime, patents,
which are costly to obtain.

This helps explain why the drug-discovery and development projects place
their work in the public domain, rather than trying to enforce some form
of reciprocal openness through an open-source licensing agreement, as
software does. Those involved in the human-genome project investigated
the possibility in 2000 of applying an open-source licensing agreement
to the results, but decided that simply throwing the results into the
public domain-without any restriction on their use-was better. Its
successor project, the International HapMap Project, which is mapping
the common patterns of variation within the genome, imposes an
open-source licence for research in progress. But it places the
completed data in the public domain and allows patents on subsequent
discoveries.

This suggests that continued reciprocal sharing, a key part of
open-source software development, may not have a meaningful equivalent
on the biological side of the fence. With open-source drug discovery in
the public domain, where there is no legal obligation to share one's
inventions, there is no guarantee that philanthropic sentiments will
override self-interest. Participants can always choose to send their
results to the patent office rather than the communal web site. While
the open-source approach shows much promise in drug discovery, it is
certainly no panacea.

Back to the source
More broadly, two big questions remain unanswered as the open-source
approach starts to colonise disciplines beyond its home ground of
software development. The first is whether open-source methods can
genuinely foster innovation. In software, all that has been developed
are functional equivalents of proprietary software-operating systems,
databases, and so on-that are sometimes slightly better and sometimes
glaringly worse than their proprietary counterparts. Their main
distinction, from users' point of view, is simply that they are
available free of charge. Curiously, this matches the complaint levelled
against pharmaceutical companies for developing "me-too" drugs to
compete with other firms' most successful product lines-witness the
current crop of Viagra imitators-rather than spending their research
money in an entirely new area.

The second question is semantic. What does it mean to apply the term
"open source" in fields outside software development, which do not use
"source code" as a term of art? Depending on the field in question, the
analogy with source code may not always be appropriate. It seems the
time has come to devise a new, broader term than "open source", to refer
to distributed, internet-based collaboration. Mr Benkler calls it
non-proprietary peer-production of information-embedding goods. Surely
someone, somewhere can propose something snappier.

------------------
New Institutions for Doing Science:
>From Databases to Open Source Biology

Stephen M. Maurer
2632 Hilgard Ave.,
Berkeley, CA. 94709
E-Mail: maurer at econ.berkeley.edu
Richard & Rhoda Goldman School of Public Policy
University of California at Berkeley

A paper presented to the
European Policy for Intellectual Property Conference on Copyright and
database protection, patents and research tools, and other challenges to
the intellectual property system

Held at the University of Maastricht, The Netherlands, November 24-25,
2003
http://www.merit.unimaas.nl/epip/papers/maurer_paper.pdf
http://www.merit.unimaas.nl/epip/

Recently, several authors have suggested that a new method of doing
science called "open source biology" is about to emerge. However, very
little has been written about how such an institution would differ from
existing research institutions. Scientificdatabases provide a natural
model. During the 1990s, scientists experimented with several new
database initiatives designed to reconcile private support with the
ideals of open science. Despite significant controversy, this paper
argues that private/public transactions that unambiguously promote
academic science should be encouraged. In principle, research
communities can also organize database collaborations to pursue social
and political goals. Examples include discouraging software patents,
promoting "green" investment, and improving internet security. Finally,
the new field of computational genomics blurs the traditional line
between database creation and product development. This paper describes
how traditional database institutions can be modified and extended to
discover pharmaceuticals. The proposed institution ("open source drug
discovery") would be particularly useful for combating Third World
diseases. Success would demonstrate that the open source institution is
not limited to computer science and can develop products other than
software.