MRI and Orphan Drug articles

[Guest guest]

Translating the Tunes of Brain Resonance

by Mike May

(Posted December 11, 1998 · Issue 44)

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The image of a human head rotates slowly. With the top portion of the skull

removed, viewers can see the hills and valleys that cover the surface of the

underlying brain. Bursts of yellow and red indicate activity at the rear of

the brain, where a large segment has been removed to expose the inner workings

of the optical cortex. These colors, though, raise a fundamental question -

what does the recorded activity mean?

The search to answer that inquiry creates the foundation of so-called

functional magnetic resonance imaging (fMRI), which uses the imaging power of

MRI in an effort to understand how the brain performs a variety of tasks, from

vision to long division. An intriguing overview of this field awaits visitors

at a site hosted by the Oxford Centre for Functional Magnetic Resonance

Imaging of the Brain (FMRIB).

To get some general background on this research facility, one can head to the

Introduction to FMRIB. This link explains that An important

goal of the Centre is to promote research to understand the brain mechanisms

necessary for complex cognitive phenomena such as language and

memory. To explore these areas, investigators at FMRIB rely on

a 3 Tesla magnetic resonance imaging system. (The site includes photographs of

this system being installed.) Using this system, investigators will explore

how our brain heals, say, after a stroke, what patterns of activity in our

brain accompany pain, and many other phenomena.

When asked who uses this site, Jezzard, head of the physics

group at FMRIB, said, Mostly other labs in the business of

functional brain imaging, potential students, and our collaborating scientific

sites. He added that visitors also include any

volunteers who might go in our magnet, and, of course, whoever stumbles across

it.

Some aspects of this site, however, serve only members of the Oxford

University system. Steve , head of image analysis at FMRIB and author of

its Web site, explains: Obviously, we have a very large amount

of information available only to Oxford computers with all sorts of stuff

about fMRI - how to book experiments, how to analyze data, etc.

Nevertheless, added that this site also serves

interested researchers who want to find out more about [the Centre] and

functional magnetic resonance imaging, as well as

researchers who want to know what we are working on, or want to download

papers or software from our site.

For those just getting started in this field, or simply interested in the

mechanics of fMRI, follow the link labeled Introduction to FMRI. The text

therein explains that fMRI is a technique for determining which

parts of the brain are activated by different types of physical sensation or

activity, such as sight, sound or the movement of a subject's fingers. This

'brain mapping' is achieved by setting up an advanced MRI scanner in a special

way, so that the increased blood flow to the activated areas of the brain show

up on Functional MRI scans.

This introduction continues with a more detailed explanation of fMRI.

For example, it describes simple experiments, and also includes a link to a

high-resolution scan, which shows a brain from sagittal, coronal, and

transverse views. In the sagittal view, for instance, visitors can see

considerable detail in the brain, such as the relatively fine features of the

cerebellum. This page also leads to a rendered three-dimensional image that

shows an up close view of active areas inside a brain. Visitors can also view

an up close animation of the rendered brain, spinning continuously. Loading

the rotating images takes some time, but it's worth the wait.

When asked where visitors should go if they had time to see only part of the

site, Jezzard said, I suppose the examples of MRI images,

although we could do with updating them. Perhaps updated images

might further fascinate viewers, but the current images - see Recent MRI

Images - seem intriguing enough and more.

At the moment, says ,

the most popular part of the Web site is the SUSAN Web page, by a long

way. SUSAN stands for the Smallest Univalue Segment

Assimilating Nucleus, which the page calls algorithms that

cover image noise filtering, edge finding and corner finding,

and can improve MRI images. A link to the SUSAN principle gives visitors

a brief introduction to this process, along with explanatory diagrams.

says, This [part of our site] includes a report and software on

image-processing algorithms. Over the next few months more similar pages will

appear.

Some of the most exciting aspects of this site lie ahead. The

main research attraction, within 12 months, says,

will be online reports and even software which people can

download. The reports will cover MRI physics, analysis, and

applications. So add this site to your bookmarks and keep

coming back to see what and his colleagues add to their site - and to

our general understanding of how our brain works.

Mike May is the contributing Web Resources editor of HMS Beagle.

Up for Adoption

Pharmacogenetics and the Orphan Drug Law

by Mignon Fogarty

(Posted December 11, 1998 · Issue 44)

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Abstract

The demand for personalized drugs may grow as information increases about

individual genetic variation. Will orphan-drug status make this class of drugs

economically viable?

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In the near future - maybe five years, maybe ten, but definitely within my

lifetime - it will be technologically possible to make medical decisions based

on an individual's specific genetic makeup. I was convinced of this at a

recent symposium, Individual Genetic Variation: Implications of

the Coming Transformation of Medicine, sponsored by the

Stanford University Program in Genomics, Ethics, and Society. It was an

intellectual journey exploring the possibilities of what the future might hold

in the upcoming genomic age.

However, although any number of technologies might be possible, other

factors determine whether they become common practice. Aside from the obvious

ethical and legal issues associated with genetic testing, the

so what factor could prevent doctors and patients from

enthusiastically embracing the practice. Simply stated, it does patients

little good to know they carry a susceptibility gene for Alzheimer's or a

predictive gene for Huntington's if they can do nothing about it except look

forward to a dismal future.

The so-what factor could be decisively eliminated through pharmacogenetics -

the development of drugs tailored to the genotype of the patient (or the

patient's tumor or pathogen). Because such drugs are targeted very

specifically, they hold great promise of being both highly effective and safe.

Most major pharmaceutical companies have initiated pharmacogenetic drug

development programs in the last few years. The pharmacogenetic approach not

only targets clinical trials to the most responsive patient population, but

also may resurrect drugs that have failed clinical trials because of low

response rates in the general population.

One drawback, however, to the pharmacogenetic approach, generally

less publicized than the benefits, is that pharmacogenetic drugs usually are

targeted to smaller markets than are traditionally developed drugs. Given the

high cost of bringing a drug to market, estimated at $500 million per

successful drug, pharmaceutical companies typically analyze whether a drug

will reach certain sales goals before entering human clinical trials. If the

market for a drug is perceived as being too small, the company often opts to

discontinue development, even if things are going well in the lab. This

roadblock can be cleared if the drug with a small market is able to receive

orphan-drug status.

The U.S. Food and Drug Administration (FDA) created orphan-drug status to

encourage companies to develop certain drugs for rare diseases - diseases or

conditions afflicting fewer than 200,000 people. Companies that develop these

orphan drugs receive such generous perks as tax

breaks on clinical trials and seven years of marketing exclusivity. As noted,

the market for a drug developed pharmacogenetically could fall into this

category.

Herceptin is one such drug. Discovered by Genentech and just recently

approved by the FDA for the treatment of a subset of patients with metastatic

breast cancer, Herceptin is a monoclonal antibody directed against the

HER2/neu protein (a cell-surface receptor) that is present in all normal

tissue and overexpressed in some breast tumors. Before a woman receives

Herceptin, her tumor must be tested to ensure that it is a HER2/neu

overexpresser and that she is thus eligible for treatment. An estimated 30

percent of all breast cancer patients have tumors that overexpress the

HER2/neu receptor, and it is presumed (although not proven) that the drug will

be effective only in patients with HER2/neu overexpressing tumors.

Approximately 165,000 people in the United States have metastatic breast

cancer. Of these, 30 percent overexpress HER2/neu - clearly under 200,000. Yet

Herceptin was denied the orphan-drug designation. One does imagine that

treatment of breast cancer was not exactly the scenario the FDA had in mind

when creating this special class. Indeed, as more companies take a

pharmacogenetic approach to drug development for traditionally large disease

areas and these drugs advance in the pipeline, a dramatic increase in requests

for orphan drug status is likely.

While declining to comment directly on the Herceptin case,

Dreis at the Office of Orphan Products Development (OOPD) explained that

products are most commonly denied orphan-drug status because of disagreements

over how the target population is defined. In other words, companies tend to

carve markets up creatively so that they can claim fewer than 200,000

patients, and the OOPD scouts for reasons why the population should be larger.

Nevertheless, at first glance, Herceptin seems to qualify without question as

an orphan drug.

The OOPD defines a drug's patient population as the total expected treatment

population, not as only those patients whom the company identifies as eligible

for clinical trials, or for whom they can get an FDA indication. For example,

companies are often able to enroll in trials only patients for whom standard

therapy has failed; thus the drug is only approved for use with these

refractory patients. There is no scientific reason, however, why the drug

could not be used as first-line therapy. Trying for an orphan-drug

designation, companies may attempt to define the market as refractory patients

only, but the OOPD would include the entire potential patient population.

In the Herceptin case, the OOPD may have questioned whether Herceptin

legitimately could be restricted to metastatic patients. In fact, HER2/neu is

overexpressed in multiple cancers, not just in breast cancer. A potential

patient population thus enlarged may have resulted in the denial of the

orphan-drug designation. In any case, Dreis emphasized that the OOPD does not

treat pharmacogenetic drugs differently from other drugs. If a pharmacogenetic

drug were to be submitted that was scientifically appropriate for use only in

a small subset of a larger population, it would have no trouble achieving the

orphan-drug designation.

It would appear, therefore, that there is no immediate cause for concern

regarding the reluctance of the OOPD to grant orphan status for drugs targeted

to subsets of large populations. However, long-term questions remain. It is

hard to imagine that there would be no legislative response if within ten

years pharmacogenetic techniques take off, and half of all drugs developed are

orphans. The waters could be further muddied

over definitions of eligibility. If a drug is found to be significantly more

effective in one sub-population, but it also has minimal usefulness in the

general population, which group would the OOPD use in its calculations? There

has been speculation that HMOs are likely to limit coverage for such drugs to

the optimal population - one wonders if the OOPD would follow suit.

Another possibility is that the orphan drug designation will matter

less as pharmacogenetic approaches bring down the cost of drug development. It

has been hypothesized that the use of pharmacogenetics will increase

pharmaceutical companies' success rates in drug development. The $500 million

price tag for bringing one drug to market incorporates development costs for

4,999 other drugs that fail. The actual cost of developing a single drug is

closer to $75 million. With pharmacogenetics, although the market for each

drug may be smaller, companies may be able to produce more drugs for less

money. However, the opposite side of this coin is that pharmacogenetics may

actually increase the cost of running clinical trials, for example requiring

enrollment of more participants to sort out multiple combinations of relevant

genotypes.

Whether drug development through pharmacogenetics will be more or less

expensive than traditional techniques remains to be seen, as does whether

these drugs will be safer or more efficacious. Companies undertaking this new

approach to drug development are assuming a great risk. Nevertheless, drug

discovery through pharmacogenetics is logical and promising. If the advantages

created by the orphan-drug designation can encourage pharmaceutical companies

(and biotech companies) to take a pharmacogenetic approach to drug

development, I believe we will all benefit down the road as consumers of

highly directed therapeutics. If we are to eliminate the so-

what of genetic testing, we need more Herceptins. If the

orphan-drug designation can be a means to that end, I hope it is used often.

Mignon Fogarty is a pharmaceutical management consultant at Plan A, Inc. She

received her M.S. in developmental biology from Stanford University, where she

was an active member of the Program in Genomics, Ethics, and Society's working

group on genetic testing for Alzheimer's disease.

Andrzej Krauze is an illustrator, poster maker, cartoonist, and painter who

illustrates regularly for HMS Beagle, The Guardian, The Sunday Telegraph,

Bookseller, and New Statesman.