A Pill Is Born: Let a new drug show you how it (and other drugs) came to be

[Guest guest]

A Pill Is Born: Let a new drug show you how it (and other drugs) came to be.

By Downs WebMD Feature Reviewed By Louise Chang, MD

http://www.webmd.com/content/Article/125/115967.htm

I'm just a pill. Yes, I'm just a pill. And I'm sitting here ...

Oh, hi. My name is Nupil. I'm a new drug, or at least I hope to be. Right

now, the FDA is deciding whether to approve me. See that big office

building? That's the Center for Drug Evaluation and Research. It's as

important as it sounds. The fate of all new medicines that want to be sold

in the U.S. is decided here.

Inside, FDA reviewers are carefully examining all the information that's

known about me and talking it over together. They sure are busy. There are

more than 100,000 pages of data, and it will take a team of reviewers

several months to review. I guess I'll just have to sit here and be patient.

How did I end up here? Why, I'm glad you asked. That's an interesting story.

A Molecule Stands Out

About 12 years ago, I started out as a molecule, one of thousands

researchers created in a laboratory. The scientists screened us, one by one,

looking for some special properties. I was added to some cells in a test

tube to see what I would do.

It was a long time ago, but I remember I liked almost everything about those

cells, except for one awful little enzyme -- an enzyme that could make

people sick. That enzyme really annoyed me, so I blocked its production, but

left everything else alone. Well, the scientists were plenty pleased. I only

did what came naturally to me, but now I know it was exactly what they were

hoping for. I didn't have a name yet, just a number: ABCD-523.

The Testing Begins

The scientists then started testing me in laboratory rats. The purpose of

this was to see if I did the same thing in live animals that I did in the

test tube. They also wanted to know if I had any toxic effects. They

measured how I was absorbed and passed though the animal's body.

As Alan Goldhammer, PhD, associate vice president of regulatory affairs for

the Pharmaceutical Research and Manufacturers of America (PhRMA), told me,

" It's easy to identify lots of things that work inside a test tube. " The

challenge is finding something that works in a living body.

The results of the experiments were good. It's pretty rare for that to

happen. Only one in 50 promising compounds will pass these tests. The vast

majority don't work as expected, or they prove to be too toxic.

Meanwhile, researchers studied how I could be made into a pill. They wanted

to make sure I wasn't too fragile -- that I could exist within a wide range

of temperatures without degrading. They also looked at how difficult it

would be to manufacture me on a large scale. It seems I'm not fussy about

the weather, and I'm not impractical to make in bulk.

Many Hurdles to Clear

I had been through a lot of experiments already, but I still had a long way

to go. To move to the next step, the drug maker sponsoring me needed the FDA

to approve tests in humans. The company showed the FDA how well I performed

in the animal tests and explained how they would study me in people, in

what's called a phase I clinical trial.

With a thumbs-up from the FDA, the researchers started looking for people to

try me. They needed 20-100 healthy volunteers. The purpose of the study was

not to see if I worked, but rather to test my safety and side effects in

humans.

Some people had mild side effects, like headaches and upset stomachs. Hey --

no one's perfect! I'll bet you've given someone a headache before. The fact

is, all drugs cause side effects sometimes. But I didn't cause any serious

problems for the people in this study.

I Got a Name

I got my " nonproprietary " name around this time: noperalate. That's my

generic chemical name, the one scientists use when they're talking about me.

It's different from my brand name, which was given later by the companies

that will sell me. A group called the United States Adopted Names Council

assigns generic names to new pharmaceutical compounds. I never thought

WBMD-523 was really me, so I was happy to be called noperalate.

So far, so good. But in the next step, a phase II trial, I had to prove that

I worked. Up to this point, I only had to show that I was likely to work.

Now I had to perform. The researchers wanted to see that I could inhibit

that enzyme reliably, in a larger number of people -- around 100 to 500 --

without harming them. I would also be compared to a placebo, that is, to a

dummy pill. The researchers and test subjects wouldn't know who took me and

who took the placebo until after the study was done.

Seven years had passed since I was first noticed in the lab and chosen for

development. A lot of time, brainpower, and money had been invested in me,

but there was still a chance I might fail. Clinical trials are kind of like

the Olympics. Often very promising athletes make it to the games but

ultimately don't measure up. About four out of five drugs don't make it

through clinical trials.

Not everyone was cheering me on, either. Many scientists in the field were

skeptical. They thought the early study results weren't convincing. By the

time the phase II studies wrapped up, however, a lot of people were getting

excited. It was clear I would go on to phase III.

The final phase of clinical trials lasted four years. I had to be tested on

thousands of people, and show beyond a doubt that I really worked and that

my benefits far outweighed any potential problems.

The Review

So, that brings us up to date. A few days ago, my sponsor filed a " new drug

application " with the FDA. That's a formal request for the FDA to review a

drug.

Like I said before, the drug company had to turn over every bit of

information it had on me. That includes data from all the test-tube

experiments, animal studies, and all the clinical trials.

I was curious about how the review process works, so I asked Kweder,

MD, deputy director of the FDA's Office of New Drugs. The FDA has many

different experts on staff to review various parts of the application. They

look at all aspects of it, not just the study data.

" For example, there will be a chemist who is reviewing the entire

manufacturing and quality control system, " Kweder explains.

Other ingredients will be mixed with me to make pills. Those ingredients

have to be safe, too, and they can't react with me in a way that changes how

I work.

Then there are the other experts:

Physicians

Toxicologists

Statisticians

Microbiologists

Pharmacologists

They're all looking for problems with the evidence my sponsor submitted.

They sometimes ask for more data, for example, from a study done over a

longer time or one that includes more test subjects. I'm confident we have

given the reviewers all they need, though. My sponsor has kept in touch with

the FDA throughout the clinical trials, and even asked how to design studies

to best meet the FDA's requirements.

The reviewers don't have to rely entirely on the sponsor's interpretation of

the data, either. Because they have access to all the study data, they can

do their own analysis if they see fit.

" That is what makes the U.S. review system so unique, " Kweder says. " No

other countries do that. "

The application also includes proposed label information: instructions on

how to use me, what I'm supposed to do, and what side effects and safety

issues I have. Often the FDA wants to tweak what will be printed on the

label.

Advisory Committees

In some cases, but not mine, the FDA will convene an advisory committee.

Clinical trials may reveal that there are serious risks to be balanced with

the drug's benefits, or there may be doubt about whether the drug really

works. " Even before the application comes in, we have some sense of what the

studies show, and we know that this is going to be a close call, " Kweder

says. " Those close calls are a common reason to take something to an

advisory committee. "

An advisory committee may also be useful if a drug is controversial, or if

it's so new that nothing like it has ever been approved before. The

committee is made up of independent experts. Its recommendations are weighed

seriously, but the FDA is not legally required to follow them.

Finally, every reviewer will write a report. A top official will consider

the reviewers' recommendations and make a decision: " approved, "

" approvable, " or " not approvable. "

An approved drug has a green light to be marketed that very day. For an

" approvable " drug, final approval may depend on the drug maker meeting

certain conditions, such as providing additional data. A drug that's " not

approvable " is essentially shot down.

In 2003, it took the FDA about 17 months, on average, to finish a review.

But some drugs get a priority review. That's when there is an urgent need

for it to reach patients as soon as possible. Many drugs developed to treat

AIDS had priority reviews, for example. " For priority reviews, we have a

six-month review clock, " Kweder says.

The FDA also has to approve a drug's brand name, which the drug maker

invents. A brand name can't be misleading, self-promoting, or too similar to

an existing drug name. A name like " Curezital, " or " Lipitar " would never be

allowed.

If I'm approved, I'll be sold as Nupil® (noperalate).

I'm really excited for that day. Hopefully I won't have too long to wait.

The drug maker's factories are poised to swing into production; ad campaigns

are prepared; and legions of salesmen are ready to fan out across the

country as soon as the approval letter arrives.

The Rest of the Story

There's one last thing I want to mention before you go. My story won't

necessarily end with approval and marketing. The drug maker and other

researchers will keep on studying me. Someone may see a new use for me, in

which case I'll have to go through the approval process again to be marketed

for that use. For instance, drugs first developed to treat a certain kind of

cancercancer have later been put to different uses. " There are many cases in

the development of cancer drugs where companies will be studying new

indications throughout the life cycle of the drug, " PhRMA's Goldhammer says.

Of course, you also know that several drugs have been pulled off the market

recently because of safety problems. Others have had special warnings added

to their labels. Constant testing and careful attention to reports from

doctors and consumers using prescription drugs sometimes uncovers problems

that can't be ignored.

Nevertheless, I believe I'll end up helping millions of people for many

years, until a better treatment comes along to replace me. Wish me luck!

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SOURCES: Kweder, MD, deputy director, Office of New Drugs, Center for

Drug Evaluation and Research, FDA. Alan Goldhammer, PhD, associate vice

president of regulatory affairs, Pharmaceutical Research and Manufacturers

of America (PhRMA). FDA web site: " The Beginnings: Laboratory and Animal

Studies. " FDA web site: " The FDA's Drug Review Process: Ensuring Drugs Are

Safe and Effective. " PhRMA web site: " Research and Development. "