Corrections or additions?

This article was published in U.S. 1 Newspaper on December 8,

1999. All rights reserved.

Safe Drug Development

Just why is getting a drug to market so expensive? A

course for physicians who work in the pharmaceutical industry will

explain why. Explore the world of clinical protocols and

investigations

at a two-day seminar conducted by the Center for Professional

Advancement,

at the New Brunswick Hyatt, Thursday, December 9, 8:30 a.m. Cost $800.

Call 732-613-4500 or go to http://www.cfpa.com.

The course will cover government regulations pertaining to clinical

protocols with a focus on drug research. Denise T. Resnik, a

pharmaceutical industry consultant, will be presenting with

Forrest

Greenslade, founder of Intercare, a resource to the pharmaceutical

industry, and Edward H. Wolf, a statistics professor at Baruch

College, City University of New York.

First on the agenda will be how a clinical program is designed toward

the goal of getting a drug approved for a particular use or

indication.

Second will be the design of a protocol, the document that clearly

defines all of the parameters of investigation. "The protocol

specifies which drug is being investigated, who the subjects or

patients

are, and how they will be studied," says Resnik.

"The protocol also sets forth how long the patients will be

studied,

what doses of drug will be used, what kind of safety precautions will

be taken for the welfare of the patients or subjects, where the study

will be conducted, who is conducting the study, what the regulatory

environment is, and what the constraints are for conducting the

clinical

trial, within the program." The third consideration is managing

the studies where the protocols are being carried out.

The four phases in the approval process for a new drug:

Phase 1. After a drug compound has been tested in animals

and in "in-vitro" (studies conducted on a cellular level,

not requiring human beings as patients), a drug company will go to

the Food and Drug Administration (FDA) to request permission to study

a novel compound. If the FDA grants permission for further study based

on the strength of the animal investigations, it will grant approval

to study the drug in healthy normal volunteers.

Individuals participating in the first phase of clinical trials are

known as subjects, not patients. Dosage amounts are low. "Healthy

individuals are considered the most resistant to anything if there

would be a severe reaction to the drug. Phase 1 studies are done in

hospitals starting at a very low dose on a small number of patients.

In this phase what investigators are looking for is not efficacy

(whether

the drug works against a particular disease) but to get a sense of

the drug’s safety," says Resnik.

Phase 2. These studies are conducted in controlled

situations

with patients who have not responded well to other medications in

their class. Resnik uses a fictitious new drug for hypertension to

illustrate her point. "Many hypertensive patients are on multiple

drugs and their blood pressure is still not controlled. A Phase 2

study will afford an opportunity for that patient to see if a

medication

works — since no medications that work for everybody."

Phase 3. At this point, the safety data of a drug is known

and some efficacy information is available. Phase 3 studies are much

broader studies involving several thousand patients across the

country.

A large number of people with a disease, like hypertension, would

involve between 5,000 and 10,000 patients. Much rarer diseases require

Phase 3 studies with fewer patients. These studies let many patients

and many physicians get experience with the drug, and they may be

conducted in outpatient clinics and private doctors’ offices.

The big concern is whether a drug may have a very small instance of

severe side effects, occurring very infrequently, say one in 10,000

cases, says Resnik. "In controlled clinical studies, you may not

have 10,000 patients. The severe side effect may not have occurred

or may have occurred only once, and it may not be clear that the side

effect was caused by the drug. But when the drug gets approved, then

one in 10,000 is a very large number. The diet drug combination

Phen-Fen

and Thalidomide fall into this category."

Phase 4. After the drug has been approved, very often

the drug company wants to compare its drug to the benchmark drug in

that class of compounds that have been approved. So head-to-head

competition

is usually done in Phase 4.

How is the decision made as to who participates in clinical

studies? It begins with the doctors. "Physicians are provided

with a fair amount of information to make a decision about whether

they want to participate in a study. Studies are always done very

carefully, with the patients’ well-being in mind. The patient is given

all the information in order for them to made an intelligent decision

as to whether to participate in the study or not," says Resnik.

There is another layer of protection for study participants. An

institutional

review board is usually convened at the hospital or university where

the study is being conducted. Before an individual investigator can

conduct a clinical study, the institution or medical center where

the study is to be conducted has to approve the study. There is a

written consent that a patient has to read and sign indicating the

information known about a drug at the time of the study, and what

the possible side effects are. The patient provides emergency contact

information. "Signing the document does not mean they have

abdicated

any rights that they would have. If the patient has a relationship

with the physician, they will be more willing to participate,"

says Resnik.

What about patients receiving money as an enticement to participate

in a clinical study? We have all heard the advertisements on the radio

for medical trial volunteers that offer some sort of incentive.

"In

the old days, study subjects were inmates, and around the 1960s it

was decided that these were people not making decisions on their own

free will — that they were indeed being coerced." Typically,

out-of -pocket expenses will be reimbursed if a patient has to take

a bus or a taxi, but lost wages are not. "Nobody wants to leave

the impression that patients can make money through their

participation

in the tests."

Based in East Brunswick, with a European headquarters in the

Netherlands,

the Center for Professional Advancement was established in 1967 by

Charles Bendel. It offers intensive two- to five-day courses at a

post graduate level for scientist and engineers. Instructors emphasize

practical technlogy rather than theory. The CFPA courses, in 19

subject

areas ranging from food technology to plant engineering, offer

accreditation

by many trade organizations. In particular, more than 130

pharmaceutical

courses are offered annually through the CFPA’s sister organization,

the Institute for Applied Pharmaceutical Sciences. The CFPA’s favored

New Jersey venue is the New Brunswick Hyatt.

The daughter of an engineer and a medical school administrator, Resnik

has a BA in biology from Clark University and an MS in pharmacology

from Northeastern University; she began her career at Harvard Medical

School in 1976. She has worked at Astra Pharmaceuticals in animal

and clinical research and at Ives Laboratories (American Home

Products).

For Pfizer she managed a cardiovascular program and integrated safety

sections for regulatory submissions. In 1982 she established her

consulting

practice in Yonkers, where she lives with her husband and two teenage

sons. Resnik traces her interest in science to the Bronx High School

of Science and summer internship programs at Columbia College of

Physicians

and Surgeons doing pharmacology research. "I found that I like

working with animals more than I liked working with test tubes."

Resnik feels that compared to days gone by, the patient has become

the central figure in the entire drug approval process. "It used

to be much more the investigator, and I think now patient safety and

the effort in making information available to them is much

greater."

— Jeff Lippincott


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