Pharmaceutical Manufacturers Association,
1100 15th Street, NW,
Washington, DC 20005.
Tel: (202) 835-3400           FAX-ON-DEMAND SERVICE: (202) 895-6060

****************************************************************************
The inclusion of this material in this area does not imply endorsement.
It is being reprinted for general information only.
****************************************************************************

THE DRUG DEVELOPMENT AND APPROVAL PROCESS
By Dale E. Wierenga, Ph.D. and C. Robert Eaton
Office of Research and Development
Pharmaceutical Manufacturers Association

In reviewing this report, it is important to keep in mind the realities
 of the drug discovery and development process. The U.S. system of new
 drug approvals is perhaps the most rigorous in the world. 
On average, it costs a company $359 million to get one new medicine from the laboratory to the pharmacist's shelf, according to a February 1993 
report by the Congressional Office of Technology Assessment.

The flow chart accompanying this article gives the success rate of drugs 
and the length of time each step takes. Overall, about one in five of the 
medicines that begins clinical testing makes it through the trials and 
the approval process.

New medicines are developed as follows:

Preclinical Testing.   A pharmaceutical company conducts laboratory and
animal studies to show biological activity of the compound against the
targeted disease, and the compound is evaluated for safety. These tests 
take approximately three and one-half years.

Investigational New Drug Application (IND).   
After completing preclinical testing, the company files an IND with FDA 
to begin to test the drug in people.  The IND becomes effective if FDA 
does not disapprove it within 30 days. The IND shows results of previous 
experiments; how, where and by whom the new studies will be conducted; 
the chemical structure of the compound; how it is thought to work in the 
body; any toxic effects found in the animal studies; and how the compound 
is manufactured. In addition, the IND must be reviewed and approved by 
the Institutional Review Board where the studies will be conducted, and 
progress reports on clinical trials must be submitted at least annually 
to FDA.

Clinical Trials, Phase I.  
These tests take about a year and involve 20 to 80 normal, healthy 
volunteers. The tests study a drug's safety profile, including the safe 
dosage range. The studies also determine how a drug is absorbed, 
distributed, metabolized and excreted, and the duration of its action.

Clinical Trials, Phase II.  
In this phase, controlled studies of approximately 100 to 300 volunteer 
patients (people with the disease) assess the drug's effectiveness and 
take about two years.

Clinical Trials, Phase III.  
This phase lasts about three years and usually involves 1,000 to 3,000 
patients in clinics and hospitals. Physicians monitor patients closely to 
determine efficacy and identify adverse reactions.

New Drug Application (NDA).   
Following the completion of all three phases of
clinical trials, the company analyzes all of the data and files an NDA 
with FDA if the data successfully demonstrate safety and effectiveness. 
The NDA must contain all of the scientific information that the company 
has gathered.

NDAs typically run 100,000 pages or more. By law, FDA is allowed six 
months to review an NDA. In almost all cases, the period between the 
first submission of an NDA and final FDA review time for new molecular 
entities approved in 1992 was 29.9 months.

Approval.   
Once FDA approves the NDA, the new medicine becomes available for 
physicians to prescribe. The company must continue to submit periodic 
reports to FDA, including any cases of adverse reactions and appropriate 
quality- control records. For some medicines, FDA requires additional 
studies (Phase IV) to evaluate long-term effects.

     Discovering and developing safe and effective new medicines is a 
long, difficult and expensive process. The research-based pharmaceutical 
industry will invest $12.6 billion in research and development this year, 
and that investment has been doubling every five years.

DRUG DEVELOPMENT AND APPROVAL PROCESS

It takes 12 years on average for an experimental drug to travel from lab 
to medicine chest. Only five in 5,000 compounds that enter preclinical 
testing make it to human testing. One of these five tested in people is 
approved.

                                         Clinical Trials
                              _____________________________________________
           Preclinical          Phase        Phase           Phase
             Testing              I            II              III
 _________________________     ____________________________________________
| Years |      3.5        | F |    1     |      2        |       3         |
|-------|-----------------| I |----------|---------------|-----------------|
| Test  | Laboratory      | L | 20 to 80 | 100 to 300    | 1,000 to 3,000  |
|Popula-| and             | E | healthy  | patient       | patient         |
|tion   | animal studies  |   | volun-   | volunteers    | volunteers      |
|       |                 | I | teers    |               |                 |
|-------|-----------------| N |----------|---------------|-----------------|
|       |   Assess safety | D |  Deter-  | Evaluate      |Verify effective-|
|Purpose|     and         |   |  mine    | effectiveness |ness, monitor ad-|
|       |  biological     | A | safety & |  look for     |erse reaction    |
|       |  activity       | T |  dosage  | side effects  |from longterm use|
|-------|-----------------|   |--------------------------------------------|
|Success| 5,000 compounds | F |                  5                         |
|Rate   |  evaluated      | D |           enter trials                     |
|_______|_________________| A |____________________________________________|

                                             Phase
                     FDA                       IV
     __________________________________________________
 F  | Years   |      2.5        | 12      |            |
 I  |---------|-----------------| Total   |            |
 L  |  Test   |                 |---------|            |
 E  | Popula- |                 |         | Additional |
    |  tion   |    Review       |         |   post     |
 N  |         |    process/     |         | marketing  |
 D  |---------|    approval     |         |   testing  |
 A  |         |                 |         | required   |
    | Purpose |                 |         |    by      |
 A  |         |                 |         |    FDA     |
 T  |         |                 |         |            |
    |---------|-----------------|         |            |
 F  | Success |       1         |         |            |
 D  |   Rate  |   approved      |         |            |
 A  |_________|_________________|         |____________|


GLOSSARY OF TERMS

application submitted - An application for marketing has been submitted by
                        the company to the Food and Drug Administration

cognition enhancer - A drug that helps improve aspects of Alzheimer's disease
                     and other dementias. Cognition describes high-level
                     brain functions, such as thinking and memory.

Phase I - Safety testing and pharmacological profiling in humans

Phase II - Effectiveness testing in humans

Phase III - Extensive clinical trials in humans