BACKGROUND
Prior to 1938, a vast range of pills, creams, potions, and extracts could be administered to the public for the general purpose of treating medical conditions. These treatments could and were dispensed by non-medical sources, as well as by properly certified medical practitioners. However, there was very little attention prior to this time to the determination of the potential dangers, or proven effectiveness, of these treatments. A particular drug or pill need not be proven safe nor effective to be dispensed to the public at large. An incident occurred, however, that changed forever the way drugs are prepared and disseminated in this country. In the 1930s, many people died from what appeared to be a contaminated supply of "sulfa" drugs, which were used at that time as an antibiotic. Because of the justifiable pubic uproar over this incident, the U.S. Congress for the first time got seriously involved in the drug business.

LEGISLATION
In 1938, the Food, Drug and Cosmetic Act was passed and became the law of the land, and in effect established the Food & Drug Administration (FDA). The primary focus and legal responsibility of this body was to determine and test drug safety. Whether or not a particular drug was effective in its intended medical purpose was not a central issue, nor the legal responsibility of the FDA. However, in 1962 the Food, Drug and Cosmetic Act was significantly amended to address issues of product effectiveness. Among the changes included in the legislation was the provision that all experimental drug studies must be registered and tested according to an IND (Investigational New Drug) format. This format dictated that any drug must have undergone preliminary testing on animals or other non-human test system to determine whether the particular drug was safe and potentially effective for the intended purpose. For the first time, drugs had to show documented evidence of relative safety and effectiveness before they could be used in the human body. Once the preliminary IND testing has been accomplished, the test data are then submitted to the FDA in what is called a New Drug Application (NDA). If the FDA determines that the drug appears to be both safe and effective, permission is then given the applicant to initiate a series of limited, and highly controlled human trials. First, healthy human volunteers are recruited, which is subsequently followed by including patients who may benefit from the particular drug under study. If after the completion of the human testing a particular drug exhibits relative safety and effectiveness, the FDA then formally approves the drug for public use. In addition to providing a formalized system of drug testing, the 1962 amendments to the original FDC Act of 1938 also specified that drugs introduced between 1938 and 1962 must be reevaluated according to the new FDA guidelines to determine both verifiable safety and effectiveness. Furthermore, the 1962 amendments also for the first time regulated product labelling, as well as product advertising, in major attempts to infuse truth and accuracy within the commercial and medical spheres.

DEVELOPMENT AND TESTING OF NEW DRUGS
Today, the discovery, development, testing, and marketing of a single, new drug may cost between $50 to 100 million dollars over a 7- to 10-year period. However, since the dawn of civilization, a diverse array of relatively common and inexpensive extracts (from mineral, plant, or animal sources) have been used with varying degrees of success to treat the infirmities of mankind. Together these extracts represent an immense pharmacopoeia (or drug compendium) from which to treat an ailment. But as mentioned above, prior to 1938 there was little if any assurance that any of these known drugs or extracts were safe to use or were actually effective. Figure 1 below briefly outlines the current approach to drug development and testing as regulated now by the FDA.

OVERVIEW OF FDA APPROVAL PROCESS

DRUG SELECTION PROCESS: The choice of drugs to develop is based upon a combination of medical, scientific, and economic factors.

            Health Needs: Is there a need for a particular drug for a specific illness? Is the illness common or is it relatively rare? For example, would the relatively rare disease come under the Orphan Drugs & Diseases category where the FDA has a separate but expeditious approval process?

            Research Observations: What do we know about the biological activity of the drug in question? For example, has the drug been shown to increase or decrease some particular function of a cell? a tissue? an organ? a body system? Can the drug be isolated from natural products, such as plants, fungi, animal tissues, minerals? Can the drug be synthesized in the laboratory by either chemical or biological means such as recombinant DNA technology? In 1970, over 126,000 substances were either isolated or created, each of which has the potential of being a drug candidate.

            Company Policy: Does the applicant company have the interest and resources to develop a new drug candidate? Is the potential market small or large? What are the limits of the company's capabilities? Does the company have the resources to involve itself in each stage of the approval and marketing process? For example, does the company have the staff and resources to deal with the scientific issues of animal testing, toxicology, quality control, and chemistry? Does it have the medical aptitude and administration to run and coordinate the human clinical trails? What are the capacities of the company to package, advertise, and market the new drug?

PRECLINICAL STUDY:

            Chemical Characterization: Highly-trained personnel using modern lab facilities and equipment characterize the chemical properties of the drug in question. For example, what is the chemical nature of the drug? Is it similar to pre-existing compounds with other known properties? Can the drug be synthesized in the lab, or must it be extracted from some natural source? Is the compound soluble in water, or will it dissolve in some fatty substance which might make it pass through the skin?

            Animal Testing & Screening: Concurrently, the drug entity is rigorously tested for its biological activity on living cells and animals.
                    In Vitro Screening: Isolated cells, tissues, and organs provide an in vitro model system to initially determine the biological activity of the drug. For example, many specific and fundamental questions can be answered, such as does the drug kill cells, cause mutations, inhibit growth, easily accumulated or difficult to enter cells, and what specific process inside the cell is affected by the drug?
                    In Vivo Screening: While it would be ideal if not desirable to only use isolated cells or a computer simulation for the preclinical study of a drug, it is only with intact animals that verifiable biological activity can be assessed. Typically for this purpose, a minimum of 2 or 3 mammalian species are selected as the in vivo screen; for example, rodents like mice, rats, or guinea pigs are used in the initial screen to be used later in combination with other species such as dogs and monkeys.

                    A reliable and reproducible animal screen should be able to answer a series of questions fundamental to the FDA approval process, which is based upon demonstrable safety and effectiveness. For example, a good in vivo screen should be able to determine an optimal administration route (IP, IV, oral, IM?), an optimal dosage with fewest side-effects, the fate of the drug in the body (is it accumulated within the targeted tissue or organ?), and the side-effects of the drug (minor, or carcinogenic?). On the other hand, a good in vivo screen should be able to yield evidence of efficacy; that is, does the drug alter some particular component of an illness for which it is initially intended? Often this latter issue of proving effectiveness in the preclinical phase of study is more of a hurdle than proving safety; this is the case because there are very few if any animal models which replicate the human disease in all aspects. Hence, the animal studies only provide a foundation in which to enter into the later human clinical phases of assessment.

         Limitations & Precautions of Preclinical Study

1. Most human ailments do not have animal models
2. Useful screens have small % false positives and negatives
3. Useful screens rank active drugs.
4. Cause of large % of diseases not known.
5. Goals of diseases such as mental illness not clear.
6. Single vs. chronic dosage effects need to be known.
7. Multiple drug effects need to be known.
8. 22 of the 45 most common side-effects are unlikely to be recognized in animal screen (i.e., nausea,  nervousness, lethargy, heartburn, headache, depression, stiffness, etc.)
9. Margins of safety need to be statistically achieved (i.e., ED50-median effective dose, TD50-median toxic dose, and LD50-median lethal dose; Note-large TD50/ED50 and LD50/ED5 ratios indicate large margin of safety, and low ratios reveal low margins).
10. Reliable areas of drug screening include antibiotics, diuretics, and blood pressure and nerve impulse drugs; less reliable areas include behavioral modifications.
11. Cancer causing drugs are usually discontinued.
12. Long-term studies need to be included, to establish potential effects during pregnancy and fetal development.
 
 

IND APPLICATION TO THE FDA: The formal application is a major body of research reflecting significant time, money, personnel and research ideas. At the minimum, each IND application contains the following:

1. Chemical and biological activities of the proposed drug
2. Dosage form specifications for humans
3. Quality control details
4. Description of company equipment, facilities, and personnel
5. Scientific qualifications of the clinical investigators
6. Specific details of the clinical protocol to be followed (e.g., dosage, route, duration, clinical & laboratory test procedures).
• clear statement of objectives
• suitable method to select volunteers
• test groups arranged to avoid bias
• test and control groups equally weighted to allow for variables such as gender, age, disease status, other medications
• double-blind drug administration and testing
• include placebo controls where an inert chemical substance is substituted for the drug
• clear procedure to evaluate drug effects
• procedure for the statistical evaluation of drug effects
• uncontrolled or partially-controlled trials are NOT acceptable

CLINICAL STUDY:

Phase 1 - The initial cautious trial involving a relatively small number of normal humans. Trial is usually short (1 to 6 months) where the drug's biological activity and effects on target or gans are determined (e.g., kidney, liver, bone marrow, and heart).

Phase 2 - More detailed observations of drug effects on normal volunteers, as well as the initial testing on diseased patients. Dosage range is established. Critical observations of the disease process are made in relationship of the new drug candidate. In addition, long-term chronic toxicity studies on laboratory are initiated.

Phase 3 - Broad clinical trials designed to determine whether the drug is of clinical benefit in the disease state or syndrome. Hospital-university specialists are recruited to work along with company physicians and scientists in this expanded phase. Final dosage forms are established. Risk/benefit ratio is assessed, if possible. Long-term chronic toxicity studies with lab animals in Phase 2 are reviewed and provide a basis on which to study the drug's effect on  reproduction and fertility; additional animal studies are conducted to determine the drug's potential to induce cancer or other abnormalities in the fetus. If the drug has use in children or the elderly, Phase 3 study must also include safety and effectiveness determinations at various ages.

If after the completion of the Phase 3 trial, a drug is believed to be safe and effective, the company then submits a new drug application to the FDA for formal approval and license.

NEW DRUG APPLICATION: The formal application to the FDA is another significant body of scientific work which includes the following completed results:
                        - Phases 1, 2, & 3
                        - Long-term toxicity studies of animals
                        - Effects on fertility & reproduction
                        - Special studies on young animals
                        - Any requested supplementary study

If the drug is approved by the FDA, the company can proceed to make this drug available to the public through normal channels of distribution for prescription drugs.

PHASE 4 TRIALS: Post-marketing clinical trials begin to test the long-term effects of the newly-approved drug. Usually a new drug is scrutinized closely for one to two years after approval but, in effect, all drugs are continuously monitored by the FDA for many years.