Allen Cato

Cato Research Ltd., Durham, North Carolina Lynda Sutton

Cato Research Ltd., Durham, North Carolina Allen Cato III

Cato Research Ltd., San Diego, California

It may be easier for a camel to pass through the eye of a needle than it is for a new chemical entity to reach the marketplace. Drug development is a long and costly process fraught with tribulation. The tortuous pathway traveled by a new drug from synthesis to sale requires the constant percolation of data through rigorous clinical and regulatory filters. This process is complex, and success cannot be guaranteed. The ability to always predict which drug will have all the qualities necessary to gain regulatory approval and to be marketed remains as elusive as a camel in a needle's eye.

New drugs do make it from discovery to the market, but only at the approximate rate of one in every 10,000 new molecules synthesized. It is a long, costly, and extremely risky process involving a steady progression through multiple stages, with treacherous decision points along the way. Most of all, it is a process involving the constant percolating of data through rigorous filters strewn with tribulations and complicated by the difficulty of making decisions that affect human health when all the facts are not known.

Despite the daunting challenge of bringing a new drug from discovery to market, new medicines continue to be developed that may have a significant effect on our health. You may wonder, ''What has medicine done for mankind lately?'' In the United States, the adult life expectancy increased by nearly

30 years over the last century, primarily because of the availability and management of vaccines and immunization schedules, antibiotics, and sanitation measures. As evidenced by the following statistics from the Centers for Disease Control (CDC) (1), the development of vaccines has had a major impact on our health:

Smallpox killed an average of more than 1500 people per year between 1900 and 1904; it is now eradicated worldwide, and children are no longer vaccinated against the disease.

Polio struck more than 16,000 people annually in the early 1950s; today, it has been eliminated from the Western Hemisphere.

During the past 50 years, vaccines also have been responsible for drastically reducing the morbidity and mortality from measles, Haemophilus influenzae type b (Hib), diphtheria, pertussis, tetanus (DPT, typically administered together), hepatitis B, and chicken pox. In addition to improved health, substantial economic benefits have been realized. For example, the CDC estimates that the United States recoups its investment in the eradication of smallpox every 26 days. Despite the obvious advances of modern medicine, many patients still have infectious, chronic, or genetic diseases and will benefit from the research of today finding the effective treatments of tomorrow. Pharmaceutical research targeting the top 12 major medical needs exceeds $645 billion annually in direct medical expense and lost productivity. The diseases included in this figure are Alzheimer's disease, arthritis, asthma, cancer, congestive heart failure, coronary heart disease, depression, diabetes, hypertensive disease, osteoporosis, schizophrenia, and stroke (2). Just as it did 50 years ago, innovation continues today to bring us new knowledge through genetic research, molecular biology, and enhanced computer technology. This is the promising future of drug development.

However, developing the vaccines or any of the drugs potentially used to treat the indications listed above is a substantial undertaking. To comprehend clearly the magnitude of the drug-development process, it is useful to consider the many different areas involved. Figure 1 depicts some of the key disciplines contributing to the process. Information from each of these areas feeds into a common funnel with a filter, where multiple decisions must be made progressively regarding the compound's survival, or lack thereof.

Figures 2 and 3 illustrate the process broken down into preclinical and clinical segments. Keep in mind, however, that the process is a dynamic one. The various disciplines listed are constantly interacting, and the entire flow of data requires constant feedback and fine tuning. For example, a compound's tox-icity, however slight, may be considered to outweigh its pharmacological effect. This information would be given by the toxicologist to the chemist, who would make other compounds with slight modifications, attempting to retain the pharmacological effect while decreasing or eliminating the toxic effect.

Figure 1 Overall drug development.

Once a compound has been synthesized in the lab and tested in animals, an Investigational New Drug (IND) application is submitted to the U.S. Food and Drug Administration (FDA), requesting permission to initiate clinical studies of the drug in humans. The IND summarizes the preclinical work and includes the first clinical protocol. It is not until the drug has been experimentally tested in humans under controlled conditions (after Phase III) that the company may file an application to market the drug (a New Drug Application [NDA] if filed with the FDA, or a Marketing Authorization Application [MAA] if filed in Europe). The application summarizes all preclinical (safety and efficacy in animals), clinical (safety and efficacy in humans), and manufacturing data known about the drug, and requests permission to market this new drug.

Figure 4 illustrates the attrition ratio of a new chemical entity as it works its way from synthesis through preclinical development to IND, and subsequently through clinical development to NDA. An attrition ratio of 10,000:1 (not considered good betting odds by most people) is the bad news. The good news is that 95% of all drugs for which an NDA is submitted are ultimately approved for marketing.

Clinical Development Funnel
Figure 2 Preclinical drug development.

The tribulations involved in getting a compound through all the decision funnels is a costly process, as seen in Fig. 5. The cost per new drug approved is growing steadily every year. On average, the cost in 1987 was $231 million per approved drug, but by 1998 that figure had increased to $500 to $600 million or more (3). As figures demonstrate, the costs are approximately split between preclinical and clinical development. This average cost represents the expenses in maintaining a full preclinical and clinical research unit for each new drug approved. It perhaps makes it easier to understand why large pharmaceutical companies are sometimes reluctant to pursue development of new drugs likely to have a sales potential of less than several hundred million dollars per year (see Chapter 13 on orphan drugs for a more thorough discussion). This reluctance on the part of large companies leaves opportunities for smaller companies to develop new drugs with smaller potential earnings. If successful, these smaller companies may then grow into large pharmaceutical companies and provide additional treatments that otherwise might have never been made available to patients in need.

Figure 3 Clinical drug development.

Drug development is not only a costly process, it is time-consuming as well (Fig. 6). Although all pharmaceutical companies and many doctors and patients would like to see the FDA approval times reduced, it is obvious that if approval times were substantially reduced, it would still require many years for the development of a new chemical entity. In fact, the average time of review by the FDA has decreased over the past few years, but the actual time to market has remained about the same because the clinical development time has increased (3,4).

The lengthy time required for drug development markedly reduces the patent life remaining after drug approval for marketing (Table 1). The shrinking patent protection afforded newly marketed drugs is one reason patent applications are usually not filed with the first synthesis of a new compound. Pharmacological and toxicological testing is usually performed before a patent is filed; it usually takes a year or two before the patent is accepted and officially issued. Therefore, the remaining patent life is still slightly greater than the original patent life minus the total developmental time (Fig. 6). The delay in patent filing helps explain why pharmaceutical companies are somewhat secretive about their preclinical research process. The danger in delaying filing for a patent is the risk that another

Figure 4 Attrition rate for overall drug development (average).
Pharmaceutical Development
Figure 5 Average cost of overall drug development.
Figure 6 Average time required for overall drug development.

Table 1

Average Effective Patent Life (from NDA approval date)

Patent life without

Patent life with

Year

extension

Waxman-Hatch extension

1966

13.6 years

NA

1979

9.5 years

NA

1984

9.2 years

11.1 years

1987

10.4 years

12.2 years

1995

7.8 years

11.1 years

NA = not applicable—before Waxman-Hatch enacted.

Total patent life (from patent approval date) Before June 8, 1995 After June 8, 1995

20 years 17 years 20 years

NA = not applicable—before Waxman-Hatch enacted.

Total patent life (from patent approval date) Before June 8, 1995 After June 8, 1995

20 years 17 years 20 years company or individual may discover the same treatment modality and be the first to file the patent.

Having looked at an overview of the drug development process, it is appropriate to explain how the decision filter works. In preclinical testing of a drug, a toxicological screen is performed with the intent of demonstrating not only a safe dose, but also the toxic effects. In general, doses of drug that will induce significant toxicity are administered to animals. Some types of toxicity are more acceptable than others; for example, if animals were to die unexpectedly and sporadically throughout several dose ranges without less severe, prodromal preceding toxicities, administration to humans would be prohibitive. There would be no way to assure that the same phenomenon (e.g., unexpected death) would not occur in humans.

How, then, are such judgments made regarding ''acceptable'' potential toxicities? As an example, a great need exists for new antipsychotic compounds. One such compound was shown to induce lipidosis in the rat after 3 months' exposure, though no such effects were seen in the dog (Table 2). Lipidosis is the deposition of fat in cells, and if carried to an extreme, can kill the cell. In particular, lipidosis-induced vacuoles in the rat were noted in the spleen, liver, and lymphocytes. Because the anticipated dose in humans was 5-10 mg/kg per day, this finding in rats at 12-100 mg/kg per day was a cause of concern. The compound looked promising if the lipidosis problem could be solved. To help with the decision, a review of the literature was performed. As shown in Table 3, only one marketed compound known to have caused lipidosis in rats also had a similar effect in humans. Thioridazine (Mellaril), a widely used compound in humans, was used as a positive control (Table 2). In addition, many other compounds have been shown to induce lipidosis in rats but not in humans (5). These agents, like our compound, are mostly for central nervous system diseases. A decision had to be made to proceed to humans or to stop developing the compound. What would you do?

The actual decision made in this case was to proceed to clinical trials. The reasoning was as follows:

Table 2 Preclinical Toxicology (Anticipated dose in humans: 5-10 mg/kg/day)

Dose

Time

Species

Drug

(mg/kg/day)

(months)

Effect

Rat

Inv. drug

12-100

3

Lipidosis

Rat

Mellaril

24

3

Lipidosis

Dog

Inv. drug

20

3

No effect

Dog

Inv. drug

40

3

Increased liver weight

Table 3 Drugs Known to Induce Lipidosis

Drug

Therapeutic action

In animals

Imipramine (Troframil) Fenfluramine (Pondimin) Thioridazine (Mellaril) Chlorcyclizine (Fedrazil) Zimelidine

Antidepressant Anorectic

Antipsychotic Antihistamine Antidepressant

In humans and animals Chloroquine (Plaquenil)

Antimalarial

1. Other marketed compounds are known to induce lipidosis and lymphocyte vacuolization in laboratory animals, but not in humans.

2. A peripheral marker is available. Although the drug may induce fatty vacuolization in the liver, a liver biopsy is not needed to detect it because the process, should it occur, would likely be detected in the lymphocytes.

3. The cytoplasmic vacuolization observed in animals was found to be reversible when the drug was discontinued. Should lipidosis occur during clinical trials, subjects or patients should undergo a full recovery when the drug is discontinued.

The drug was subsequently tested in humans at dosages as high as 500 mg/day for up to 6 weeks. Blood was routinely drawn for careful examination of the lymphocytes and liver chemistries; no toxic effects were discerned. The compound ultimately failed the decision filter, however, because of its lack of efficacy.

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