Drug (Therapeutic) Evaluation

Clinical trial

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In the drug development process, The Food and Drug Administration (FDA) in the USA requires that all potential drug treatments pass through several phases of experimentation and review before they are deemed safe and effective in treating a disease, such as Alzheimers. This approval process usually takes more than 10 years, from start to finish, and involves the following steps:

Preclinical Testing - Phase I
Clinical Trials - Phase II
Clinical Trials - Phase III
Clinical Trials - The New Drug Application (NDA)
FDA Review
Continued Studies

Preclinical Testing

One purpose of preclinical testing is to establish a "mechanism of action" for the drug compound, which involves a close examination of how the drug works. Test tube studies are performed to seek out potential benefits of the drug compound and to learn how the drug interacts with other substances within a test tube (in vitro). Drug compounds for Alzheimers are tested against various processes thought to be involved in the disease, such as accumulation of amyloid, the presence of apolipoprotein E4, or deficiencies in certain neurotransmitters. During these studies, researchers are looking for both effective and potentially harmful interactions between the drug and other molecules.

Next, the drug is tested in animal studies in order to determine its ability to achieve desirable results (preclinical efficacy). Used as partial models for Alzheimers disease, both aged animals and those suffering from neurological defects are tested to see how the drug acts within a living system (in vivo), and how a living system, in turn, reacts to the drug. Varying doses of the experimental drug are administered to test the drugs ability to improve performance and behavior in animals, and to reveal harmful side-effects that may occur. Further testing also is done to determine the toxicity of the drug, whether it may be cancer-causing, or whether it is likely to cause genetic mutation within living systems. Based on results from these studies, the drug compound may be altered slightly to make it more effective. Animal studies are an integral part of most drug studies because they help researchers predict reactions in living organisms before the drug is given to humans.

Preclinical testing of a new drug compound can last from one to six years, because extensive data needs to be gathered and analyzed before the drug moves into human studies. If data proves that the experimental drug may be effective in treating a specific disease, the pharmaceutical company will file an Investigational New Drug Application (IND) with the FDA. The IND gives specific details of all experiments completed during the preclinical testing phase, including the chemical structure of the drug compound and how it is manufactured. The IND must also explain how the new drug works in living systems, how it may be beneficial in treating symptoms of the disease, and what side effects it is known to cause.

In this application, the pharmaceutical company also must describe its plans for the next phase of human clinical study, specifically including: how many participants the study will involve; what criteria will be used for enrolling participants; where the studies will take place; and, how drug safety and efficacy will be measured. If the FDA accepts the IND, drug testing in human subjects can begin within 30 days.

Phase I Clinical Trials

Human clinical trials generally occur in three phases. In Phase I clinical trials, the experimental drug is tested in approximately 20-100 healthy volunteers. Researchers are testing to see how the body absorbs, breaks down, and eliminates the drug, and how the drug affects the different organ systems within the body. Different dosage levels of the drug are administered and all side effects are documented. This helps researchers establish appropriate dosage levels and determine what precautions may need to be established (such as warnings about mixing the drug with alcohol or other substances that may cause adverse reactions). As more is known about the safety of the drug, the number of participants in Phase I trials will likely increase. If a new drug provides few therapeutic benefits and causes many harmful side effects, it may fail this round of testing. Phase I clinical trials can take approximately one year to complete before enough data is gathered to begin Phase II clinical trials.

Phase II Clinical Trials

In Phase II clinical trials, the experimental drug is tested in approximately 100-300 individuals who suffer from the disease or condition the drug was intended to treat. At this stage, researchers primary objectives are: (1) to determine the effectiveness of the drug in treating the intended disease or condition; (2) to uncover less common side effects, that may not have appeared during the animal studies or the smaller Phase I clinical trials; and, (3) to determine effective dosage levels and decide how often the drug should be administered. In Phase II, researchers are mostly interested in gathering data about the safety and efficacy of the experimental drug.

During Phase II clinical trials, researchers employ a method known as a double-blind, placebo-controlled study to ensure observations made during these trials remain unbiased. In a double-blind placebo-controlled study, participants are randomly placed into two groups. One group is given the experimental drug, while the other group receives a placebo (sugar pill). The studies are considered double-blind because neither the participants nor the researchers know who is receiving the drug and who is receiving the placebo until after the study is complete. A third party keeps record of this information and can access it if a participant experiences extreme side effects or other complications resulting from the medication.

During the study, participants are carefully monitored and all pertinent information is recorded and analyzed by the researchers. The double-blind placebo-controlled study design prevents researchers from allowing their expectations to influence their observations, and also prevents participants from being influenced by what they expect to gain from using the drug.

Phase III Clinical Trials

Phase II clinical trials can last up to two years. At the end of this round of testing, if the side effects of the drug outweigh the therapeutic effects, it may be dropped from further testing. If the results of Phase II clinical trials are positive, the drug will then move into Phase III trials.

The number of participants involved in a Phase III study of Alzheimer drugs increases considerably -- usually including 1,000 or more people who have received a diagnosis of "probable Alzheimers." As in Phase II, double-blind placebo-controlled studies are employed to ensure accuracy of the data collected. The results of Phase III clinical trials should determine whether the use of the drug is beneficial and if its "user-friendly" (easy to access and administer).

Phase III clinical trials can last from two to four years. The FDA requires results from two completed Phase III studies to ensure accuracy of the findings, and to eliminate the possibility that the findings occurred by chance. If the results of Phase III clinical trials do not show clear, positive results, the drug may be dropped from further study.

Also, during Phase III clinical trials researchers may offer an open-label study to the participants to enhance enrollment. In an open-label study, all participants (both in the experimental drug group and placebo group) who have successfully completed the study are given the option of continuing to take the experimental drug for six months to one year prior to FDA approval. This allows participants to continue receiving the drug treatment until their own physicians can begin prescribing it. At this point, the experimental drug trials are complete, and the pharmaceutical company can move forward to the next step of development by filing a New Drug Application with the FDA.

The New Drug Application, FDA Review and Continued Studies

The New Drug Application (NDA) is an extensive report the pharmaceutical company must submit to the FDA for review. This report gives general information about the drug and its chemical structure, and also includes everything that has been learned about the drug -- from preclinical testing through Phase III clinical trials. The FDA reviews all information collected in order to determine the overall safety of the drug, weighs potential benefits against risks, and ultimately determines whether the drug should be approved for public use. If the amount of information provided in the NDA is not sufficient, the FDA may require future clarification from the pharmaceutical company or request additional testing.

Once the NDA is approved by the FDA, the drug can be made available to the public (usually through a doctor’s prescription). However, testing of the drug does not end at this point; the pharmaceutical company is still required by the FDA to continue submitting reports describing the drugs efficacy and long-term effects, as its use becomes more widespread.