Preclinical and Clinical Testing

To establish safety and efficacy of a bio-pharmaceutical candidate for a defined therapeutic indication, the company or sponsor must provide the FDA with pre-clinical and clinical data assembled and summarized in the BLA. The preclinical and clinical testing process can vary depending on drug candidate and complexity of the therapeutic indication (Figure 4.18).

Preclinical Studies

The preclinical studies include chemical and physical characterization, qualitative and quantitative analytical methods development, dosage formulations, and animal testing procedures. Issues related to dosage formulations are discussed in Chapter 5. Animal testing is an integral part of pre-clinical studies. These data provide essential information for estimating a dosing regimen that is likely to be safe for testing in humans (Figure 2.1, Chapter 2). The FDA does not stipulate what preclinical tests the sponsor must perform; however, the agency publishes guidelines and regulations on the kinds of data expected for human testing of the new drug candidate. Two or more animal species are typically tested to ensure that drug effects not seen in one species might be detected in another. These animal tests also allow researchers to determine potential side

Structural and dosage optimization

• Optimize pharmacologic and pharmaceutical profiles

• Optimize dosage formulation

• In vitro testing to verify and characterize structural modifications for predicted performance

• Pharmacology

• Toxicology

• Absorption, Distribution,

' Metabolism and Elimination (ADME)

• Develop dose range, route, and frequency for human administration

f Human clinical studies >

• Submission of IND application

• Phase II; efficacy and short term safety

• Phase II; efficacy, dosage and safety y» Phase IV; post approval safety may be neededy f Human clinical studies >

• Submission of IND application

• Phase II; efficacy and short term safety

• Phase II; efficacy, dosage and safety y» Phase IV; post approval safety may be neededy

Figure 4.18. Interrelationship of preclinical and clinical studies.

effects and overall safety at much higher doses than one would ever administer to humans. Some of this information, including long-term toxicity data, guides the development of protocols for human testing and generates information for final product labeling.

In preclinical studies researchers collect data on the effects of the new drug candidate after administration in a defined dosage regimen. In other words, scientists, in a series of systematically designed controlled experiments, determine the time course of drug concentration in relationship to pharmacologic and toxicologic effects, as well as the pathological consequences of the drug. In addition, animal studies allow scientists to determine the absorption, distribution, metabolism, and excretion in the selected species. They determine how much of the drug dose is absorbed from the site of administration (intramuscular, subcutaneous, and in some cases the gastrointestinal tract), how the drug is metabolized in the body, and the rate of elimination of parent drug and metabolites from the body. The biologic activity and toxicology of the metabolites are also often defined.

Occasionally a metabolite may provide a safer or more effective pharmaceutical than the parent compound selected for development. For example, fexofenadine, a widely sold nonsedating antihistamine, is the active metabolite of terfenadine. Fex-ofenadine is a safer drug than terfenadine and has replaced it on the market.

Animal testing allows researchers to develop dosage forms with optimal pharmaceutical properties. If the new drug candidate is poorly absorbed into the systemic circulation, formulation strategies such as producing salts or other derivatives, modifying pH, and the addition of excipients are implemented to maximize absorption. If the new drug candidate is metabolized or inactivated rapidly, a derivative that may resist inactivation might be designed through structural modification. The interrelationship between in vitro optimization and in vivo animal testing provides information essential for administration of the drug candidate to humans in an optimized dosage regimen (Figure 4.6). Any significant change in structure of the new drug candidate requires an additional series of preclinical and clinical tests. Significant time and resources are needed to iterate in vitro and in vivo animal tests and optimize the efficacy and safety of the derivative. To increase efficiency, researchers have developed in vitro models that may predict in vivo animal test results. In this way only a few selected derivatives might be studied in laboratory animals to identify the most promising candidate for humans.

Clinical Studies

Human studies are designed to determine "Does the drug work?" To provide an answer, pharmaceutical companies, through a series of controlled clinical trials, must, according to the FDA, collect and submit "substantial evidence of effectiveness, as well as confirmation of relative safety in terms of the risk-to-benefit ratio for the disease that is to be treated." It is critical from the outset to design clinical studies that pose the right question and provide an answer to the question in the intended patient population.

The need to discuss issues related to clinical studies early is highlighted by the FDA's refuse-to-file response letter to ImClone Systems for Erbitux, a novel anticancer monoclonal antibody. The FDA took this drastic measure because the agency, despite all the early warnings given to the company, was not provided with the complete documentation needed for clinical evaluation. A failure to engage the FDA with the clinical trail design was aknowl-edged by the CEO of ImClone System, and eventually led to his resignation.

Preclinical data are compiled in the Investigational New Drug (IND) application—a request for permission to initiate human studies—and submitted to the FDA for approval. The IND application requires full disclosure of all the preclinical study results as well as where and how the drug itself is manufactured and formulated to ensure quality and stability. The IND also contains pharmacology and toxicology data, evidence of desired and unwanted effects in disease models, and proposed analytical methods. A human subjects protocol that lists all the investigators who will participate in clinical trials must also be submitted to the FDA. In response the FDA must provide an answer within 30 days after submission. Under current FDA regulation the lack of a timely response is considered as "no objection" and permits the drug's sponsor to proceed to human testing.

When the sponsor obtains approval or tacit approval on the IND application and clearance from an independent local institutional review board (IRB), charged with the responsibility of protecting human subjects and consisting of scientists, ethi-cists, and nonscientist or community participants, clinical investigators will for the first time give the new drug candidate to a limited number of healthy volunteers or patients. The first human study, generally known as a phase I clinical trial, is designed to assess the most common acute side effects of the drug and determine the highest dose that the recipients can tolerate. Typically about 20 to 30 subjects are enrolled in phase I clinical trials, but the number can sometimes reach 100. From a series of blood samples collected after administration, clinical investigators can determine drug concentration in plasma and estimate the persistence of the drug in the body and determine metabolites of the parent drug. Phase I studies, however, do not reveal potential safety problems that occur infrequently. Therefore additional safety data are required from more advanced patient-based studies with larger enrollments (Table 4.15).

If no major safety problems are observed in phase I studies, the next step is to perform another clinical study enrolling patients who have the medical condition that the new drug candidate is intended to treat. The main objective is to determine whether the drug has a beneficial effect. Therefore it is critical to define the medical condition

■TABLE 4.15. Progression of drug candidates in human clinical trials.

Clinical trial


Number of Patients


Success Rate (%)"

Phase I






Phase II

Efficacy, some short-term








Phase III

Overall safety and efficacy


1-4 years


for risk and benefit analysis

hundred to


"Success rate is estimated based on average of all the investigation new drug (IND) applications submitted to FDA;according to FDA data, on the average about 25% of the original IND will clear phase III and about 20% will gain approval for marketing.

"Success rate is estimated based on average of all the investigation new drug (IND) applications submitted to FDA;according to FDA data, on the average about 25% of the original IND will clear phase III and about 20% will gain approval for marketing.

and the means to assess therapeutic outcome in a way that can be measured— clinically or by diagnostic or prognostic tests—and compared to controls.

Assessing the effectiveness of a new drug candidate can be complex and often difficult. This is because some diseases or symptoms do not follow a predictable path. For example, acute conditions such as influenza or insomnia may resolve without intervention, while chronic conditions such as multiple sclerosis or arthritis follow a varying course of progression. Depending on age, treatment, and other risk factors, heart attacks and strokes may produce variable mortality rates. Additional difficulty is introduced by subjective evaluation, which can be influenced by the expectations of patients and physicians. Some of these issues can be addressed in controlled clinical trials.

While not required by the FDA, more and more phase II trials are being conducted under well-controlled conditions. In such trials, a group of patients that are well-defined for age, weight, disease severity, general health, and other risk factors are randomly assigned (randomized) to either a control or a treatment group. It is critical to ensure that the treatment group and control group are as similar as possible so that differences will not influence the outcome of the efficacy study. The controls receive a placebo—an inactive dosage form similar to the dosage form containing the active drug—or another drug known to be effective for the disease. Sometimes, the control group receives a lower dose of the same drug candidate. When a placebo is employed, the study design is called a randomized, placebo-controlled clinical trial.

To prevent bias introduced by patients and clinical investigators during the course of a controlled study, a design feature known as "blinding" is frequently incorporated. Single-blind and double-blind studies keep patients or both patients and investigators from knowing which patients in the study receive the active drug. When possible, it is advisable to perform randomized, double-blind, placebo-controlled clinical trials. A phase II clinical trial enrolls several hundred subjects and takes several months to complete. According to data from the FDA, about one third of new drug candidates successfully complete phase II clinical trials (Table 4.15).

The new drug candidate that successfully emerges from phase I testing is then required to be tested further in at least one phase III clinical trial. This phase of human study is designed to collect data under rigorously controlled conditions that are adequate to definitively evaluate the drug's effectiveness and safety with respect to an overall analysis of benefit-risk relationship. Very often many medical centers participate in a phase III trial, enrolling several hundred to several thousand subjects. The exact number depends on the therapeutic end points and anticipated differences between the active drug group and the control group. Phase III trials enroll a much larger and more diverse patient population than do phase II trials, thereby revealing infrequent untoward events missed in earlier clinical trials.

On completion of phase III, which typically takes up to four years, the data are compiled and analyzed for overall safety and efficacy with regard to the defined indication set forward in the IND application. These data are assembled in a Biologic License Application (or New Drug Application for chemical and small peptide drug candidates) package for FDA evaluation of overall benefit and risk. About 25% of drugs with approved INDs successfully complete phase III testing and gain marketing approval.

In recent years the FDA has amended several rules regarding clinical trials, requiring that new drug candidates be studied in women, children, and the elderly, when appropriate. As the population of individuals over 65 years of age continues to grow and life expectancy continues to rise, there is concern that medications may produce different effects in the elderly than in younger patients. For example, elderly patients are more likely to take multiple drugs, suffering the consequences of drug interactions. Furthermore the elderly may not be able to metabolize or excrete drugs as well as their younger counterparts. In 1998 the FDA added the requirement of safety and efficacy data for demographic subgroups as part of the BLA submission.

The subjects enrolled in clinical studies for small molecule and biologic products must be tabulated within relevant demographic subgroups (e.g., age, gender, and race) in annual IND reports and must be included in all BLAs.

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