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Why You Can Trust the Drugs You Take (and How Statisticians Contribute)
James A Bolognese, Biostatistician, Merck Research Laboratories

Suppose you go to your doctor because you sometimes have difficulty breathing. Your doctor tells you that you have asthma and there is a new drug that can help you breathe better. How do you know the new drug will work and be safe for you to take? You might also wonder where this new drug comes from. You can trust the drugs you take because current drug approval regulations require extensive, extremely accurate testing to demonstrate the safety and effectiveness of drugs before marketing. Statisticians enable scientists and reviewers to establish the accuracy and validity of these tests.

In the United States, the 1962 amendments of the Food, Drug, and Cosmetics Act require substantial evidence of the safety and efficacy of drugs before they can be sold. They charge the Food and Drug Administration with evaluating the adequacy of the evidence and approving drugs with adequate evidence for marketing.

Most countries have an agency similar to the FDA that evaluates drug research and approves drugs for marketing. Consequently, the FDA and regulatory agencies of other countries have drafted numerous guidelines, including statistical guidelines, for studying and documenting the safety and efficacy of drugs. These guidelines are modeled after the four basic steps of the scientific method: hypothesis, experimentation (observation), interpretation, and conclusion (or refined hypothesis for the next experiment).

To ensure adherence to these guidelines, there is extensive critical review by sponsor companies that make the drug, the FDA (and/or other regulatory agencies), and independent academic experts (FDA advisory committees) of all aspects of a drug's safety and efficacy from experimental studies prior to approval.

Role of the Statistician

Statisticians play a key role in the drug experimentation process leading to drug approval, particularly in determining the extent and complexity of the experiments and interpreting the results of those experiments. However, before a drug can be studied for its safety and efficacy in humans, it must be discovered! Statisticians are actually involved in the development of new drugs from the discovery of new drug chemicals through marketing approval and post-marketing surveillance for safety problems.

Drug discovery begins in the laboratories of basic research scientists. Samples of natural substances are collected from the far reaches of the globe and run through screening experiments to identify drug chemical candidates with desired effects; these are referred to as active drug candidates. Each screening experiment is designed to reveal active chemicals for a specific targeted disease. Statisticians work with basic research scientists to design these experiments so they make the most efficient use of time and materials and to ensure the analyses of resultant data lead to appropriate identification of active drug chemicals (also called compounds). Once a natural substance is found to possess activity toward a disease target, chemists work to isolate the particular molecule responsible for the activity.

Another way drugs are discovered is by combinatorial synthesis. In combinatorial synthesis, molecules of several types, each known to have a certain desirable chemical property, are chemically combined to form all possible combinations of resultant combination molecules. In this way, thousands of potential drug chemical candidates are produced and tested in screening experiments. Statisticians work with chemists and use probability theory to ensure sufficient quantities of all combinations of molecules are produced for the screening experiments.

Once an active drug candidate is identified, its safety is tested under strict ethical guidelines using laboratory animals. This laboratory safety assessment ensures that harmful properties of the drug candidate are identified before it is tested on humans. Statisticians work with scientists who study the drug's safety in lab animals to design these experiments and their analyses to identify unsafe compounds using minimal research animals. In addition, statisticians work with other scientists to design and analyze experiments that yield the best production processes for making the raw drug chemical.

Other experiments are designed and analyzed to formulate the drug chemical into tablets, capsules, solutions, etc., with appropriate properties for use, including dissolution (i.e., dissolving in solution), potency over long-term storage, etc. This research must occur before a single human takes the drug.

Once a drug candidate is demonstrated to be safe in animals and can be reliably produced, it goes through three phases of testing in humans before marketing. Phase I clinical trials verify the drug's acute safety in humans and document its basic pharmacologic properties (i.e., effects on targeted enzymes, hormones, tissues, etc., in the body).

In Phase II, the candidate drug is tested in patients with the target disease to identify proper dose(s) for further testing. Once the proper dose range is found, large-scale Phase III clinical trials are designed to definitively document the drug's safety and efficacy in the target population.

Statisticians play an integral part in this clinical study process. They assist the clinical research scientists, usually physicians, to design the clinical trials-including selection and validation of study measurements-and definition of subsequent statistical analyses. This design work must be done carefully to yield valid scientific conclusions in support of particular properties of the drug's safety and efficacy.

Statisticians are key drug development project team members; they help plan the overall experimental strategy (sequence of clinical trials) and execute it. They coauthor the reports of the trials' results, which are assembled into volumes that are submitted to drug regulatory agencies worldwide for approval to sell the drug. Statisticians also make presentations at national and international scientific meetings and coauthor research journal articles; these presentations and articles summarize original statistical methodology and/or unique medical results for the worldwide research community.

Statisticians in regulatory agencies review the New Drug Applications (NDAs). Sponsor (i.e., drug company) statisticians meet with their counterparts in the regulatory agencies and other reviewers to address questions. The drug's labeling for prescribing physicians and patients contains information about the drug's proper use. Statisticians contribute to the design and content of the product's labeling. The labeling information is reviewed by statisticians for correctness. The entire drug development effort from discovery to approval takes at least six years and costs on average $400,000,000.

It's Not Over …

After drug approval, the statistician's job is not over. Further testing may be necessary to address specific questions from regulatory agencies (Phase IV of the clinical development process) or for new and different uses of the drug (Phase V). Statisticians work with economists to document the drug's impact on costs compared to the costs of necessary treatment of the disease via alternatives that do not involve the drug. Market research involves statisticians who help assess the drug's potential financial impact on the company. Statisticians help design strategies and interpret results for studies of drug safety during marketed use.

Statisticians are key collaborators in all aspects of drug discovery, development, approval, and marketing. Consulting statisticians must learn as much as possible about the specific scientific areas in which they work to most effectively contribute their expertise to the research team.

In the pharmaceutical industry, statisticians work with research scientists in many fields, including biology, chemistry, pharmacology (i.e., the study of drugs' actions in humans), pharmacokinetics (i.e., the study of the drug's passage through the body), and clinical medicine (i.e., the drug's effect on the target disease). Opportunities for statisticians exist in all phases of pharmaceutical research: pre-clinical (i.e., laboratory) research, clinical trials (i.e., studies in humans), epidemiology (i.e., studies of the spread of disease), health economics, market research, and publication in scientific journals.

Returning to the title question, you can trust the safety and efficacy of the drugs you take because they are extensively tested according to strict guidelines. The results of this testing are carefully reviewed by the world's leading medical and statistical experts prior to approval for marketing. Without extensive statistical analysis, the implications of scientific data would be less clear and important information might be lost.

Statisticians are essential in the drug development process because they ensure the validity and accuracy of findings at all stages of drug discovery, development, approval, and marketing.