Different stages of the drug development and approval process in the USA, lead from preclinical trials (testing in animals), first application in humans through limited and broad clinical tests, to postmarketing studies.


By Dale E. Wierenga, Ph.D. and C. Robert Eaton
Office of Research and Development
Pharmaceutical Manufacturers Association

'In reviewing this report, it is important to keep in mind the realities of the drug discovery and development process. The U.S. system of new drug approvals is perhaps the most rigorous in the world. On average, it costs a company $359 million to get one new medicine from the laboratory to the pharmacist's shelf, according to a February 1993 report by the Congressional Office of Technology Assessment.'

See also Phase 1 2 3 4 Drug Trials, Food and Drug Administration, and European Medicines Agency.

Fetal ultrasound is a safe and non-invasive imaging technique used to visualize and monitor the development of a fetus during pregnancy. It employs high-frequency sound waves to create detailed images of the baby, the placenta, and the uterus. Fetal ultrasound provides valuable information about the baby's growth, organ development, and overall well-being. It is commonly used to determine gestational age, assess fetal anatomy, detect abnormalities, and monitor fetal movements and heart rate. This essential tool enables healthcare professionals to ensure the optimal health of both the mother and the baby throughout the pregnancy.
The FDA (Food and Drug Administration) has established regulations governing ultrasound usage, including specific guidelines for fetal ultrasound examinations. These regulations permit an eight-fold increase in ultrasound intensity for fetal scans. They place considerably responsibility on the user to understand the output measurements, the mechanical index (MI), the thermal index (TI) and to use them in their scanning. The primary safety concern in prenatal diagnostic imaging is temperature rise. It is known that hyperthermia is teratogenic. The efforts of investigators have concentrated on defining the temperature increases and exposure times which may give rise to biological effects and on determining the ultrasound levels which might, in turn, lead to those temperature rises.
In fetal ultrasound, the highest temperature increase would be expected to occur at bone and the thermal index with bone at/near the focus (TIB) would give the 'worst case' conditions. The mechanical index and thermal index must be displayed if the ultrasound system is capable of exceeding an index of 1. The displayed indices are based on the manufacturer's experimental and modeled data. However, an independent study has demonstrated significant discrepancies over declared spatial peak time averaged intensity (I-SPTA) output of up to 400%.

See also ALARA Principle, Pregnancy Ultrasound and Doppler Fluximetry in Pregnancy.

Different stages of testing drugs in humans for example ultrasound contrast agents, from first application in humans through limited and broad clinical tests, to postmarketing studies. Preclinical trials are the testing in animals.

See also Drug Development and Approval Process USA, Food and Drug Administration, and European Medicines Agency.

A guidance document available from the 'Center for Devices and Radiological Health, U.S. Food and Drug Administration', which provides information for manufacturers seeking U.S. marketing clearance of diagnostic ultrasound systems and transducers.

Regulations governing the output of diagnostic ultrasound have been largely set by the USA's Food and Drug Administration (FDA), although the International Electrotechnical Commission (IEC) is currently in the process of setting internationally agreed standards.
The relevant national societies for ultrasound users (e.g. American Institute of Ultrasound in Medicine (AIUM), British Medical Ultrasound Society (BMUS)) usually have safety committees who offer advice on the safe use of ultrasound. In 1992, the AIUM, in conjunction with the National Electrical Manufacturers Association (NEMA) developed the Output Display Standard (ODS), including the thermal index and mechanical index which have been incorporated in the FDA's new regulations.
Within Europe, the Federation of Societies of Ultrasound in Medicine and Biology (EFSUMB) also addresses safety and has produced safety guidelines (through the European Committee for Ultrasound Radiation Safety). The World Federation (WFUMB) held safety symposia in 1991 (on thermal issues) and 1996 (thermal and non-thermal issues), at which recommendations were proffered.
The FDA ultrasound safety regulations from 1993 combine an overall limit of spatial peak time averaged intensity (I-SPTA) of 720 mW/cm2 for all equipment. A system of output displays allows users to employ effective and judicious levels of ultrasound appropriate to the examination. The output display is based on two indices, the mechanical index (MI) and the thermal index (TI).

See also ALARA Principle, and Radiological Society of North America.