System for Thalidomide

Restricted distribution program requiring registered prescribers and pharmacists in the S TE PS, program (System for Thalidomide Education and Prescribing... 

To prevent severe birth defects and possible death of the newborn child, when thalidomide is used in women of child-bearing age or in sexually active men (due to levels of thalidomide in semen) adherence to strict guidelines adopted by the FDA is required. The specific guidelines fall under the term S.T.E.RS. program or System for Thalidomide Education and Prescribing Safety . All prescribers (physicians) and distributors (pharmacists, etc.) must register and adhere to these guidelines. Other toxicides include headache, dizziness, rash, pruritis, drowsiness, somnolence, peripheral neuropathy, leucopenia, and venous thrombosis. 

STEPS—System FOR Thalidomide Education and Prescribing Safety... 

Drugs that are clearly contraindicated in pregnant women are isotretinoin and thalidomide as indicated hy the nse of these products with distribution programs such as iPLEDGE (a computer-based risk management program) and STEPS (System for Thalidomide Education and Prescribing Safety). 

An official product assessment and registration system for pharmaceuticals exists in each of the 10 countries. Their functions are determined by legal provisions. Systems for registration of pharmaceutical products came into operation at quite different times in the 10 countries — as early as 1942 in Tunisia and as late as 1993 in Uganda. Some of the systems have evolved in response to dmg-related crises such as the thalidomide disaster, public pressure to expand the scope of dmg assessment and the pressure from industry and consumers to expedite the registration process. 

There are many examples of systems for which one or more important responses were unknown. One of the most tragic involved the drug thalidomide. It was known that one of the responses thalidomide produced when administered to humans was that of a tranquilizer it was not known that when taken during pregnancy it would also affect normal growth of the fetus and result in abnormally shortened limbs of the newborn. 

Classification based solely upon lethality can communicate a false sense of security because other determinants of toxicity are not addressed in such a classification system. For example, a teratogenic substance such as thalidomide could be classified as slightly toxic based upon its LDJ0 but highly toxic on the basis of producing fetal malformations. Therefore, classification schemes must always be assessed with their inherent limitations in mind. 

Recently, thalidomide has gained approval for use in the United States as an immunomodulatory agent in the treatment of HIV-associated diseases, arthritis, myeloma, and diabetic retinopathy. The FDA has instituted the System of Thalidomide Education and Prescribing Safety (STEPS) to prevent accidental exposures during pregnancy. 

There is clear evidence from many different sources that the metabolism of compounds may be involved in their teratogenic effects, as will be seen in the final chapter in the discussion of thalidomide and diphenylhydantoin teratogenicity. The embryo and foetus of some species clearly have metabolic activity towards foreign compounds which may be inducible by other foreign compounds. Thus, foetal liver from primates has a more well-developed metabolic system for xenobiotics than does that from rodents and rabbits for example. This may be due to the late development of the smooth endoplasmic... 

The ramifications of the thalidomide tragedy were many-fold but the key lesson for the development of pharmacovigilance was that active systems for detecting hazards are needed. Within a few years this had been taken forward with the introduction of voluntary (or spontaneous ) schemes for reporting of suspected adverse drug reactions (ADRs). These have stood the test of time as an alerting mechanism or early warning system and wiU be covered in more detail in Chapter 3. 

The second major change enacted under the 1962 amendment was the change in the approval process from premarket notification to a premarket approval system. Under the terms of the 1938 law, an NDA would take elfect automatically if the FDA did not respond. For example, the only reason thalidomide was not approved was because Dr. Kelsey returned the application to the sponsor with a request for more information. In contrast, the 1962 law required affirmative FDA action before a drug could be put on the market. Under the terms of the 1962 amendments, the FDA was also empowered to withdraw NDA approval and remove the drug from the market for a variety of reasons, including new evidence that the product was unsafe or that the sponsor had misrepresented or under-reported data. 

The WHO system, created in response to the thalidomide disaster, seeks to capture worldwide adverse events and identifies problems (WHO, 1975 Olsson, 1998). It is proposed that all such gathered reports should first be analyzed for mortality effects and trends (Rose and Elnis, 2000) as such would identify the most critical trends and be easiest to evaluate. 

The ideal solubility equation has significant value in chiral systems, where a single enantiomer is desired as the product [20]. The behaviour of chiral compounds is very important in biological systems and in drug development, where it is typical for just one enantiomer of an API to be biologically active. The undesired enantiomer may be inert, or possess more serious toxicity effects, as in the case of Thalidomide. Many enantiomeric systems form three discrete solid phases, depending on the solution concentration. Pure crystals of each enantiomer will form at high concentrations of their respective enantiomer. At... 

The thalidomide traged) was a powerful stimulus for the setting up of an effective system of adverse event monitoring. An excellent early publication which set out many of the basic principles and definitions of terms and procedures is that of Finney. ... 

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