This month’s expert is 











Question:  "How can the understanding of toxicology with regard to the innovation  process affect the current degree of regulations (food, pharma, etc.) and vice versa?"


Disclaimer- Dr. Cue’s response to this question is based solely on his own views, information and perspectives and, in no way, is he representing those views of any pharmaceutical company, group of companies, the American Chemical Society or its Green Chemistry Institute, nor is her a trained toxicologist.

Regulations are an important component of the pharmaceutical industry-government partnership to ensure patients receive the safest and most efficacious medicines.  In many instances regulations can also be a catalyst to stimulate innovation within this industry and can provide competitive advantage to those companies who not only meet the regulations, but also redesign their business practices to stay ahead of the emerging regulations.   Today, environmental safety is emerging as a new regulatory landscape, especially in Europe but also in the US and elsewhere.  But any regulations that emerge must be established on the basis of sound risk-based science and not on the premise that risk should be zero.  And the science must be validated and rigorous, and not based on some unvalidated observations and a few one-off experiments.   It is my opinion that regulations should not be imposed on industry unless the science and the technology is available to be in compliance with them.

Toxicology and Pharma  

In my opinion no industrial sector studies and understands the toxicology of its products more extensively than the pharmaceutical industry.  At each step in the R&D process, from conception of a possible approach to a drug, through drug discovery and development, regulatory review and in the market place toxicology plays an import role in determining whether a molecule becomes a successful drug.  Starting with the creation of the Food and Drug Administration (FDA) in the 1950’s patient safety has been an important consideration-essentially the FDA’s mandate. 

In the late 1980’s a multinational work group comprised of pharmaceutical industrial, academic and regulatory experts from the major markets, United States, European Union and Japan, came together to develop a series of science-based and risk-based guidelines to describe the process of drug development leading to product registration in these markets. The International Conference on Harmonization of Drug Development (ICH) has produced a comprehensive set of ten safety (toxicology) Guidelines to uncover potential risks like carcinogenicity, genotoxicity and multi generation reproductive toxicity.  More information about these guidelines can be found at:

Toxicology in the drug R&D process

For every drug that starts out in development, a best, there is a 5% chance it will become a commercial product.  And that’s just development-including the drug discovery process lowers the chance of success to well below 1%.  While some may see this as a high failure rate, and it is, many in this industry see dropping drugs from development that do not meet strict acceptance, or go forward criteria, as a very successful outcome.  The two main reasons why drugs fail in the R&D process are lack of efficacy and the presence of toxicity.  A major focus of the pharmaceutical R&D process is to identify molecules that have the right therapeutic index.  Therapeutic index (TI) is the ratio of the dose where a drug gives its maximum benefit to the dose at which the drug expresses unacceptable toxicity.  We select drugs that have as low an as practical efficacious dose and a very high toxic dose.  At each step in the R&D process, after studies are complete, the results of these studies are examined for signals that the drug should advance or that its development should be stopped.  This industry takes a conservative and responsible view in interpreting these results, dropping drugs early rather than continuing to progress them.  It is important to recognize that toxicology studies not only assess the safety of the active drug, but also its metabolites and manufacturing related impurities (trace solvents, degradants, unchanged reactants, etc). In the drug discovery and development paradigm the normal progression of toxicology studies is in silico -> in vitro -> in vivo, with rodents the first animal species in the in vivo studies.  Sometimes canine or non-human primate studies are also conducted if these species mirror human performance.  Much less frequently non-human primates are used.  Every effort is made to minimize the amount of animal testing conducted while meeting regulatory requirements.

But these studies are screens, and all screens have a mesh size that allows some to progress to the next stage of R&D.  In all experiments, and drug studies are sophisticated experiments, there are false positives, good and safe drugs that, in a particular study, give a signal that they may be toxic, even when they aren’t, and false negatives, toxic drugs whose toxicity is not manifested in a given study and progress to the next stage.  Even the marketplace can be a screen. In the drug development process clinical studies are designed using statistical algorithms to show a significant difference between drug and a placebo, basically a look alike version without the active drug, or between the new drug and a commercial comparator.  Thousand, perhaps tens of thousands of patients are exposed to the drug for up to a year or more, to determine whether the drug is efficacious and safe (e.g. the drug has the right TI).  When the drug is sold, in many cases millions of patients can take it, generating more experience in a relatively short time than in the entire clinical program.  Pharmaceutical companies and regulators track this patient experience database.  If the level of side effects (toxicity) becomes a concern a dialog between the regulators and sponsor-company happens and action occurs, from alerting prescribing physicians, to labeling and package insert changes, to withdrawal of the drug, in extreme cases.  The patient, the prescribing doctor and the sponsor company each have an obligation to report side effects.

In the context of green chemistry, the pharmaceutical industry is regarded as one of the chemical enterprise leaders in its adoption and application to the design of new products and processes.  Two questions come up frequently when considering the pharmaceutical industry and green chemistry: (1) why can’t drugs be designed to degrade rapidly in the environment?  2) Why aren’t all commercial drug-manufacturing processes redesigned using green chemistry design principles?  Most recently, the Natural Resources Defense Council (NRDC) in its white paper, “Dosed without Prescription” also have raised these questions. 

In the next blog:  Answering these questions.

In future blogs by Dr. Cue

  • Prospects for greener drugs
  • Emerging Regulations
  • Federal endocrine disruptor act
  • Sweden
  • Federal GC Act
  • California GC legislation
  • Michigan Executive Order
  • Drug take-back programs
  • Maine
  • Illinois
  • National
  • Pending Federal Legislation
  • Summary