TRANSITION THERAPEUTICS INC. T.TTH

Drug Toxicity........ from an EXPERT

[deninsask]

Toxicity: Not a Dirty Word

By Dr. David G. Barnes and Colin G. Rousseaux, PhD

Innovators and therapeutic product developers in the world of biotechnology often fear the word toxicity. But the reality is that all drugs are toxic at high enough doses. Just read the product monograph (PM/label/package insert) for penicillin, or acetylsalicylic acid (ASA) for that matter. The litany of details appearing in these documents (as a strict regulatory requirement) — including potential side-effects, warnings and precautions, contraindications (circumstances under which the product is not to be used), and interactions with other drugs, non-therapeutic agents or foods — would be enough to
put many patients off taking them if they were fully aware.

Given that all drugs are toxic, why does the U.S. Food and Drug Administration, Health Canada, European Agency for the Evaluation of Medicinal Products and other regulators assess these products and give marketing authorization? The answer, of course, is context. First, it is the dose that makes the difference between a poison and a therapy, and toxicity assessment is a small part of the regulatory assessment process. Second, each product assessed by federal regulators is considered in a systematic way, and on its individual merits; potential harm (risk) and benefit is carefully weighed for the proposed clinical indications, including patient demographics and the seriousness of the disease. (The seriousness of a disease is not to be confused with severity, as a serious disease kills or maims, whereas a severe disease need not be serious. For example, a toothache can be severe but is rarely serious.) Third, the burden of illness on individuals, families and society is considered in the harm-benefit assessment, as are the availability, safety and effectiveness of other therapeutic options.

In order to assess the toxicity of investigational new therapeutics, federal bodies evaluate data submitted by the sponsor as part of a Clinical Trial Application in Canada, or as part of the Investigational New Drug Submission in the U.S. This review, as well as a critical review of the intended human exposure by a Research Ethics Board, is a necessary step to comply with the Nuremburg and Helsinki agreements regarding human experimentation, before human studies can start. The basic requirements for assessment of a New Drug Submission (NDS) in Canada, a New Drug Application and Biological Licensing Application in the U.S., and a Marketing Authorization Application in Europe, include all non-clinical data as well as clinical data generated in product development clinical trials, with strong emphasis on safety.

The evaluation of the toxicity studies, which uses validated in vitro and in vivo assessment, is an important part of elucidating potential human adverse effects following exposure of the population to the therapeutic product. The importance of this overall assessment is recognized in determining potential unintended effects: clinical trials might miss a serious adverse drug reaction that may become apparent when the larger population is exposed (a statistical power issue).

The burden of responsibility on the sponsor does not finish when a Notice of Compliance (NOC) is obtained following a successful evaluation of the NDS package. Post-market surveillance is required of all manufacturing authorization holders, that is, those who have received a NOC under the Canadian Food and Drugs Act and are required to submit Periodic Safety Update Reports for ongoing assessment. In fact, if adverse drug reactions indicate a specific detrimental effect, the sponsor may be requested to conduct a Phase IV post-marketing study. Soon, Health Canada will have authority to demand sponsors take such actions.

Assessing toxicity in therapeutic product development is aimed at providing an upper benchmark dose and characterizing toxic effects near this dose. The results of all toxicity studies completed during drug development are used to determine the starting clinical dose for “first-in-human” clinical trials. Recognizing the importance of hazard (interactions, adverse events or side-effects) identification and dose-response assessment, mandatory toxicity studies not only help in predicting, labelling and managing adverse events but are also now considered critical in mitigating financial and product liability risk. These data appear in summary form in the product monograph, and in doing so, the sponsor not only highlights potential toxicity issues for the prescriber and patient, but also reduces liability regarding known toxicity issues.

Not all therapeutic molecules can be assessed by the regulator in the same manner — there are fundamental differences between small molecules and biologics. The toxicity of small molecule drugs or traditional pharmaceuticals is usually hepato-centric and related to the ability and capacity of the liver to metabolize and eliminate drug and drug metabolites by making them more water soluble (urinary excretion) or more fat soluble (biliary excretion).

These days, small molecule toxicity can often be predicted using in silico modelling, which can sometimes be achieved using Quantitative Structure Activity Relationship analyses. Further, the toxicity of small molecule therapies follows a systematic development process, most of which has been harmonized among other countries through the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The most recent effort of the ICH has been to introduce a Common Technical Document (ICH), which provides a single document for submission to regulators around the globe.

In contrast, the evaluation of non-clinical safety for biological therapies can be difficult, as these molecules tend to be immunogenic, which may cloud the evaluation of toxicity. Therefore, they often cause negative effects in toxicity evaluation due to the proteinaceous nature of the molecule, rather than toxicity caused as part of therapeutic activity. Although the immunogenic and immunotoxic findings are often related to the inherent nature of the molecules, immunological alterations in humans and non-human primates are of special importance to regulators, particularly regarding recombinant signalling molecules.

There are a number of immunologic effects that are important in the regulation of biologic therapies including immuno-modulation in humans, the potential to form immune complexes, and a number of class effects that have been recognized for some biological therapies such as recombinant monoclonal antibodies. In addition to predictable toxicity, biological therapies have shown toxicity that was not predicted on the basis of biology (e.g., Herceptin® and left ventricular dysfunction). This unique nature has led to evaluation of biological candidates on a case-by-case basis. Nonetheless, there are certain non-clinical requirements that are mandated and are available from the ICH (S6). Health Canada also has specific requirements of biologics, including special considerations in the pediatric population.

Unfortunately, the term toxicity has a negative connotation, in that toxicity assessments can result in a compound’s failure to reach the clinic at any stage of development. Although this fear of failure is real, the benefit of having data to decide whether to proceed with or stop development can save endless dollars being spent on a drug that will never reach the clinic: toxicity studies allow an early decision to be made regarding whether the drug should be killed, or less toxic analogues developed.

Ultimately, the responsibility to supply appropriate data to the regulators lies with the sponsor. This responsibility includes providing data demonstrating the product has been tested adequately for toxicity and that the product’s toxicity profile has been fully described. Regulators and investors agree fully on this score — no surprises please!

Dr. David G. Barnes is managing partner of BioTheraGene Consultants Inc. (Ottawa, ON), CEO of Boreal Primum Inc. (Montreal, QC), and regulatory advisor to and member of the board of directors of TrialStat Corp. (Ottawa, ON). Barnes is a former clinical evaluator, Biologics and Genetic Therapies Directorate and former head, Biotechnology Products Surveillance Unit, Marketed Health Products Directorate, Health Canada. A physician and molecular biologist, Barnes has been consulting to industry and government since 2001 in the development, regulation and safety of biologics. E-mail: [e-mail]”>[e-mail]”>[e-mail]. Web: www.biotheragene.com”>www.biotheragene.com. BioTheraGene offers FDA services through Biologics Consulting Group (BCG LLC) in Washington, D.C.

Colin G. Rousseaux, PhD is a renowned toxicology expert and president of Colin Rousseaux and Associates (Ottawa, ON). Rousseaux has a veterinary degree and a doctorate in toxicologic pathology. He is a diplomate of the American Board of Toxicology Inc. (Raleigh, NC), a fellow of the Royal College of Pathologists and a fellow of the International Academy of Toxicologic Pathology (Valhalla, NY). He has authored hundreds of papers and abstracts; he is co-editor of Handbook of Toxicologic Pathology, co-editor of Fundamentals of Toxicologic Pathology and co-author of Bioavailability in Environmental Human Health Risk Assessment. Rousseaux also has extensive regulatory experience in drug toxicology at Health Canada