Putting Safety at the Center of Clinical Studies


For several decades, life sciences companies’ clinical development of products has focused predominantly on efficacy and specific mechanisms of action to drive efficacy forward. But as competitive pressures intensify and demands by patients and regulators for better-tolerated drugs increase, progressive companies are exploring safety as a product differentiator during the clinical trial process. Cheryl Key explores that development.

For several decades, life sciences companies’ clinical development of products has focused predominantly on efficacy and specific mechanisms of action to drive efficacy forward. But as competitive pressures intensify and demands by patients and regulators for better-tolerated drugs increase, progressive companies are exploring safety as a product differentiator during the clinical trial process. Cheryl Key explores that development.

After the withdrawal of thalidomide from the market in the early 1960s, the finding of phocomelia in many of the children whose mothers took the drug during pregnancy was catalytic in the development of a systematic and comprehensive safety-monitoring process now known as pharmacovigilance. And the science of pharmacovigilance has continued to evolve and improve.

Since the advent of pharmacovigilance, a still growing number of initiatives have been introduced to safeguard patients-especially postauthorization, wherein risk management and risk minimization are becoming standard considerations and approaches instead of exceptions. Within the life sciences industry-even though safety is a requirement in all clinical trials-pharmacovigilance has tended to take a back seat to efficacy at the decision-making table. The starting point for a target or molecule to be developed is based on its ability to treat or manage a condition, but safety monitoring hasn’t necessarily been a strategic part of the process. Increasingly, though, companies are recognizing that safety can serve as a differentiator when it’s part of a holistic approach to risk–benefit. During the clinical trial process for some products, safety endpoints are being set in much the same way that efficacy endpoints get set. Such trials establish targets and goals to measure safety and to benchmark the product under investigation against other products for which safety data is known.

To establish safety as a product differentiator, it’s vital that companies understand and be familiar with the safety profiles of other drugs in the same clinical arena and that the safety profile of their own products are key parts of overall target product profiles from the outset.

Improving Tolerability and Patient Adherence

For many years, cancer treatments have involved the use of highly toxic chemotherapy and radiotherapy treatments to kill cancer cells. Typically, though, the regimens also resulted in the killing of healthy cells and patients’ experiencing of significant side effects. That remains the public perception of cancer treatments and is a source of much fear and anxiety among patients on receiving a diagnosis of cancer. Today, however, a concerted drive is developing targeted therapy that reaches and attacks a tumor while bypassing healthy tissues and leaving them intact.

Researchers are studying a number of modalities to facilitate that kind of therapy, including nanotechnology, viral vectors, and immunotherapies whereby antibodies that target proteins specific to the cancer cell can deliver a treatment directly and thereby minimize effects on the surrounding tissue. Understanding the issues, tolerability, and outcomes of currently available treatments will help emphasize the benefits of improved safety-separate from efficacy.

Researchers are also investigating whether combining established products with experimental drugs that enhance and utilize the body’s own immune system to target cancer cells and enhance chemotherapy treatment might also result in less-severe side effects and increased effectiveness.1

Safety is often the driver for some prodrugs because often, difficulties with regard to how a medicine gets absorbed, distributed, and metabolized pose barriers to a medicine’s effectiveness. Tenofovir alafenamide fumarate (TAF), a prodrug of tenofovir disoproxil fumarate (TDF), was approved in the United States and Europe in 2016. TDF, often used in combination with other medicines, is an effective treatment for HIV and hepatitis B but is associated with severe kidney toxicity and decreased bone mineralization. TDF gets converted initially to tenofovir in the blood and is then taken up into cells and phosphorylated, whereas TAF gets metabolized intracellularly to tenofovir in the lymphoid cells and phosphorylated to active drug-with better activity and lower doses required. The driver for the development and ultimate approval of TAF was safety, and TAF was shown to have more significantly-reduced adverse effects than TDF has.2

Not all drugs can be converted to prodrugs, but when it’s possible to do so, safety can and should take the lead in identifying issues and helping drive potential solutions.


Stamping a mark with safety

One of the most widely used group of medicines, antibiotics-which are potential lifesavers-also face issues related to the indiscriminate elimination of normal bacterial flora in addition to the bacteria causing the infection, which results in increased resistance and opportunistic infections such as clostridium difficile.

Researchers are currently seeking ways to make antibiotics more specific in their targets. One example is a method aimed at manipulating the immune systems of certain bacteria by introducing programmable antibiotics into them that would target specific bacteria and leave healthy floras intact.3

In the race to bring to market certain medicines in certain pharmacological classes, inevitably some products will end up being followers, or me-too drugs. Such products are usually structurally similar to those already on the market but may differ in certain ways-in, say, either chemical structure or pharmacological action. And even though safety is a priority for all products, for those that aren’t going to be first to market in these types of classes, safety may be even more critical. One example is that of thiazolidinediones, or glitazones, which first came out in 1997 for the treatment of diabetes. After less than a year, the first of these products, troglitazone, was withdrawn due to cases of acute liver failure.4 Two follow-on products, rosiglitazone and pioglitazone, didn’t have the same risks associated with the first product and enjoyed reasonable success on the market. Later, rosiglitazone was withdrawn for cardiovascular toxicity,5 and today pioglitazone remains the only product in use in the class.

How safety knowledge creates new opportunities

In the wake of the thalidomide tragedy, it would have been hard to imagine a reintroduction of the drug, but drugs once considered out of bounds because of safety issues have reappeared to treat fatal or extremely serious conditions, and thalidomide is authorized for treatment of multiple myeloma as well as for leprosy. Knowledge about its mechanism of action led to further studies, but equally-by way of risk management and risk minimization activities-safety insights have helped drug developers find ways past the barriers raised by side effects. Nevertheless, the repurposing of old drugs can result in different safety concerns-perhaps due to higher doses or new formulations-so it’s vital that pharmacovigilance have a prominent say.

Sometimes the very side effects that appear during clinical trials lead to a product’s redirection from one area of research to another. The best-known example is Viagra, which was being investigated initially for treatment of high blood pressure and angina. When it was discovered that one of the side effects was penile erection, the product subsequently got developed very successfully as a treatment for erectile dysfunction.

Safety into the future

One clear example of an area in which safety could play an integral role in the future is in personalized or precision medicine. A medicine gets developed with the objective of improved benefit for a patient population with common characteristics, which are typically determined by pharmacogenetics. Pharmacogenetics helps exclude patients who are at higher risk of side effects based on their genetic predispositions and who would have less-favorable risk-benefit profiles as a result. Patients and prescribers can move through different therapies in turn to find the right medicine instances, but the task is often time-consuming and offers no guarantee of satisfactory conclusion. Safety will have a role in providing a scientific basis for that process, and it may be that the collection of subjective, patient responses to a medicine as to how well that medicine suits those patients will become routine in the future and will cross-reference to patients’ DNA profiles.

It’s already known that some patients, depending on their phenotypes, will be poor or fast metabolizers of some drugs and therefore at higher or lower risk of adverse events as a result. For instance, issues with poor metabolism in patients with nonfunctional CYP2D6 enzymes have already been highlighted in the summary of product characteristics for the drug atomoxetine. That type of information about the product and the influence of phenotype/genotype on its use are likely to become more commonplace in the future.

As companies take more-diverse approaches to priorities for clinical development by bringing pharmacovigilance into the core of the decision-making circle, the establishment of an integrated risk-benefit approach means that safety becomes a product differentiator. And to make it happen, pharmacovigilance and clinical safety departments must equip themselves with the resources and know-how needed to conduct clinical trials that will ensure that the perceived advantages around a product’s better tolerability and better safety are real, measured, quantified, and making a real difference to patients.

Cheryl Key, MBBS, MFPM, is head of pharmacovigilance/principal medic at ProductLife Group. She can be reached at ckey@productlife-group.com www.productlifegroup.com


  1. A Phase Ib Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Avelumab in Combination with M9241(NHS-IL12) (COMBO), January 2017, https://clinicaltrials.gov/ct2/show/NCT02994953.
  2. Liz Highleyman, Switching from tenofovir DF to TAF improves bone and kidney safety, 11 July 2016, http://www.aidsmap.com/Switching-from-tenofovir-DF-to-TAF-improves-bone-and-kidney-safety/page/3070140/.
  3. “Programmable” antibiotic harnesses an enzyme to attack drug-resistant microbes, 5 October 2014, Rockefeller University, http://newswire.rockefeller.edu/2014/10/05/programmable-antibiotic-harnesses-an-enzyme-to-attack-drug-resistant-microbes/.
  4. Hepatotoxicity with thiazolidinediones: is it a class effect? Scheen AJ, Drug Safety, 2001, https://www.ncbi.nlm.nih.gov/pubmed/11735645
  5. Evaluation of Drugs With Specific Organ Toxicities in Organ-Specific Cell Lines, Lin Z and Will Y., Toxicological Sciences, 2012, https://academic.oup.com/toxsci/article/126/1/114/1713735/Evaluation-of-Drugs-With-Specific-Organ-Toxicities
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