Evaluating safety of new cancer treatments – the challenge for pharmacovigilance

As our safety and pharmacovigilance month continues, Jabeen Ahmad discusses the challenges in evaluating the safety of new cancer treatments.

Evaluating the safety of new cancer treatments in early phase research is a complex business.

Patients on First in Human trials have often exhausted all standard treatments and have complicated medical histories. Typical patient numbers on a phase I trial are 20-40, meaning data sets are small. Determining whether a new study drug is the cause of serious adverse events against this backdrop is challenging.

Oncology treatment types vary hugely, and newer molecularly targeted drugs are posing novel safety challenges. Pharmacovigilance departments and medical monitors draw on a number of resources to assess the benefit risk and build the safety profile of new drugs.


First in man or phase I trials in oncology differ from other phase I trials as they are conducted in actual patients, rather than healthy volunteers. They are often dose escalation studies exploring the best possible drug dose, and only a handful of patients may receive the recommended phase II dose.

“New drugs being tested often have very limited safety data and clinical experience.”

New drugs being tested often have very limited safety data and clinical experience. With First in Class drugs, only pre-clinical toxicology data may be available. This gives some indication of the potential adverse effects of a drug, some of which can be mitigated in clinical trial protocols, but more data is needed. A good understanding of the mechanism of action of the drug is therefore required to monitor and evaluate safety issues effectively.

All adverse events are considered unexpected in regulatory terms in a First in Man trial of a novel drug, as there has been no experience in humans. This contributes to larger volumes of serious, unexpected, suspected, adverse reactions (SUSAR) reports, than in other therapy areas. Continuous monitoring and carefully considered safety strategies help mitigate safety risks and support real time responses to emerging safety issues.


Real-time monitoring of potential and identified events is required in early phase oncology. CRUK trials typically take place in hospitals against a backdrop of hospital admission for trial drug administration and standard patient care. Patients have often tried all other standard cancer treatments.

Early phase clinical trials can be a last hope for some, or a way of giving something back for future generations.

When assessing benefit risk for oncology drugs, the unmet medical need or lack of other treatment options for patients can sometimes be the main benefit.

Serious Adverse Event (SAE) reports in cancer trials are lengthy with multiple concurrent medications, co-morbidities, relevant medical history and previous treatments to consider. The patient population is complex with lots of background “noise” when evaluating causality of SAEs. Patients typically have late stage disease with underlying disease progression symptoms, and are often taking multiple concurrent medications.

“When assessing benefit risk for oncology drugs, the unmet medical need or lack of other treatment options for patients can sometimes be the main benefit.”

This makes determining causality of adverse events challenging, and medical review of cases requires a good understanding of normal disease progression. SAEs could be due to your trial drug (s), or a number of other factors:


• the trial protocol

• interactions between concurrent drugs

• the patient’s medical history

• previous treatments including surgery, radiotherapy & chemotherapy


Typically, we find patients have had on average five prior lines of treatment in phase I trials, such as chemotherapy, radiotherapy, surgery and sometimes other experimental medicines. In one case, a patient had received 30 previous treatments making meaningful causality assessment virtually impossible.

Early phase clinical trials have a larger number of protocol amendments as new information, often emerging safety issues are identified, and inform the progress of the trial.

Examples include:


• introduction of prophylactic drugs to manage adverse events

• changes to eligibility criteria to protect at-risk patients groups


Non-serious events of interest can be upgraded to medically important events which allows for rapid reporting to sponsor Pharmacovigilance departments. Significant changes to safety information may also require updates to Patient Informed Consent information and to the Investigator Brochure.

Molecularly Targeted drugs

Molecularly Targeted drugs are commonly used in oncology practice, and many novel targeted drugs are being tested in clinical trials. Although targeted drugs are thought to be more specific and less toxic than traditional cytotoxics, they are associated with a variety of specific target related effects.

“…targeted therapies may require increased safety surveillance and specific risk management strategies…”

Examples of this are inhibitors of Epidermal Growth Factor Receptor 1 (EGFR), a promising target for solid tumours. Target-related adverse reactions such as acne-like dermatitis (related to widespread expression of EGFR on epithelial cells) and ocular toxicities (related to inhibition of corneal epithelial cell proliferation) have been documented with EGFR monoclonal antibodies1,2. Therefore targeted therapies may require increased safety surveillance and specific risk management strategies to mitigate target-related adverse reactions.

New methodology

Traditional oncology First in Man trials with cytotoxic treatments focus on identifying the Maximum tolerated Dose (MTD) of a drug with pre-defined Dose Limiting Toxicity criteria. With molecularly targeted medicines however, the current methodology to review DLTs may not be appropriate.

In a recent study, 50% of patients treated with molecularly targeted drugs developed their most severe toxicity after the first cycle of treatment i.e. after the DLT period3. New criteria are therefore needed for defining DLTs for these agents. A multi-academic project is underway to develop criteria for DLTs and a recommended phase II dose, in phase I trials of molecularly targeted agents as single agents4.

DLTs do not always fulfil the criteria of an SAE. Depending on the sponsor organisation’s structure, DLTs are reported directly into the pharmacovigilance team or to clinical study teams. Clear communication is needed between these teams to ensure a full picture of the safety a new drug is formed.

“Good communication is required between pre-clinical, medical and pharmacovigilance groups to identify potential safety issues…”


Early phase trials give an early indication of the safety profile of the drug, but they are the tip of the iceberg. It is unlikely that rare side-effects are observed in early phase trials, and long-term effects are often only seen when drugs are on the market for some time and larger numbers of people are receiving the treatment. The focus of early phase trials is to evaluate the tolerability of novel treatments.

Can serious adverse reactions be managed to ensure the benefit risk profile of a drug remains acceptable?

Building the safety profile of a drug occurs over a long period of time. Significant safety issues can be identified in early phase trials. Good communication is required between pre-clinical, medical and pharmacovigilance groups to identify potential safety issues and develop the safety profile of new cancer drugs.



1. Hansel, TT, Kropshofer, H., Mitchell, AJ., Singer, T., Mitchell, JA. And George AJT. The safety and side effects of monocolonal antibodies, Nature Reviews, April 2010, Vol 9.

2. Renouf DJ, Veazquez-Martin JP, Simpson R, Siu LL and Bedard PL. Journal of Clinical Oncology, Sept. 2012, Vol 30, No 26.

3. Postel-Vinay, S., Gomez-Roca, C., Molife, L.R., Angam, B,. Levy, A., Judson, I, de Bono, J., Soria, J-C., Kaye, S.B. and Paoletti, X. Phase I trials of Molecularly Targeted Agents: Should we pay more attention to late toxicities? Journal of Clinical Oncology May 2011., Vol 29, no 13.

4. EORTC- NCI-NCIC Phase I project: Guidelines for the definition of DLT / MTD and RPIID in Phase I trials of non-cytotoxic agents.



About the author:

Jabeen Ahmad is Head of Quality, Regulatory and Pharmacovigilance at The Drug Development Office at Cancer Research UK. She has extensive pharmacovigilance experience in pharmaceutical and drug development settings.

The Drug Development Office at Cancer Research UK sponsors early phase clinical trials with novel, translational drugs. Cancer Research UK pioneers life-saving research to bring forward the day when all cancers are cured. We’re the world’s leading cancer charity dedicated to saving lives through research. Our groundbreaking work into the prevention, diagnosis and treatment of cancer has seen survival rates double in the last 40 years.

What unique challenges are faced when assessing the safety of new cancer treatments?