Conducting a clinical safety review in drug development: the regulatory environment
Posted on 10 December 2014 in Clinical Trials
Author: Linda Hermans, Scientist and Product Specialist, Cambridge Cognition
- In Europe1 and the US2, regulatory bodies have issued guidance on conducting clinical safety reviews.
- Any drug that crosses the blood-brain barrier can produce cognitive deficits that can interfere with everyday functioning, it is crucial these risks are quantified during the early stages of the development process.
- Clinical safety reviews for new compounds that include special studies identifying adverse effects such as decreased cognitive function will be given more credence by the FDA.
- Cantab Connect provides simple, sensitive and validated cognitive safety measures that comply with regulatory requirements.
- As well as adhering to guidance issued by regulatory bodies, cognitive safety assessments can:
- aid decision making throughout drug development programmes
- reduce risk of failure at later stages
- provide differentiating label claims
The early stages of drug development programmes aim to prove a new drug’s safety by determining the safe dose range and identifying any potential side-effects. Phase I clinical trials in particular are intended to highlight key information related to the safety aspects of new therapeutics. A successful early stage clinical trial should be able to report on the drug’s interaction with another drug, as this can often have unpredictable consequences by increasing the magnitude of the effect of either drug or even creating new adverse effects that are not usually observed by either drug independently. The pharmacokinetics of a compound and its actions in the body should be established, as well as its tolerated safe dose range with minimal side effects. Furthermore, the acceptability of the compound’s toxicity and reliability to target the appropriate biological processes must also be determined.
Any drug that crosses the blood-brain barrier can produce cognitive deficits
Both in Europe1 and the US2, the regulatory bodies have issued guidance on conducting clinical safety reviews and, more recently, attention from these regulatory bodies has turned towards the assessment of a drug’s impact on cognitive functioning. Any drug that crosses the blood-brain barrier can produce cognitive deficits that can interfere with everyday functioning.This includes drugs for both Central Nervous System (CNS) indications and non-CNS indications (e.g. oncology drugs, pain drugs, hypnotics, antihistamines, cardiovascular drugs (including statins), HIV drugs, anticonvulsants and antimuscarinics). For example, a study reported that 80% of over 60 year olds taking anticholinergics met the diagnostic criteria for mild cognitive impairment (MCI)3. It is therefore crucial that these risks are quantified during the early stages of the development process. This is especially true when drugs are intended for populations where cognitive impairments may already be present, such as the elderly, or where drugs are intended for paediatric populations, where cognitive toxicity could have long-term consequences for cognitive development.
Safety reviews give data submissions more credibility with regulators
The US Food and Drug Administration (FDA) has issued reviewer guidance on conducting clinical safety reviews for new compounds which states that data submissions including special studies that aim to identify adverse effects such as decreased cognitive function will be given more credence than those which do not. This guidance has resulted in an increased demand to evaluate the impact of compounds on cognition. The importance placed on cognitive assessment in a clinical trial can be determined by the risk-benefit relationship of the compound in relation to the target indication. For example, a therapeutic developed for life-threatening illnesses (e.g. cancer) will have a greater tolerance for cognitive impairment than one developed as a symptomatic treatment to manage disease pathology (e.g. asthma drugs).
In addition to novel therapeutics, post-marketing surveillance studies that include a safety assessment of the impact of medication on cognitive performance can result in detection of adverse effects. Depending on the nature and extent of the finding, this can result in either a re-call of the drug for re-evaluation of its cognitive safety or notifications by the regulatory bodies mandating warnings on drug labels. For example, in 2012 the FDA mandated warnings on all statin labels following a study that revealed adverse effects of statins on cognitive function, such as memory loss, sleep disruption and altered mood4,5.
How is cognitive safety assessed in a clinical trial?
Cognitive assessments are typically performed at baseline and at regular intervals post-treatment and performance on cognitive tasks are compared to a positive control (i.e. a drug that is known to cause cognitive impairment), or a competitor drug, and a placebo. The ability to benchmark a drug in relation to other cognitive impairing compounds, socially acceptable levels of impairment (e.g. legal driving limit of alcohol) or impairments observed in clinical populations enables direct comparisons of the magnitude of the impairment to be made which can aid decision making in the development process, as well as provide opportunities for drug differentiating label claims.
Determining the cognitive profile of a compound can provide a pharmaceutical company with many benefits. As well as adhering to guidance issued by regulatory bodies, cognitive safety assessments can aid decision making at the early stages of drug development programmes, monitor cognitive safety throughout clinical development, reduce risk of failure at later stages and provide differentiating label claims.
1 Directive 2001/20/EC of the European parliament and of the council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, Official Journal of the European Union, L121/34
2 Food Drug Administration Center for Drugs Evaluation Research (2005). Review Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, FDA Maryland
3 Ancelin, M. L., Artero, S., Portet, F., Dupuy, A-M., Touchon, J. & Ritchie, K., (2006), Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study, British Medical Journal, 223:455
4 http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm#references and http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm293623.htm
5 Sahebzamani, F. M., Munro, C. L., Marroquin, O. C., Diamond D. M., Keller, E. & Kip, K E., (2014), Examination of the FDA warning for statins and cognitive dysfunction, Journal of Pharmacovigilance, 2:4