21 September 2018
Bringing a drug to market: How do we find and monitor suitable patients?
What will happen when we eventually develop a treatment that halts the development of early Alzheimer’s disease? Being first-in-class, pharmacovigilance post-marketing will be vitally important to ascertain the long-term effects of the drug: both positive and negative. We need to be prepared for a breakthrough and pre-emptively identify technologies which can find the right patients likely to benefit from the drug and monitor treatment effects in the real world.
Pharmaceutical companies are making substantial efforts to develop effective treatments for early Alzheimer's disease (AD) 1 - but how can they prepare for Phase IV?
A drug which halts the progression of AD at the early stages will require a targeted patient group and years, or even decades, of pharmacovigilance.
What is pharmacovigilance?
Pharmacovigilance refers to the detection and monitoring of adverse events (side effects), resulting from drug administration, with a view to ascertaining if these events are preventable and, if not, whether these events are tolerable for patients compared to the benefits offered by the medication 2.
The act of pharmacovigilance refers to monitoring drug safety from post-marketing to end-of-use 2. This is crucially important, as once a drug is brought to market there is a substantial increase in drug exposure (number of patients taking the drug) 3. Furthermore, there is a significant increase in exposure for those patients with co-morbidities 3, which could lead to unanticipated interactions (pharmacokinetics / dynamics) between medications.
Drugs administered early in the course of AD, with the aim of halting or slowing the progression of dementia symptoms, are likely to require long-term use. Therefore, it will be essential to closely monitor any side effects which develop as a result of this prolonged exposure.
Because pharmacovigilance occurs post-marketing, it may be delivered within the context of a Phase IV clinical trial.
What are Phase IV clinical trials?
Phase IV clinical trials are the point in the drug development process where the real world effectiveness of a drug is assessed 4. This occurs when the drug has been brought to market and continues for the life course of the drug.
Phase IV is qualitatively different from the pre-marketing, randomised controlled trials which will have come before (Phases I-III), in that it is observational, and occurs at scale, outside the lab 4.
In summary, Phase IV clinical trials are used to continually characterise and assess the safety profile of the drug, by monitoring adverse events 4.
How are Phase IV clinical trials different from post-marketing surveillance?
Post-marketing surveillance (PMS) is a regulatory-mandated Phase IV, observational study 4. PMS is very likely to be requested when a drug which tackles early AD is developed, as by being first-in-class it is likely to follow a novel therapeutic pathway.
For example, the clearance of the neurotoxic products associated with AD (beta-amyloid, hyperphosphorylated tau) is a therapeutic strategy which is currently being explored. However, what are the long term effects of this clearance? Currently, this is little understood and would therefore need to be closely monitored within a cost-benefit analysis framework.
The difference between PMS and Phase IV trials more generally is that all PMS studies are Phase IV trials, but the inverse is not true as not all Phase IV trials are requested by regulatory bodies 4.
How can we screen the right patients with early Alzheimer’s disease into Phase IV trials?
If recruiting patients with early AD into Phase II and III clinical trials poses a significant time and resource burden 5, then the costs rise exponentially at Phase IV when all patients who may potentially benefit from the drug need to be identified and monitored.
CANTAB Mobile as a CE-marked, FDA-cleared and TGA-approved medical device, offers a potential, in-clinic triage solution for this post-marketing problem.
CANTAB Mobile can differentiate adults with mild cognitive impairment from healthy adults (the worried well) with 83% sensitivity and 82% specificity 6.
How can we monitor patients in real time?
A central part of pharmacovigilance is monitoring patients in the real world. But how best to achieve cost effective, moment-to-moment, naturalistic monitoring with minimal effort for patients? The leveraging of technological advancements, such as wearables, may be the answer.
A preliminary study using Cognition Kit wearable technology, sponsored by Takeda Pharmaceuticals, has demonstrated high compliance among patients with major depressive disorder (MDD).
This technology could easily be modified to monitor drug efficacy and side effects, expanding the scope for high frequency, near-patient testing.
In terms of translating these findings to older adults in the early stages of dementia, there are concerns about how this group will fare with computerised assessments and wearable technology.
However, a recent survey of older adults in Australia found a preference for computerised assessments 7, which suggests a willingness to engage with technological advancements. Furthermore, an advantage of wearable technologies is that reminders can be delivered directly to the person at any time.
Data from Earl, J.K., Gerrans, P. and Hunter, M (2017). Better ways of assessing cognitive health. Brisbane: National Seniors
When a drug to treat AD at the early stages is eventually developed and approved; then finding and monitoring the right patients will be crucially important to ascertain whether efficacy in the lab translates to effective and acceptable treatments in the long term.
Here we have discussed some potential technological solutions to prepare for this next step in tackling AD.
- Science. Congress apporove largest U.S. research spending increase in a decade. Science. doi:10.1126/science.aat6620.
- EMA. European Medicines Agency - Overview - Pharmacovigilance. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000258.jsp&mid=WC0b01ac0580b18c76. Published 2018. Accessed May 18, 2018.
- FDA. Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. 2005:301-827. http://www.fda.gov/cder/guidance/index.htm. Accessed May 18, 2018.
- Suvarna V. Phase IV of Drug Development. Perspect Clin Res. 2010;1(2):57-60. http://www.ncbi.nlm.nih.gov/pubmed/21829783. Accessed May 10, 2018.
- Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2017. Alzheimer’s Dement Transl Res Clin Interv. 2017;3(3):367-384. doi:10.1016/J.TRCI.2017.05.002.
- Chandler JM, Marsico M, Harper-Mozley L, et al. P3-111: Cognitive assessment: Discrimination of impairment and detection of decline in Alzheimer’s disease and mild cognitive impairment. Alzheimer’s Dement. 2008;4(4):T551-T552. doi:10.1016/j.jalz.2008.05.1676.
- Earl JK, Gerrans P, Hunter M. Better Ways of Assessing Cognitive Health. Brisbane; 2017. https://nationalseniors.com.au/system/files/09172697PAR_CognitiveHealth_Report_FNREV_WEB.pdf. Accessed November 22, 2017.