An objective risk-benefit analysis of each investigational drug conducted in the scope of clinical trials is a fundamental step in the development of novel therapies.1 Early detection of safety signals not only results in better patient protection, but also has the potential to save development costs for drug manufacturers.2

The first step in ensuring clinical trial safety is the generation of a safety plan, the objective of which would be to characterize risks of the drug under investigation through systematic data collection and reporting. Detection and communication of safety signals that arise during the trial, and development of risk minimization measures, are additional aspects of clinical trial safety monitoring.1 In rheumatoid arthritis (RA) trials, it is important to take into consideration the epidemiology of RA-associated risks when interpreting safety data. Some well-recognized RA-specific risks include an increased risk for infection,3 certain malignancies (lymphoma and lung),4,5 and comorbidities including other autoimmune diseases6 and renal dysfunction.7

Yousaf Ali, MD, FACR, professor, Mount Sinai Department of Medicine, and chief of the Division of Rheumatology at Mount Sinai West, New York City, New York, discussed several important aspects of drug safety monitoring in RA clinical trials.


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What are the essential steps/components of clinical safety monitoring in RA clinical trials?

Initial steps include the selection of a nominal drug dose and regimen. Thereafter, any new drug will be tested in both phase 1 and 2 trials to determine the appropriate safety and tolerability profile in humans. Once the appropriate drug dose and interval of administration is known, it is ready to be studied in a larger number of patients. A central and local safety board, such as an Institutional Review Board (IRB), with central and local monitors in place is standard practice. Sponsors and study investigators generally will follow the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines to maintain clinical safety. Frequent study visits which include a physical exam and lab testing will help monitor for [potential drug] side effects. Patients should be provided with a user-friendly means to report potential side effects. A culture of openness and a unified means of transparent reporting is essential.

What is the objective of the safety plan for an RA trial and what considerations should be taken into account when developing it?

When studying a new drug or regimen, the major objective is to protect the participants of the study and ensure their safety. Most studies are done in various phases, so that the correct dosing and interval of the medication can be ascertained. This will raise any potential red flags early on, and it is key before enrolling a large number of patients. Key considerations for an RA trial include balancing a trial to show efficacy while still being able to show longer-term safety of the drug.

How is reporting and communication of safety information conducted in RA trials?

There is a clinical trial monitor who will be appropriately trained by the institution and may undergo further study-specific training by the sponsor. Appropriate consent is obtained from the patient by the monitor and study investigator. As part of this consent, potential adverse events are discussed and the participant is made aware of what to watch for. The patient attends regular study visits and is monitored for both efficacy of the drug and potential adverse events.

Laboratory monitoring is performed regularly, and these results are reported back to the study sponsor and the investigator. If a potential adverse event is noticed, a clinical decision is made as to whether it is related to the study and whether there is any potential harm. A central database can track trends in events across the entire study.

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What is the role of the independent data monitoring board?

[The role] is to provide independent safety monitoring that can assess safety and harm to participants and assess compliance with any regulations.

What are the potential obstacles to rigorous clinical safety monitoring in RA trials? Are any of these unique to RA clinical trials?

Since studies are often multicenter and both national and international, there can be challenges in the uniformity of training the safety monitors and getting timely access to data. Since RA is a chronic disease, it can take longer to see an effect of the intervention; short trials minimize potential toxicity to the patients but are more difficult to show a meaningful difference.

If study visits, blood draws, and testing [become] overly burdensome, it will lower patient compliance with reporting and increase drop out. In RA trials, patients are exposed to repeated infusions or injections of immunosuppressive agents, which can [reduce] immune tolerance and give rise to potential infections and immediate side effects.

Long-term monitoring is also key since side effects such as potential malignancy can take years to become apparent. The use of placebo arms in RA trials that run >6 months is no longer feasible because of the risk for progressive joint damage in uncontrolled RA.

Can you identify any other challenges associated with safety in RA clinical trials?

It has become more and more challenging to enroll patients [into clinical trials] in the United States because of lack of biologic-naive patients and more studies being performed outside the US in areas such as central Asia. Since the patient makeup and pharmacogenomics in these areas may be very different, the generalizability of the data remains a potential issue and needs to be taken into account when interpreting the data.

References

1. Neagu MR, Weinreich MA, Doan TT, et al. Monitoring drug safety in rheumatoid arthritis  prevention trials. Clin Ther. 2019;41(4):1366-1375.

2. Yao B, Zhu L, Jiang Q. Safety monitoring in clinical trials. Pharmaceutics. 2013;5(1):94-106.

3. Doran MF, Crowson CS, Pond GR, et al. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 2002;46(9):2287-2293.

4. Smitten AL, Simon TA, Hochberg MC, et al. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):R45.

5. Simon TA, Thompson A, Ghandi KK, et al. Incidence of malignancy in adult patients with rheumatoid arthritis: A meta-analysis. Arthritis Res Ther. 2015;17:212.

6.  Kronzer VL, Crowson CS, Sparks JA, et al. Family history of rheumatologic, autoimmune, and non-autoimmune diseases and risk of rheumatoid arthritis [published November 30, 2019]. Arthritis Care Res. doi:10.1002/acr.24115

7. Mori S, Yoshitama T, Hirakata N, Ueki Y. Prevalence of and factors associated with renal dysfunction in rheumatoid arthritis patients: a cross-sectional study in community hospitals. Clin Rheumatol. 2017;36(12):2673e2682.