Applying real-world evidence in drug approvals: an interview with Murtuza Bharmal
In this interview, Murtuza Bharmal discusses how Merck KGaA, Darmstadt, Germany utilized real-world evidence in the approval process for avelumab. Murtuza is a member of The Evidence Base’s Expert Panel.
Up until 2017, no approved treatments existed for the treatment of metastatic Merkel cell carcinoma (mMCC), a rare and deadly form of skin cancer. Since then, avelumab has been approved by the FDA, EMA and many other health authorities across the world for this indication, and more recently, pembrolizumab has been approved by FDA, with several other immune checkpoint inhibitors in clinical trials for mMCC.
We spoke to Murtuza Bharmal, Head, Oncology Brands & Life Cycle Management at Merck KGaA, Darmstadt, Germany about how they used real-world data (RWD) to gain approval for avelumab for mMCC.
Please describe your current role at Merck KGaA, Darmstadt, Germany and your involvement in real-world evidence (RWE)?
Within R&D/Global Evidence and Value Development, I lead the function Oncology Marketed Products & Life Cycle Management (LCM). We routinely use RWE to demonstrate the comparative effectiveness of our innovative therapies in real world clinical practice.
Describe how real-world data was used in the approval of avelumab as monotherapy for mMCC in the US, Europe and Japan?
mMCC is a very rare and aggressive cancer, with high medical unmet need. Before the approval of avelumab, there existed no standard of care. Chemotherapy treatments traditionally had very poor longer-term efficacy. Conducting a traditional randomized controlled study was ethically challenging and not feasible from an operational perspective. Hence, we proposed a novel clinical development pathway, which was agreed upon with the FDA and European Medicines Agency (EMA).
The development strategy included two single arm open label studies1,2 providing data on the long-term efficacy of avelumab in mMCC, supported by historic treatment pattern and effectiveness data from RWE3,4. The RWE enabled the regulatory authorities to put the efficacy of avelumab, as measured in the single arm trials, into context, like a historic control arm.
"We routinely use RWE to demonstrate the comparative effectiveness of our innovative therapies in real world clinical practice."
Why did Merck KGaA, Darmstadt, Germany choose to use RWE in this way, where it had never been used previously in a drug approval?
We wanted to get our treatment to patients as soon as possible, which required innovative scientific thinking. This is strongly encouraged at Merck KGaA, Darmstadt, Germany. Any traditional development approach would have required much longer time, leaving patients without any efficacious treatment option. mMCC patients have had a very poor prognosis and avelumab helps to increase overall survival in this aggressive cancer.
What challenges did Merck KGaA, Darmstadt, Germany face when collecting the RWD and generating the RWE?
It was very difficult to identify high quality data sources in the US and EU for such a rare cancer. We also spent a fair amount of time designing the study to assure quality in patient selection, endpoint definition and data collection, to mirror as far as possible our clinical trial.
Similarly, did you face any challenges when using this study in the discussions with regulators?
One of the biggest challenges was the sample size that we were able to obtain from the RWD sources. However, on discussing and explaining the epidemiology of the disease, and the trade-off between quality and quantity of data, this was understood and accepted by the regulators. We aligned with the regulatory authorities on the protocol for the RWE study, which was very helpful.
"I think [RWE] will be increasingly used to complement clinical trial data in drug approvals..."
Since its approval, has additional RWE been collected on avelumab in mMCC?
Yes, we continue to collect RWE from a variety of data sources, including administrative claims data, electronic medical records, or MCC registries from the US and across other geographies5,6,7,8.
If so, how has this been utilized?
The studies have been utilized to underpin the evidence-based comparative value of our innovative treatment in mMCC, its relative effectiveness and impact on healthcare resource utilization, etc.
Are there other examples that you know of where RWE has been used in a drug approval?
Yes, in the last few years, there have been some, primarily in the context of rare diseases. One recent example that comes to mind is cerliponase alfa for treatment of a form of Batten disease, a rare inherited disorder that primarily affects the nervous system9. Approval was achieved based on efficacy from a single-arm study, supported by RWE from a natural history cohort, serving as a historic control group.
In your opinion, do you ever see RWE replacing randomized controlled trials (RCTs) in new drug approvals?
No, I don’t think RWE will replace RCTs. However, I think they will be increasingly used to complement clinical trial data in drug approvals, especially in very rare diseases or supporting new indications of existing products.
"I see a huge potential for RWE in oncology, not only for drug approvals but also in the context of post-licensing evidence development..."
How do you see RWE being used in the field of oncology in the next 5-10 years?
I see a huge potential for RWE in oncology, not only for drug approvals but also in the context of post-licensing evidence development to demonstrate longer-term comparative effectiveness and manage uncertainties of payers, physicians and patients. Fortunately, an increasing number of high-quality data sources will be available and accessible to accomplish this important research in oncology, ensuring patient access to innovative therapies and supporting healthcare decision making. For example, especially in the US, we are seeing rich data sources emerging, such as the Flatiron data or ASCO’s CancerLinQ initiative.
- D'Angelo SP, Russell J, Lebbé C et al. Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial. JAMA Oncol. 1;4(9):e180077 (2018)
- Kaufman HL, Russell J, Hamid O et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 17(10):1374-1385 (2016)
- Lance Cowey C, Mahnke L, Espirito J, Helwig C, Oksen D, Bharmal M. Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA. Future Oncol. 13(19), 1699–1710 (2017)
- Becker JC, Lorenze E, Ugurel S et al. Evaluation of real-world treatment outcomes in patients with distant metastatic Merkel cell carcinoma following second-line chemotherapy in Europe. Oncotarget. 8:79731-79741 (2017)
- Kearney M, Thokagevistk K, Boutmy E, Bharmal M. Treatment patterns, comorbidities, healthcare resource use, and associated costs by line of chemotherapy and level of comorbidity in patients with newly-diagnosed Merkel cell carcinoma in the United States. J Med Econ. 21:12, 1159-1171 (2018).
- Jain R, Menzin J, Lachance K, McBee P, Phatak H, Nghiem PT. Travel burden associated with rare cancers: The example of Merkel cell carcinoma. Cancer Med. 8:5, 2580-2586 (2019).
- Klink AJ, Phatak H, Bharmal M, Kaufman J, Feinberg B. Merkel Cell Cancer: Poor Response To Chemotherapy Exposes Significant Unmet Need. Value Health. 20:9, A415 (2017)
- Fonfria H, Llombart B, Arance A et al. Burden of Healthcare Costs for Merkel Cell Carcinoma Management in Spain. Value Health. 20:9, A427 (2017)