Evolution of Value for Oncology Therapies


Applied Clinical Trials



In recent years, the United States has witnessed significant progress in the fight against cancer, with survival rates increasing from 49% in the mid-1970s to 68% today (R Siegel, et al., 2011; American Cancer Society: Cancer Statistics 2015).  Improved therapies   have contributed significantly to these advances in cancer care, with new medicines accounting for 50-60% of the increase in cancer survival rates since 1975. The progress driving these advances is commonly the result of an accumulation of knowledge over time, as a greater understanding of the biology underlying the more than 200 cancer-related diseases is accumulated. 

Initial approval by the FDA is a significant milestone based on demonstration of a treatment’s safety and efficacy, which are evaluated through carefully designed and controlled clinical trials, with research often continuing beyond FDA approval. Clinical experience is gained through post-approval research and the accumulation of evidence from the real-world use of oncology medicines in patients. While the intrinsic “value” (or clinical properties) of a therapy does not change, our understanding of the benefits and risks of the therapy evolves over time as evidence accumulates, resulting in significant interest in understanding the overall value of cancer therapies through this development life cycle.



We have examined this issue and identified a number of pathways that many cancer therapies have in common for providing incremental value following an initial FDA approval.  We summarize these pathways and several examples to illustrate the benefits and challenges in drug development below.



Use Within a Single FDA Approved Indication

In some cases, when patients are in need of new treatment options, the FDA may approve cancer treatments based on compelling surrogate endpoints (e.g., tumor shrinkage) before the completion of definitive long-term studies. The adequacy of the surrogate endpoint in accelerated or regular approval is also contingent upon other factors such as the size of the treatment effect, its duration, and the benefits of other available therapy available to patients. As clinical investigation of safety and efficacy continues, the impact on overall survival and tumor progression can be fully realized using the long-term clinical outcomes data, as demonstrated by the example of crizotinib.

Crizotinib (Xalkori®). Crizotinib was granted accelerated approval by the FDA in 2011 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that tests positive for the protein anaplastic lymphoma kinase (ALK).   Approval was based on two studies that demonstrated that 50% and 61% of patients, respectively, experienced tumor shrinkage, indicating that the medicine was reasonably likely to predict a defined clinical benefit in these patients. In 2013, the FDA updated labeling to reflect the clinical benefit of crizotinib that had been proven through ongoing studies. Patients receiving crizotinib experienced an average increase in progression-free survival of 7.7 months (time from randomization until objective tumor progression or death), which was more than double the three months of the chemotherapy arm of the trial.


Use Earlier In Treatment Line and Earlier Disease Stage

Because cancer is frequently progressive and life-threatening investigational therapies are necessarily tested first in patients with advanced stages of cancer, who have exhausted existing standard treatment options. Indeed, there is evidence that an increasing number of products in oncology are entering market with advanced stage indications.  This creates a theoretical “ceiling” on the amount of clinical benefit that can be expected during initial clinical research impacting economic modeling which attempts to demonstrate value across a broad population of patients, disease severity, and indications. As additional testing is conducted following FDA approval, a therapy may demonstrate efficacy earlier in treatment line (when used prior to other available therapies) and/or disease stage (when used earlier in disease progression) as illustrated by the case of bortezomib.

Bortezomib (Velcade ®). Bortezomib was approved in 2003 to treat multiple myeloma patients who had received two prior therapies and were not responding (third-line therapy). In 2005 the label was expanded to include use earlier in the treatment regimen as a second-line therapy. Study data revealed that the time for the disease to progress was significantly longer in patients receiving bortezomib (6.2 months) compared to those receiving standard treatment (2.5 months).  In 2008 the FDA granted approval for the use of bortezomib as a first-line multiple myeloma treatment after study results demonstrated that patients treated with bortezomib experienced significantly longer time to progression (20.7 months) compared to standard treatment (15 months). Ongoing research revealed the value of bortezomib as a first-line treatment, earlier in the progression of the disease, than initial results suggested.


Use in Additional Disease Indications

Oncology therapies often have clinical value in cancers distinct from the original indication(s) for which they are approved. Studies conducted and reported after the initial approval commonly explore additional indications. Recent (pilot) regulatory considerations for the summary review of Supplemental NDA/BLA Submissions in Oncology may further accelerate approvals given the focus on only summary documents and trial reports. In many instances, a therapy demonstrates significant clinical benefit in a different disease as demonstrated by the case of lenalidomide below.

Lenalidomide (Revlimid®). Lenalidomide was originally approved in 2005 to treat patients with myelodysplastic syndrome (MDS) who had a specific genetic mutation.  MDS is collection of disorders where the bone marrow fails to produce enough healthy blood cells. In clinical studies, patients treated with lenalidomide no longer needed blood transfusions. In 2006, lenalidomide received approval for use in combination with dexamethasone to treat patients with multiple myeloma who had failed other treatments (and in 2015 lenalidomide was approved as a first-line treatment). In 2013, lenalidomide was approved for use against mantle cell lymphoma, as the first oral therapy available for patients with this rare blood cancer.


Use in Combination with Other Agents

Cancer research frequently involves investigating different combinations of new and existing therapies to improve outcomes. Combinations of targeted products may modulate different nodes in the same causal pathway for tumorigenesis, or impact parallel pathways with implications regarding patient segmentation, and the use of concurrent biomarker selection strategies. The use of combination therapies with targeted agents has often produced superior outcomes by enhancing anti-tumor activity by both allowing patients to receive a full-dose of drugs while managing adverse effects, and by attacking the tumor through multiple mechanisms of action to enhance response, expressed as either rate of response, survival rates, or duration of response, as illustrated by the case of everolimus below.

Everolimus (Afinitor®) Everolimus, a rapamycin (mTOR) inhibitor, was approved by the FDA in 2009 for the treatment of advanced renal cell carcinoma (RCC). In July 2012 everolimus was approved for use in combination with exemestane to treat post-menopausal women with advanced hormone-receptor positive, HER2-negative breast cancer. In this form of cancer, a class of medicines called aromatase inhibitors had proven effective at controlling tumors by depriving them of the estrogen hormone, which stimulates their growth. However, over time, many tumors developed resistance to these treatments. Everolimus helped prolong the effectiveness of these treatments by combatting that resistance.


Use in Combination with Specific Biomarkers

Growing understanding of cancer at the molecular level has translated to new diagnostic tools that allow physicians to identify patients as candidates for a therapy based on the presence or absence of a particular gene or mutation (a prognostic biomarker). Biomarkers are used to predict therapeutic response and/or sensitivity to adverse events (a predictive biomarker), allowing clinicians to better select the patients who are most likely to benefit from particular targeted therapies. Ibrutinib illustrates this pathway below.

Ibrutinib (Imbruvica®). In February 2014, ibrutinib received approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have tried at least one prior therapy. In July of that year, FDA expanded the use of ibrutinib to treat patients with CLL who carry a deletion in chromosome 17 (17p deletion), regardless of whether or not they have received prior therapy. The clinical study resulting in this expanded indication demonstrated that patients with the 17p deletion who were treated with ibrutinib experienced a 75% reduction in the risk of disease progression and death.




Implications for Clinical Development Design in Oncology

Clinical trials of interventional oncology have transitioned from an exclusive reliance on measuring efficacy (effects within optimal patients at optimal sites), to assessments of effectiveness (clinical utility with representative patients and providers) toward efficiency (the economic value of the intervention).  In part, this is a reflection of the diverse stakeholders present along the drug discovery/development continuum. Although the importance of acknowledging diverse perceptions is key throughout the discovery/development process, the relative importance attached to each stakeholder perspective has varied considerably throughout the phase of drug development and can be significantly  modified by the therapeutic target. This environment substantively impacts trial design, study location, and methods of execution and analyses. For example, patients might be specifically interested in outcomes directly relevant to the most troubling sign or symptom of the presenting illness or side effects of treatment; while payers may focus on physician adoption, coverage, and pricing including reimbursement method. Correspondingly, the utility of various economic models used to estimate the value of innovative therapy may be limited, given the diverse spectrum of opinions which must be accommodated, and the differential importance given by patients to low probability, but high-impact therapeutic benefits generally obscured by population-based, and payer centric approaches (i.e., “hopeful gambles”).

Given the increasing availability of alternative regimes (often both oral and physician-administered) oncologists often require data within their specific clinical care system to maximize obtaining estimates of healthcare utilization as the most directly relevant method of forming their clinical practice. The need for actionable data necessitates the creation of “microenvironments” within closed healthcare systems in which every physician-patient encounter can be captured. “Nested studies” within overall multicenter trials which focus upon overall healthcare utilization within a specific system  or setting of care, while simultaneously addressing key primary and secondary study oncology objectives, provide one vehicle for addressing these specific needs.

Indeed, in a development program which must include studies covering the entire drug lifecycle, and potential transitions in patient disease severity, the planning for observational studies, including retrospective chart reviews, and longitudinal cohort studies best occurs at the end of first in human studies in which preliminary descriptions of product characteristics are available. Alternatively, international registries can be used to create single arm studies of efficacy and safety for patients not qualifying for controlled investigations, which ultimately complement data from randomized controlled trials. These trial designs collectively inform the type of data to be collected concurrently or within registration programs, and ultimately permit a more comprehensive examination of the clinical and economic value of new interventions at the time of product registration.



The healthcare environment is a mosaic of stakeholders, each with remarkably different demands for data addressing product attributes. Neither orderly, nor at times fully rational, these often conflicting perspectives require access to a portfolio of interventional and observational research designs to effectively demonstrate the value of a novel oncology therapy in development to meet these often varied objectives and definitions of stakeholder value.

This dynamic is accentuated by the post-approval addition of new indications for marketed products; development of combinations of targeted therapies which introduce uncertainty into the regulatory process, pricing strategy and market penetration; the explosive growth in the need for both prognostic and predictive biomarkers which further fractionate the population where therapy eventually might be appropriate, and a need to accommodate the needs for increasingly granular data for a diverse audience. A business development philosophy which incorporates a strategic, rather than study specific view offers best prospects for addressing, in the proper sequence, hypotheses that are considered relevant to both regulatory approval, and eventual commercialization. Increasingly central in this process is the inclusion of observational studies launched in tandem and sequentially to required interventional trials, which provide insights from representative patients and representative practitioners and settings, who may be missing from traditional interventional studies encountered in the course of oncology drug development.


Thomas F. Goss, Pharm.D.  is the Senior Vice President at Boston Healthcare Associates. Nicole Sweeney is the Manager of Boston Healthcare Associates.  Michael F. Murphy, M.D., Ph.D., is the Chief Medical and Scientific Officer of Worldwide Clinical Trials

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