Patient Access to Immuno-Oncology Agents - A US Policy Perspective

Developments in the field of immuno-oncology (I-O) have ushered in a new era of hope in cancer care. This new concept has forced scientists and clinicians to think beyond the organ of origin of the tumor and wonder about the dynamic interaction between the tumor and its environment.

A significant advantage of I-O, unlike chemotherapy or some of the targeted agents, is the lasting memory created by immunomodulatory drugs on the individual’s immune system. The idea of targeting the host’s immune system evolved from an improved understanding of cancer—the realization that cancer is not an individual disease arising from a single, clonal cell harboring mutations—but rather, cancer can be defined as multiple diseases with a systemic rather than a clonal origin.

The History

Pioneering work by cancer surgeon, William B. Coley, who demonstrated the importance of activating the immune system in a cancer patient (by injecting a live culture of bacteria into the tumor), generated clues leading to the important discovery of the immune system’s role in cancer.¹ Subsequent animal models documented tumor rejection, rather than tumor immunity, which misled scientists resulting in a loss of faith in tumor immunology, until the development of the syngeneic mouse model—where tumors were derived from mice with the same genetic background. This subsequently laid the groundwork for the important role of immune surveillance in cancer.²

The entire immune system participates to help defend the body from the tumor; this includes innate immunity initiated by a cacophony of natural killer cells or NK cells, macrophages, dendritic cells, T- and B cells, and cytokines. The adaptive immune system, which includes the CD4⁺ helper T cells, CD8⁺ cytotoxic T cells, and antibodies, help with the complete elimination of the tumor and help develop the body’s immune memory against tumor components to prevent tumor recurrence.³

Today

The armamentarium of immune defense against cancer has been growing: monoclonal antibodies, tumor vaccines, CAR-T or chimeric antigen receptor-T cells, and the new stream of immune activators. An overview of recent progress with the new I-O agents, including programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte—associated protein 4 (CTLA-4), can be found here. Overall, these agents have been deemed game changers in oncology care, alone or in combination, over the standard of care.

So far, FDA approvals have been restricted to melanoma, non—small cell lung cancer, and renal cell carcinoma, but numerous studies are testing these agents in a variety of solid, as well as, liquid tumors.

And the Issue Seems to Be?

There’s little question that the cost of these drugs, and the resulting copayments and high deductibles, will be a barrier to patient access. Over the years, the oncology drug cost increase has had a steep slope. Given that some of the new drugs provide significant survival outcomes (months, instead of weeks); however, cancer drugs averaged at less than $10,000 annually prior to 2000, while 12 of 13 anticancer agents approved in 2012 were priced over $100,000 annually.⁴ Ipilimumab, a CTLA-4 inhibitor developed by Bristol-Myers Squibb and approved for treatment of patients with advanced melanoma, costs $130,000 for a 12-week course. Nivolumab, developed by the same company is estimated to cost $150,000 annually ($12,500 per month). Pembrolizumab, developed by Merck, costs the same.⁵

High Patient Cost-Sharing

Financial toxicity, in oncology, is not a new phenomenon. In the December 2015 issue of Evidence-Based Oncology, we heard from patients, patient advocacy groups, and health policy experts about the economic impact of cancer, in addition to the physical and emotional cost, on the patient and their family. A recent study in 100 insured patients, who were already receiving treatment for multiple myeloma, between August 2014 and January 2015, found that:

• 59% of patients were surprised by the cost of their care
• 71% felt a small amount of financial burden
• 36% applied for assistance to pay their bills⁶

Another study, investigating the financial outcomes of 550 colon cancer patients, found nearly 40% of patients reported experiencing at least one of the following, after cancer diagnosis:

• Borrowing money from family or friends
• A minimum of 20% income decline
• Accrual of debt
• Selling their primary residence⁷

How Can We Improve Patient Access to These Treatments?

The cost issues are real, but so is the value that the new anticancer treatments bring to the table. If not “cure,” I-O, at the least, has the potential to transform the discussion on cancer outcomes into one of a chronic disease, similar to what the newer treatments have done for hepatitis C.

We need a multi-faceted approach to help patients gain access to I-O and future revolutionary oncology treatments. To guide policy changes, policy makers in Europe have formed the European Expert Group on Immuno-Oncology to encourage rapid and appropriate access to I-O therapies across Europe. You can read more on the group’s proposed framework here.

Here are a few proposed changes that could eliminate barriers to patient access to I-O, within the United States:

Clinical

1. Surrogate Markers

Need to develop surrogate intermediate markers in clinical trials that can predict long-term survival outcomes.

2. Adaptive Trials

Wider use of adaptive clinical trials that have interim analysis points, to balance safety and efficacy while accelerating patient access to life-changing medications.

a. Need for an early “adaptive licensing” plan that matches adaptive frameworks for reimbursement and health technology assessment decisions. Adaptive licensing places emphasis on early access, post-authorization, and real-world effectiveness studies.⁸

3. Trial Design

a. Head-to-head trials between competitor products could yield more value, especially in the case of drugs that yield improved outcomes over the standard of care.

b. Another important point, with respect to trial design, is to make the trials inclusive and diverse, with respect to the patient population.

c. There is also a need to identify predictive biomarkers to choose the right patient population for treatment with a specific agent.

4. Real-World Evidence

Once a product is launched, real-world evidence should be collected and analyzed to understand outcomes in the larger population. This information should then be made easily accessible (eg, by updating information on the trial database ClinicalTrials.gov) to healthcare providers and payers to help them develop a prescription and coverage strategy, respectively.

5. Care Coordination and Clinical Trials

There’s a definite need for rapid referrals and connectivity between physicians. Additionally, providers should be aware of clinical trials, in which their patients can participate, to help boost the current dismal rate of trial participation.

Health Policy

1. Raising Awareness

Spread awareness and understanding on what I-O is and how it is distinguishable from the standard of care or other targeted therapies. Patients, payers, providers, and health policy makers in oncology should all be involved in this discussion.

2. Clinical Pathways

Health plans and individual care institutions have been developing and implementing clinical pathways to streamline treatment plans and make them cost-effective. Clinical pathways mirror either the National Comprehensive Cancer Network Guidelines, or are developed based on existing medical evidence. This approach may not be the most flexible or accommodating of newly approved medications, such as I-O, but they need to be.

3. Value-Based Payments and Risk-Sharing Agreements

Risk-sharing agreements between drug manufacturers and health plans can provide the true assessment of value of a treatment, since the agreements use evidence from the real-world performance of drugs.⁹ The opportunity for outcomes-based agreements, between drug developers and payers/pharmacy benefit managers, could help expensive drugs gain coverage or inclusion on formularies, which, in turn, will improve patient access.

4. Medicare Part D

With cost being a major barrier to access, Medicare should be allowed to negotiate with pharmaceutical manufacturers on brand name drugs covered under its prescription drug benefit program (Part D), just as Medicaid does. According to a brief published last year, if Medicare could secure the same prices as Medicaid does for brand-name drugs, it would result in annual cost savings of between $15.2 and $16 billion.¹⁰

5. PCORI

The Patient-Centered Outcomes Research Institute (PCORI) was established to fund comparative-effectiveness research (CER) that can then be disseminated to patients and clinicians for meaningful clinical decisions. However, Medicare has been prevented from using the CER data that PCORI-funded research generates. This barrier should be eliminated.

6. Competition

Encourage competition to drive down drug prices.

7. Importing Cheaper Drugs

If production costs in the United States and the FDA approval process add to a drug’s development cost, could importing cheaper drugs be an answer? But this could stifle innovation and may not be the most viable alternative.

EBO

With growing healthcare cost concerns in the United States, constructive solutions, that are a win-win for all stakeholders, are the need of the hour.

References

1. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991;(262):3-11.
2. Thomas L. On immunosurveillance in human cancer. Yale J Biol Med. 1982;55(3-4):329-333.
3. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(Suppl 8):viii6-9. doi: 10.1093/annonc/mds256.
4. Kantarjian H, Steensma D, Rius Sanjuan J, Elshaug A, Light D. High cancer drug prices in the United States: reasons and proposed solutions. J Oncol Pract. 2014;10(4):e208-211. doi: 10.1200/JOP.2013.001351.
5. Incollingo BF. Considering cost: what's an immunotherapy worth? Cure website. http://www.curetoday.com/publications/cure/2015/immunotherapy/considering-cost-whats-an-immunotherapy-worth?p=2. Published July 16, 2015. Accessed January 19, 2016.
6. Huntington SF, Weiss BM, Vogl DT, et al. Financial toxicity in insured patients with multiple myeloma: a cross-sectional pilot study. Lancet Haematol. 2015;2(10):e408-16. doi: 10.1016/S2352-3026(15)00151-9.
7. Shankaran V, Jolly S, Blough D, Ramsey SD. Risk factors for financial hardship in patients receiving adjuvant chemotherapy for colon cancer: a population-based exploratory analysis. J Clin Oncol. 2012;30(14):1608-1614. doi: 10.1200/JCO.2011.37.9511.
8. Gravanis I, Vleminckx C, Jonsson B, Pignatti F. The changing world of cancer drug development: the regulatory bodies' perspective. Chin Clin Oncol. 2014;3(2):22. doi: 10.3978/j.issn.2304-3865.2014.05.08.
9. Garrison LP, Carlson JJ, Bajaj PS, et al. Am J Manag Care. 2015;21(9):632-640.
10. Gagnon MA and Wolfe S. Mirror, mirror on the wall. http://freepdfhosting.com/ff84833f9f.pdf. Published 23 July, 2015. Accessed January 20, 2016.

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