The Personalized Power of the “N-of-1” Approach

Randomized, controlled clinical trials with a large N—number of participants—are the recognized “gold standard” of evidence-based medicine. Even so, the results of large-N trials can only reveal population averages, and are not predictive of any individual’s response to a given treatment. On the other hand, one can consider every patient with cancer as the sole participant in their own clinical trial with an Nof1, even if the trial is not officially registered, reported, or supported like a traditional trial.

Here, our Curious Dr. George discusses the value of the “n-of-1” approach with Glenn Sabin, director of strategy and business development at Cancer Commons. Sabin is a 33-year cancer thriver and author of n of 1: One Man’s Harvard-Documented Remission of Incurable Cancer Using Only Natural Methods.

Curious Dr. George: Among the many people whose cancer progresses beyond guideline-based standards of curative care, how might one become an n-of-1 trial participant, if they so choose? What actions should be taken by the physicians who bear responsibility for such individuals who desire to further collective knowledge—and their own welfare—by voluntary participation in use of investigational drugs or drug combinations, or off-label use of drugs approved for other contexts by the US Food and Drug administration (FDA)?

In my view, the n-of-1 approach is clinical care and should be paid for by reputable insurance companies. And, the patient can provide fully informed consent, even with the proviso that the process and outcome be shared for educational purposes. Could this approach become a nimble form of adaptive clinical trial? What are its pros and cons?

Glenn Sabin: From my perspective, randomized, controlled trials (RCTs) will continue to be important for population-based investigational cancer drug development—especially when effectively translated to clinical practice.  Standard-of-care treatment that follows guidelines from the National Comprehensive Cancer Network (NCCN) remains effective for many patients who host early-stage and more indolent disease.

However, for those living with advanced and rare cancers—and for whom standard care has not enabled deep and durable remissions after multiple lines of treatment—it is critical to consider a more personalized approach to testing and treatment.

After all, there is only one host (the unique person living with cancer) and one tissue/tumor type (no two malignancies are exactly alike). This is why we are each an Nof1—an experiment of one. This is the distinction between population-based investigations (RCTs) and truly personalized cancer care (Nof1): averages versus individualization.

I see a future close on the horizon where each patient goes through a deep set of diagnostic testing beyond today’s molecular testing (which itself is not used nearly often enough). The resulting data, consisting of multiple datasets, are then precisely interpreted to inform—with the assistance of artificial intelligence—the patient’s best option for their next treatment. Then, the chosen therapeutics are secured, typically in combinations and often as off-label, and administered to the patient.

Alas, in today’s reality, this type of n-of-1 care—even among the most affluent, educated and connected patients—is largely inaccessible. Access is key.

Novel Testing
Testing beyond certain FDA-approved molecular (sequencing of DNA/RNA) and other diagnostics is not currently covered by Medicare or commercial insurance. Those interested in functional testing—the testing of their own tumor tissue across scores of drugs and combinations—need to pay out of pocket, and some of these novel assays can get quite expensive.

Interpretation of Testing Results
These novel tests produce lots of data. Now what? The problem is that very few oncologists can interpret beyond the “targetable” biomarkers and mutations shown in molecular sequencing reports, which typically cover a small set of genes. Add to the mix novel multi-omics assays (looking at proteins, metabolism, the microbiome, and more) and functional testing, and oncologists are not trained to review in a way that supports the treatment decision-making process. Third-party professional services are needed.

N-of-1 Physicians
Oncologists are trained to deliver standard-of-care cancer treatment as defined by NCCN guidelines. Across the US, some oncologists within community practices will consider prescribing outside of these guidelines when patients have relapsed multiple times. Other oncologists, especially within academia, will only depart from NCCN guidelines under an institutional review board (IRB) and investigative new-drug (IND) study setting, even if such a study is created for only one patient (N of 1). In general, oncologists need internal institutional support to prescribe off label, both from their tumor board colleagues and from colleagues who ensure they feel comfortable about potential toxicity when using drugs with limited or no studies capturing potential for severe adverse events.

Drug Access
Today, approximately 30% of all FDA-approved anticancer therapeutics are prescribed off label. Physicians always have the option to prescribe in this way. One major issue is getting off-label drugs covered by Medicare or commercial payors. Otherwise, providers must advocate for their patients (without reimbursement for their efforts) to apply to various programs such as Expanded Access and Compassionate Use. And there is no financial incentive to do so because drugs secured through these channels cannot be marked up.

Data Collection and Registry Studies
The most effective and efficient way to capture n-of-1 managed and treated patient data is within an IRB-compliant registry connected to a learning health system. This approach collects real-world evidence and allows us to learn from each patient in near-real time. The gold-standard comprehensive learning health system does not yet exist, but I understand that progress is moving apace.

Making N-of-1 Cancer Care a Reality
At Cancer Commons, we are actively pursuing solutions to making comprehensive, end-to-end, n-of-1 patient navigation and treatment a reality. Every day we are working on eliminating the obstacles to access, in service of improving the human condition for those hosting advanced disease, and their families and loved ones.

Progress is inexorable.

Mr. Sabin can be reached at glenn.sabin@cancercommons.org.

***

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.