21st Century Diagnostics—The Foundation of Personalized Medicine

By Peter J. Pitts

Personalized medicine is the wave of the present. Genetics, weight, diet, age, lifestyle, gender, and race, among other factors, define who we are—as people and as patients. Even so, we still can’t always accurately predict which patient will benefit, which one will suffer from a rare but serious adverse event. The good news is that, more often than ever before, we can predict which patients will benefit most from a new therapy, and which ones may be at risk for a rare but serious adverse event. 21^st century diagnostic testing[1] is the foundation of 21^st century personalized medicine.

The landscape of drug approval and regulatory oversight has undergone significant transformations in the past few decades. One of the pivotal moments in this evolution was the reintroduction of Tysabri (natalizumab) in 2006, marking a shift in how regulators and pharmaceutical companies balance risk and benefit in drug approval and management.

Originally approved by the FDA in 2004, Tysabri, a monoclonal antibody used for treating multiple sclerosis[2] (MS), was initially withdrawn from the market due to its association with progressive multifocal leukoencephalopathy[3] (PML), a rare but serious brain infection. However, a reevaluation of its efficacy and risk management led to its reapproval under a Risk Minimization Action Plan (RiskMAP)—which was, shortly afterwards, grandfathered in as a Risk Evaluation Mitigation Strategy (REMS).[4]

A Regulatory Turning Point

Prior to Tysabri’s return, regulatory decisions often followed a binary model: either approve a drug or withdraw it based on emerging safety concerns. The decision to bring Tysabri back represented a shift toward iterative risk management, where ongoing monitoring and evolving safety measures could allow high-efficacy drugs to remain available despite known risks.

Dr. Janet Woodcock, then the Director of the FDA’s Center for Drug Evaluation and Research (CDER), played a crucial role in advocating for this new approach. Instead of a blanket withdrawal, the FDA and the drug’s manufacturers, Biogen and Elan, collaborated to implement a rigorous post-marketing safety program.[5] This program enabled the continued use of Tysabri while minimizing the risk of PML through patient stratification, monitoring, and real-world evidence collection.

Building a Risk Management Framework

The risk of PML associated with Tysabri was initially estimated at around one in a thousand, a significant increase from the background risk of one in a million. This necessitated the development of new tools and methodologies to better assess and mitigate patient risk.

One of the most critical advancements was the development of the JC virus (JCV) assay,[6] which enabled stratification of patients based on their likelihood of developing PML. The assay, combined with additional risk factors such as prior immunosuppressant use and treatment duration beyond two years, helped refine patient selection and informed clinical decision-making.

To further enhance risk minimization, Biogen developed an extensive classification system for PML cases, which included a five-stage algorithm for diagnosis and verification.[7] A dedicated team of PML coordinators and in-house as well as external experts continuously monitored and evaluated cases, ensuring that patients received the safest possible treatment pathway.

Challenges in Physician and Patient Communication

One of the major hurdles in implementing REMS was ensuring that physicians could effectively communicate complex risk information to patients. The burden of risk assessment and patient education fell heavily on healthcare providers, requiring additional resources and training. To address this, Biogen established a patient service center that actively worked with both physicians and patients to navigate the complexities of risk-benefit assessment and adherence to monitoring protocols.

Despite these efforts, there remained concerns about the practicality of such a resource-intensive program. Questions arose regarding whether REMS could be streamlined and whether similar frameworks could be applied across different regulatory jurisdictions without excessive complexity.

Real-World Evidence and Adaptive Learning

A key breakthrough in Tysabri’s ongoing management was the adoption of real-world evidence in refining its use. For example, physicians began adjusting the dosing regimen by extending the interval between infusions from four to six weeks. This real-world practice eventually led to formal recognition and was incorporated into the drug’s label after demonstrating a reduction in PML risk. This exemplifies how real-world data can complement clinical trials and enhance drug safety profiles over time, reinforcing the importance of continuous learning in pharmaceutical regulation.

Global Regulatory Variability and Future Considerations

While the U.S. FDA has embraced adaptive risk management approaches, global regulatory bodies, including the European Medicines Agency (EMA)[8] and Japan’s Pharmaceuticals and Medical Devices Agency[9] (PMDA), have different frameworks. The variability in REMS-like programs across jurisdictions presents challenges for harmonization and efficient global drug development.

A case in point was the European reassessment of Tysabri under Article 20 procedures,[10] which required a full reexamination of its benefit-risk profile. This underscores the need for greater international alignment in post-market surveillance and regulatory decision-making to avoid redundant processes and optimize patient safety.

Broader Implications for Drug Development

The Tysabri experience has broader implications for future drug approvals, particularly in neurology and other complex therapeutic areas. It raises important questions about whether regulatory agencies will increasingly demand companion diagnostics during initial approval phases and how manufacturers should anticipate and integrate risk stratification into drug development.

Moreover, the lessons from Tysabri demonstrate that Accelerated Approval[11] mechanisms do not equate to regulatory failure when drugs are withdrawn or reassessed. (Tysabri was initially approved via the FDA’s Accelerated Approval pathway.) Rather, they illustrate the success of a system designed to balance innovation with patient safety, ensuring that high-benefit therapies remain available while continuously evolving based on emerging data.

Times change and science advances. In late 2022, researchers identified several rare genetic mutations that signal a higher risk—as much as 10X—of developing PML.[12] This discovery won awards and was heralded by the American Neurological Association, and the inventor of natalizumab, Dr. Lawrence Steinman[13] of Stanford University.

Unfortunately, two years later, due to negative financial incentives and the absence of a regulatory framework, this test is not a part of the FDA’s REMS plan and hasn’t become standard medical practice. Unless and until this new diagnostic tool is on the natalizumab drug label and in the REMS protocol, busy neurologists won’t know to act, and testing will not be reimbursed by insurance companies.

The slow adoption of such advanced diagnostic tools is not unique to drugs for Multiple Sclerosis. Eighty-one therapies are linked to PML risk.[14] Nor is this only an issue for MS patients. Earlier this year, a judge penalized two pharmaceutical companies one billion dollars for being a decade too slow in alerting physicians that some blood thinners would not work on certain non-white patients. According to the judge,[15] the sponsors “deliberately turned a blind eye toward the diminished response problem.” As a result, the judge continued, “physicians practiced for more than a decade without the necessary information needed to evaluate the serious limitations.”  

Conclusion

The responsibility of risk is a shared responsibility.[16] It must be more than what the FDA expects from industry and more than what industry expects from the FDA. It is what all parties to the public health conversation must expect from themselves, which means going far beyond anything to do with marketing or sales or stock price or legislative authority. It means doing what’s right in addition to what is required.

The reintroduction and continued evolution of Tysabri serves as a model for modern regulatory science. By leveraging real-world evidence, advanced diagnostics, and adaptive risk management, regulators and manufacturers can navigate the complexities of high-risk, high-reward therapeutics. As the field advances, the principles established through Tysabri’s journey will likely shape future approaches to accelerated approval and post-market surveillance, ultimately improving patient outcomes while fostering medical innovation.

Personalized medicine policies should not come via the courts, but neither should regulatory updates and the modernization of medical practice take ten years to become standard practice. Making existing drugs safer is as important as discovering the next miracle molecule. It is imperative that the FDA, pharmaceutical innovators, and the insurance industry embrace the need and develop and integrate breakthrough diagnostics as they emerge. To quote Stanford University’s Dr. Steinman, “Preventive screening . . . should become part of the standard of care.”[17]

 

[1] San Francisco Chronicle. “Trump Administration Cuts Reach FDA Employees.” Available at: https://www.sfchronicle.com/news/politics/article/trump-administration-cuts-reach-fda-employees-in-20170867.php.

[2] Mayo Clinic. “Multiple Sclerosis – Symptoms and Causes.” Available at: https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269.

[3] Cleveland Clinic. “Progressive Multifocal Leukoencephalopathy (PML).” Available at: https://my.clevelandclinic.org/health/diseases/6101-progressive-multifocal-leukoencephalopathy-pml.

[4] https://www.fda.gov/files/about%20fda/published/Standardizing-and-Evaluating-Risk-Evaluation-and-Mitigation-Strategies-(REMS).pdf#:~:text=to%20require%20REMS%20for%20prescription%20drug%20and,informed%20the%20development%20and%20implementation%20of%20REMS.

[5] Tysabri HCP. “TOUCH Prescribing Program.” Available at: https://www.tysabrihcp.com/en_us/home/touch-prescribing-program/touch-online.html.

[6] PMC. “How Tysabri Survived.” Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC4883008/.

[7] PMC. “Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group.” Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC4752634/.

[8] European Medicines Agency (EMA). “Homepage.” Available at: https://www.ema.europa.eu/en/homepage.

[9] Pharmaceuticals and Medical Devices Agency (PMDA). Available at: https://www.pmda.go.jp/files/000152996.pdf

[10] EMA. “Article 20 Referral Procedures – Q&A.” Available at: https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/referral-procedures-human-medicines/questions-answers-article-20-non-pharmacovigilance-procedures.

[11] https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program.

[12] https://pmc.ncbi.nlm.nih.gov/articles/PMC9795231/.

[13] Stanford Medicine. “Lawrence Steinman Lab.” Available at: https://med.stanford.edu/steinmanlab/lawrence_steinman.html.

[14] New England Journal of Medicine (NEJM). Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa1107829.

[15] Reuters. “Bristol Myers, Sanofi Liability in Hawaii Plavix Case Grows to $916 Million.” Available at: https://www.reuters.com/legal/bristol-myers-sanofi-liability-hawaii-plavix-case-grows-916-million-2024-05-22/.

[16] Springer. “Associate Editor’s Commentary: PEEKABOO—ETASU!” Available at: https://link.springer.com/article/10.1177/0092861512438840.

[17] Clinical Lab. “Experts Recommend Genetic Testing to Prevent Fatal Brain Infection.” Available at: https://www.clinicallab.com/experts-recommend-genetic-testing-to-prevent-fatal-brain-infection-27144.

[1] Reuters. “Bristol Myers, Sanofi Liability in Hawaii Plavix Case Grows to $916 Million.” Available at: https://www.reuters.com/legal/bristol-myers-sanofi-liability-hawaii-plavix-case-grows-916-million-2024-05-22/.

[1] Springer. “Associate Editor’s Commentary: PEEKABOO—ETASU!” Available at: https://link.springer.com/article/10.1177/0092861512438840.

[1] Clinical Lab. “Experts Recommend Genetic Testing to Prevent Fatal Brain Infection.” Available at: https://www.clinicallab.com/experts-recommend-genetic-testing-to-prevent-fatal-brain-infection-27144.