Personalized Medicine and Public Good: 3 Critical Issues (Part 2 by Johnathan Ng)

This article is the second part in a two-part series by Dr Johnathan Ng of Epibone, on personalized medicine and public good.

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Personalized Medicine and Public Good: 3 Issues that Must Be Tackled

In my first article, I gave an overview of personalized medicine: personalized disease-modifying drugs, autologous cell therapies and stem cell therapies.

It is easy to be swept away by the promises of precision medicine. In his speech on the Precision Medicine Initiative, then-President Obama made uplifting points, “And that’s the promise of precision medicine – delivering the right treatments, at the right time, every time to the right person… we want to have a nation in which the accidents and circumstances of our birth aren’t determining our fate, and therefore born with a particular disease or a particular genetic makeup that makes us more vulnerable to something; that that’s not our destiny, that’s not our fate – that we can remake it.” 

Indeed, the potential benefits are tremendous, but so are the risks: in the form of escalating medical bills, with unproven – or worse still – harmful treatments. In this article, I give Governments and Healthcare providers three areas to pay attention to when it comes to personalized medicine: Regulation,  Healthcare Finance, and democratizing the benefits of personalized medicine.

  1. New Pressures on Regulation

As new personalized treatment modalities emerge, regulators are facing increasing pressure to green-light interventions, even if clinical benefits are not clear – to provide patients with a chance to live.

A watershed case was the US Food and Drug Administration (FDA)’s ruling against a scientific advisory panel, in favor of patient advocacy groups to approve Exondys 51 marketed by Sarepta for treating Duchenne Muscular Dystrophy. Despite a majority (7 to 6) of the experts citing inadequate convincing clinical evidence, the FDA director greenlit the approval of Exondys 51 due to a lack of clinical alternatives. Many commentators felt that this case set a precedent for the approval of personalized medicine products based on surrogate endpoints without clinical benefits.

There are also many grey areas when it comes to regulating clinical trials. As with any emerging technology, the benefits come at a risk, which people desperate for a cure may be willing to take. Due to the exploratory nature of trials involving new treatment modalities, patient safety is often left in the hands of researchers: a simple search on ClinicalTrials.gov shows nearly 6000 clinical studies involving stem cells, some of which have not been approved.

Some of these trials have resulted in debilitating consequences. For example, severe adverse effects, some resulting in death, turned the spotlight on Juno Therapeutics’ lead CAR-T cell therapy for treating adults with late stage acute lymphoblastic leukemia. The risks of stem cell therapy are also not well understood. Although treatment with autologous fat-derived stem cells has been used for various indications, a poorly administered trial recently led to permanent eye damage in three elderly patients with macular degeneration (damage to parts of the retina in one’s eye).

Without proper regulation and well-controlled clinical trials, the safety and efficacy of stem cell treatments cannot be determined.

Some researchers show more caution than others. In the first human trial that uses an induced pluripotent stem cells (iPSCs) derivative, investigators from Japan successfully treated macular degeneration  by administering retinal pigment epithelial cells grown from the patients’ own stem cells. Yet, after identifying a few mutations in the second patient’s cells, the RIKEN group decided to suspend the trial in September 2015 before obtaining clearance from health authorities in Japan to resume in February 2017. Perhaps all scientists and clinicians would do well to hold themselves to a similar standard.

Regulatory bodies such as the FDA must continually engage and balance the needs of the scientific, patients, and clinical communities in meeting these new regulatory challenges – unfortunately, there are no easy answers.

2. New Pressures on Healthcare Finance

With the flood of new interventions, another issue to consider is cost. If all interventions are fully reimbursed (i.e. paid for) by state and private payers, the healthcare system will soon become bankrupt. Yet, if no help is given, the cost to patients of living longer is bankruptcy. The American Society for Clinical Oncology (ASCO) wrote in a brief that a patient living with cancer is now three times more likely to file for bankruptcy than a healthy person.

Policymakers must strike a fine balance of curbing the rapid rise in healthcare spending without disincentivizing innovation and depriving patients of access to life saving treatments.

When weighing the clinical benefits of a new drug product with the cost, healthcare economists typically apply a measure called the incremental cost effectiveness ratio (ICER) which takes the difference in cost between the new drug and existing alternatives and divides it by the change in quality adjusted life years (QALY). The National Institute for Health and Clinical Excellence (NICE) of the U.K., for example, sets an ICER limit of £30,000 per QALY gained for new drugs including targeted therapies. Most policymakers in the U.S. generally apply an ICER limit of USD$50,000 per QALY gained.

Early evidence suggests that personalized medicine tests are generally cost effective, with 20% of them resulting in cost saving and more than half achieving ICER of less than $50,000 per QALY gained. However, measures of cost effectiveness apply a single threshold to a heterogeneous population. If reimbursement was based on this alone, some people would receive more healthcare than they would choose, and others less. As such, commentators have noted that “reimbursement mechanisms for targeted therapies are still very blunt in an era of personalized medicine”.

Policymakers must leverage data and work with other stakeholders to improve reimbursement policies, especially taking into consideration the underserved population. Yet, the onus does not belong to the policymakers alone. Drugmakers, payers and clinicians are very much involved in the determining how drugs are priced and reimbursed. Recently, there have been exhortations by clinicians for more value-based pricing whereby reimbursement is contingent upon patient outcomes. The focus on outcomes could ensure that personalized medicine realizes its full clinical value. To achieve that, drugmakers could enter risk-sharing agreements with payers for partial reimbursement prior to demonstrating clinical effectiveness.

Alternatively, clinicians can also exert pricing pressure on drugmakers indirectly. In 2012, researchers from Memorial Sloan Kettering Cancer Center (MSK) evaluated the drugs Zaltrap and Avastin for treating colorectal cancer. Although Zaltrap cost twice as much as Avastin, the MSK researchers found no differences in efficacy between the drugs. Consequently, MSK decided to not recommend Zaltrap to patients and this led the drug’s co-marketer Sanofi to drop the price.

Together, stakeholders can work to ensure that personalized medicine is conscionable and cost effective.

3. Democratizing the impacts of Personalised Medicine

Finally, perhaps personalized medicine should be about more than just the diagnosis and the cure. Personalized medicine could go a long way towards disease prevention and mitigation by engaging the laymen and teaching them to monitor and manage their own health. In a recent trip with my parents to their dental appointment at a polyclinic in Singapore, I could not help but notice that the Health Promotion Board set up a booth that encouraged senior citizens to get screened for colorectal cancer. Participants were instructed to fill out their information, collect samples of their stool at home in the kits provided, and send the kits back for analyses. Though seemingly mundane, campaigns like this are probably the most effective way of bringing personalized medicine to the masses.

Low cost point-of-care diagnostics can also help to bridge the divide between first world medicine and third world need for solutions. After all, if the goal of personalized medicine is to understand and improve lives, esoteric treatments will hardly do a majority of the public any good.

Finally, it is a positive development that countries are thinking about how to democratize the benefits of personalized medicine. For example, the U.S. National Institute of Health is collecting data from underserved populations that are historically underrepresented in biomedical research, so that they too can benefit from personalized medicine.

In conclusion

We have already seen the good that personalized medicine can do. Yet, if we want the broader public to benefit from personalized medicine while minimizing both the financial and clinical risks to society and patients, there is still so much more that we must do. Stakeholders must continue working together to advance the personalization of medicine, not for fame or fortune, but for the greater good.

Johnathan Ng
Thanks, Johnny!

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Thanks for reading this two-part series on personalized medicine and public good. When I started this blog, one objective was to use it as platform for issue-experts in technology fields to give us mini crash-courses, and to sketch out the implications for society. I am sure Johnathan will be more than happy to discuss these issues further. Let me know if you’d like to be connected!

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A Crash Course on Personalized Medicine: (Part 1 by Johnathan Ng)

This week, I have my dear friend and brilliant scientist, Dr Johnathan Ng, PhD in Biomedical Engineering at Columbia University, give us a crash course on personalized medicine – what is it? what does it mean for the field of medicine and society? Johnathan now works at a start up in NYC, which grows bone for facial reconstruction. This is a two-part series, with the first part focusing on an overview of personalized medicine, and the the second part focusing on implications for healthcare systems and Governments. A super educational read for anyone with interest in the healthcare space. I certainly learned a lot while editing. Enjoy!

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Image: https://www.wilsoncenter.org/article/personalized-medicine-faustian-bargain

It’s getting personal

Personalized medicine has been hailed as the future of healthcare. At the forefront of clinical and scientific debate lie questions that could transform our healthcare landscape. Can medicine truly be personalized? Will the “personalized medicine” of today simply be medicine in the future? How can we leverage the personalization of medicine for the betterment of humanity?

A Brief History of Personalized Medicine

First, what is personalized medicine? In contrast to conventional medicine, which applies statistical information taken of the general population to the individual, personalized medicine uses information about a person’s genes, proteins and environment to prevent, diagnose and treat diseases.

As the prescient Hippocrates once said, “It’s far more important to know what person the disease has than what disease the person has.” The roots of personalized medicine predate our understanding of the human genome. For example, blood type matching for transfusion between the donor and the recipient to prevent hemolysis due to incompatibility was first reported more than century ago.

However, it is only with recent advances in genome sequencing technology that we can map the human genome and study it at an unprecedented scale. This has ushered in a new era of personalized medicine. In this overview, I cover three aspects of personalized medicine: 1. Personalized disease modifying drugs; 2. Autologous cell therapies; and 3. Stem cell therapies.

  1. Personalized Disease-Modifying Drugs

Some of the earliest breakthroughs in personalized medicine came in the form of personalized disease-modifying drugs, including:

  1. Breast cancer. In 1998, researchers found that a particular type of protein, HER2, was overexpressed in aggressive breast cancer cases. Consequently, Herceptin, an antibody therapy which suppresses HER2 activity, and a companion diagnostic test for HER2 expression in breast cancer cells were approved. These have become standard treatments today.
  2. Cystic Fibrosis. In 2012, the U.S. Food and Drug Administration (FDA) approved Kalydeco, a drug for treating cystic fibrosis by restoring the function of a protein misfolded due to mutation of the G551D gene. Restoring this protein’s function abolishes mucus buildup that leads to life-threatening respiratory and digestive problems. With that approval, Kalydeco also became the first drug that treats the underlying cause of the disease and not the symptoms.
  3. Immunotherapy. Over the last two years, a new class of antibody called checkpoint inhibitors was approved for treating some cancers. Opdivo and Keytruda are antibodies that disable checkpoints in immune cells by neutralizing the programmed death receptor (PD-1). Thus, immune cells bypassing these checkpoints are able to kill cancer cells more effectively. In a recent pivotal study, Merck showed that Keytruda reduced the risk of death by 40% among patients expressing PD-L1 levels greater than 50%.

2. Giving our cells superpowers: Autologous Cell Therapies

Besides harnessing information encoded in our genes to improve treatment response, personalized medicine is also about helping to unleash the immense capacity of our body to repair and mend itself.

Our cells contain information, latent or potent, that can be manifested into cure. Autologous cell therapy involves harvesting cells from a patient’s body, enriching the cell population outside of the body, and re-infusing the cells into the body.

The New York Times documented the miraculous journey of Celine Ryan who enrolled in a revolutionary clinical trial for her advanced colon cancer. Inherent in our immune system is the ability of lymphocytes[1] to locate, infiltrate and kill tumors. However, some tumors grow to counteract our immune response by damping or evading it. To help Ms Ryan overcome her tumors, the doctors mined her lymphocytes from the tumors, enriched and re-infused them into her body. These enriched lymphocytes intensified their attack on the tumors and after 9 months, she gradually recovered and entered full remission.

The success of Ms Ryan’s clinical trial provided scientists with a new strategy: engineering and enhancing patients’ T-cells to target and destroy tumor cells with distinct markers. These engineered cells are known as chimeric antigen receptor (CAR) T-cells, and they have both the ability to locate and destroy their targets. Emma Whitehead, 6, suffered from acute lymphoblastic leukemia (ALL) and twice relapsed from chemotherapy treatment. Without any other resort, her parents turned to an experimental treatment which used CAR T-cells to target CD-19, a marker expressed by both her healthy and malignant B-cells. The doctors rescued Emma from the brink of death and she is now cancer free.

3. Stem Cell Therapies

Stem cells are unspecialized cells with the ability to renew and differentiate into specialized cell types that make up our entire body during development. Even in adulthood, stem cells exist in multiple places in the body such as the bone marrow and fat tissues. Not surprisingly, they have also been heralded as a frontier for personalized medicine. At the biotechnology startup where I work, we engineer bone from a patient’s fat-derived stem cells to replace bone where it is needed. We successfully engineered bone from fat-derived stem cells and used it to regenerate a pig’s missing facial bone. Our next goal is to get the product into the clinic to help patients suffering from bone defect. There is reason to be optimistic: skin, trachea and bladder engineered from patients’ cells have already been successfully implanted.

Some key limitations remain in stem cell therapy as adult stem cells have a limited range of differentiation. Although embryonic stem cells are pluripotent (meaning that they can differentiate into any cell type), there are ethical limitations to using them as they require the sacrifice of embryos.

To overcome these limitations, Dr. Shinya Yamanaka and colleagues discovered a method to induce adult somatic cells into a pluripotent state. These cells, termed induced pluripotent stem cells (iPSCs), have ignited the imagination of scientists and clinicians as they could enable the treatment of diseases caused by the failure of specialized cells such Parkinson’s disease and heart failure. In a recent interview, Dr. Yamanaka (now a Nobel laureate) confirmed that clinical trials for iPSCs therapy will be underway over the next decade. However, he also cautioned against overstating the benefits of targeted stem cell therapies as they can only address a small subset of all human diseases.

What does personalized medicine mean for society?

Personalized medicine is improving the precision and efficacy of treatments by enabling the clinicians to make more well-informed decisions. Advances in pharmacogenomics have helped to reduce wastage of drugs and their incurred cost due to non-responders, and tailor the dosage according to the patient’s metabolism.

However, these efforts are not without cost. The cost of developing targeted therapies in an era of precision medicine is almost $2.6 billion. These treatments also bring about new regulatory risks for hospitals and Governments, who are facing increasing pressure to green light advances that give people unprecedented (but perhaps unproven) hope. My next article elaborates on three areas that Governments and healthcare systems need to pay attention to when it comes to personalized medicine, to maximise its benefit to public good.

Stay tuned!

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[1] Tumour-infiltrating Lymphocytes