Prognostic biomarkers, preventive medicine, and the aging population challenge

By 2050, the US Census Bureau estimated that the number of US residents 65 or older will double to reach almost 87 million, representing about 21% of the US population (2010 estimated: 40.2 million, 13%).

In keeping with this aging trend of the US population, the Alzheimer’s Association predicts that, based on current estimates of Alzheimer’s disease (AD) prevalence (5.4 million or 13% of people 65 or older), between 11 and 16 million of individuals will suffer from AD by 2050.  Similarly, the number of individuals suffering from Parkinson’s disease (PD) is also expected to increase dramatically: the incidence of PD increases dramatically in people 50 and older (see Incidence of Parkinson’s Disease: Variation by Age, Gender, and Race/Ethnicity for reference).  Considering these figures, the need for efficacious treatment of AD and PD are urgently needed (as of today, there is no preventive or disease modifying treatment for either AD or PD). 

Treatment of AD and PD is particularly challenging because when an individual starts to present the clinical sign of the disease, a great deal of damage has already be made to critical structures of the brain.  Therefore, most specialists in AD and PD believe that early intervention will be critical to successful therapies in these diseases.  Ideally, individuals at risks will be treated prior to the onset of any clinical sign of the disease in a truly preventive manner. But, how do you identify individuals at risk?  Genetic predispositions that could be detected by genetic tests only represent a minor fraction of the individuals at risk of AD or PD.  New brain imaging biomarkers and possibly cerebro-spinal fluid biomarkers currently under development could turn out to be valid prognostic biomarkers. However, in this new era of healthcare cost control, it is difficult to imagine that such sophisticated and/or complex techniques could be practically deployed to assess all individuals 50 - 60 and older.  Therefore, I would argue that one of the major challenges of addressing the rise of neurodegenerative diseases is to develop low cost and easily deployable screening prognostic biomarkers that could be used as a preliminary step to the more complex definitive prognostic tests.  Already, the PD community (See PARS study) has explored the possibility of using a low cost olfaction test (UPSIT) to screen for individuals at potential risk of PD.  Briefly, in Parkinson disease, the decrease in the sense of smell frequently occurs prior to the onset of motor symptoms.  Although the loss of smell (hyposmia and anosmia) is not specific for PD, identifying individuals with abnormally low sense of smell represents a valid first screen to enrich for individuals at potential risk for PD.

Thierry Sornasse for Integrated Biomarker Strategy

Companion In Vitro Diagnostics (IVD) Development: some clarity at last

On July 14 2011, the FDA Center for Device and Radiation Health (CDRH) posted a Draft Guidance for Industry and Food and Drug Administration Staff - In Vitro Companion Diagnostic Devices.  This draft guidance is a welcome clarification of the FDA’s position on this matter which has remained somewhat ill-defined until now.  Indeed, the rather antiquated rules applying to the approval for commercialization of medical devices have been, to put it mildly, ill-suited for the development of IVD.  Briefly, the rules used by the CDRH were primarily designed to control the commercialization of instruments (e.g. imaging, surgical, drug delivery) which pose direct physical risks to the patients (see CDRH milestones for a timeline).  In contrast, diagnostics and laboratory products impact patient health indirectly: those devices cannot directly harm the patients but the decisions driven by those devices can have a profound impact on the choice of treatment and therefore on the patient health.  Hence, the risk posed by IVD is generally much more difficult to gauge.  I would argue that the co-development of companion IVD and a new drug is even more challenging since the risk / benefit of the drug and the IVD are evaluated in parallel with little or no prior knowledge.  Hence, a modernization of this process is urgently needed.

Combined with the recent independent report from the Institute of Medicine about the FDA CDRH 510 k process (see previous post), this draft guidance on Companion IVD seems to indicate that the FDA CDRH is trying to catch up with the evolution of the field.

Thierry Sornasse for Integrated Biomarker Strategy

Genetic biomarker: the power and risk of knowing

Last year, several companies providing genetic testing to the general public received a warning from the FDA notifying them that their products may be regulated by the agency as a diagnostic device.  On July 19 and 20, 23andMe – one of the leading company in the area of personal genetic testing – participated to the FDA/CDRH Public Meeting on Oversight of Laboratory Developed Tests (LDTs) to address the possible implications of providing genetic testing directly to the public. An excellent account of this meeting is available at The Spittoon » 23andMe at FDA/CDRH Public Meeting on Oversight of Laboratory Developed Tests (LDTs).

The key issue debated at this meeting is to determine the risk of this new type of testing to the public (the main mission of the FDA). Unlike traditional diagnostics which have a relatively clear and defined impact on the course of treatment for a patient on a short term basis, personal genetic testing is fundamentally a prognosis tool, opening the door to the ill-defined area of predictive medicine.  Except for the specific genetic tests aimed at identifying the risk of responding favorably or unfavorably to a specific drug, genetic testing provides an estimate of the future risk of developing a specific genetically-linked disease or condition.  Most of the genetic traits associated with genetically-linked diseases do not constitute an inexorable sentence for the patient since these traits are substantially influenced by the environment and with other genetic traits.  For example, the presence of the mutated LRRK2 gene in ones genome carries a high risk of developing Parkinson’s disease at a relatively young age.  However, among mutated LRRK2 carriers, there are individuals who have reached old age (> 80 year-old) who do not show any sign of Parkinson’s disease.

Since genetic testing as a prognosis for future disease does not immediately impact the safety of patients, what might be the risks associated with this new type of testing?  At the personal level, I would argue that the main risk is psychological.  Depending on the individual propensity and state of mind, discovering that a specific disease is in ones future can lead to positive changes or can lead to irrational fear.  Take the example of Sergey Brin, the co-founder of Google and husband of Anne Wojcicki the co-founder of 23andMe.  In 2008, Sergey learned that he carries the mutated LRRK2 gene, putting him at risk of developing Parkinson’s disease.  Since there is currently no preventive treatment for Parkinson’s disease – the available dopamine-centric medications address the symptoms and not the cause of the disease – he decided to tilt the odds in his favor by starting a strict regimen of physical exercise designed to stimulate his brain’s motor and coordination functions that are affected in Parkinson’s disease.  Sergey’s reaction might not be typical: he is after all a fundamentally positive person.  Therefore, for the general public, counseling is, and should remain, an intrinsic part of genetic testing. 

Beyond the personal psychological impact of learning about ones medical future, the issue of privacy of genetic information is also critical.  Unlike traditional medical diagnostics which reflect a specific state of an individual at a given time, genetic information represents an unalterable and stable characteristic of an individual.  I would argue that this characteristic of genetic information forces us to attribute ownership of genetic information solely to the individual and not to the medical practitioners.  This represents a significant departure from the current practices and will require a major evolution of the medical community.  Furthermore, genetic information poses an additional challenge because at any given time, it contains information of unknown utility.  Indeed, the ability to associate disease risk with specific genetic features is still in its infancy.  It is reasonable to assume that as the field evolves, the ability to interpret an individual’s genetic information will change substantially.  Therefore, ownership of genetic information by an individual should not be limited to its current use but also to its future use: an individual should retain the right to decide whether his/her genetic information should be reanalyzed to account for updated genetic knowledge.

Thierry Sornasse for Integrated Biomarker Strategy

Missing the forest for the trees: Genome structure vs SNPs

In the July 24 issue of Nature Biotechnology, Jun Wang from the Beijing Genomics Institute reports that large scale variations in the structure (e.g. deletion, duplication) of the human genome may contain more information about an individual than the collection of Single Nucleotide Polymorphisms (SNPs) usually reported in genomic biomarker studies such as Genome Wide Association Studies (GWAS). If confirmed, this report would force the field of genomics to rethink the way genomic data is assembled and reported. Indeed, even the most advanced DNA sequencing methods available today rely on chopping the DNA into small fragments that are easy to read but extremely difficult to reassemble into a full, structurally correct full genome.

Read also the piece in Wired magazine about this article: Your Genome Structure, Not Genetic Mutations, Makes You Different | Wired Science | Wired.com

Thierry Sornasse for Integrated Biomarker Strategy

New approaches to improve biomarker discovery

The American Chemical Society released in its Chemical & Engineering News magazine an overview of the successes and failures of biomarker discovery. The conclusions of this article emphasize the urgent need to pay more attention to the critical step of novel biomarker qualification (i.e. the process of confirming the predictive value of a biomarker candidate).

New approaches to improve biomarker discovery

Thierry Sornasse for Integrated Biomarker Strategy

Medical Devices and the Public’s Health: The FDA 510(k) Clearance Process at 35 Years - Institute of Medicine

Today, the FDA CDRH released a report produced by the independent Institute of Medicine about the FDA 510(k) clearance process for devices. Although this document is not specifically about diagnostic assay devices (it covers all devices from MRI systems to pregnancy test), its main conclusion that the 510(k) clearance process is flawed will most likely have an impact on the approval of future diagnostic method derived from biomarker research.

Medical Devices and the Public’s Health: The FDA 510(k) Clearance Process at 35 Years - Institute of Medicine

Thierry Sornasse for Integrated Biomarker Strategy

Translational Biomarker Development: mind the gap

Of all the disciplines and specialties required to develop new drugs, biomarker development is, in my mind, the specialty that has the most to gain from a modern Translational Medicine organization structure (i.e. a seamless integration of all drug development stakeholders from a project inception to its conclusion).  However, throughout my career, I have experienced situations telling me that biomarker development still appears to be fragmented in many bio / pharma companies. Unlike other specialties, such as pharmacokinetics and toxicology which tend to be formally organized to facilitate connection between Research and Clinical, biomarker development still too often tends to exist in discrete, partially isolated functional groups.


If you have worked in the biomarker field, you might be familiar with the following examples of gaps in connection between biomarker stakeholders:

• A clinical team leader asks for a disease modification biomarker less than six months prior to the start of a clinical study 
• A biology research scientist scrambles to develop and validate a biomarker assay method after his/her favorite biomarker is included in a clinical study protocol 
• Regulatory and Legal produce a Patient Informed Consent form that precludes any post-hoc analysis of clinical samples

Let me suggest a two-prong approach to solve this type of issue:

• Organization structure: many companies would gain in setting up a small translational biomarker group serving as the main interface between all biomarker stakeholders. This "hinge" function should be responsible for identifying, communicating, and resolving requirements and issues associated with biomarkers throughout a program's life cycle. 
• Planning process: based on the FDA guidance "Target Product Profile — A Strategic Development Process Tool", I would argue that biomarker development should follow the same path as a drug program. Thus, I would recommend the creation of a "Target Biomarker Profile" for all drug development programs even if biomarker needs appear to be minimal (determining that nothing needs to be done is not the same as ignoring the issue). This TBP would articulate the intended overall goals for biomarkers associated with a given program, defining the intended decision to be driven by the biomarker, the expected impact level of the biomarker on the program, the timing of deliverable, and last but not least, the intended audience of biomarker data. Similarly to the TPP, the TBP should be an evolving document in which initial assumptions should be revisited and new priorities taken into account. 

Thierry Sornasse for Integrated Biomarker Strategy