Overhaul of the FDA Medical Device Pre-Market Approval Program: What Does It Means for Diagnostics

On October 19^th, the FDA Center for Devices and Radiation Health (CDRH) released its Medical Device Pre-Market Programs: An Overview of FDA Actions (link).  This document presents the center’s review of the processes of pre-market approval of all medical devices, and articulates solutions to the problems identified in this review.

First, CDRH wants to dispel the misperception that safety/effectiveness and innovation are incompatible.  Their solution is not to focus on whether more or less regulations are needed but rather to focus on smart regulation: effectively achieve both aspects of the center’s mission as a regulator and facilitator.

Second, the number one problem identified from discussions with key stakeholders (i.e. industry, academia, and payers) is insufficient predictability in the pre-market program.  This lack of clarity has resulted in inefficiencies, increased cost for both the industry and the FDA, and delays in bringing safe and effective innovative products to the market.  At the root of these problems, CDRH identified excessive staff turnover, insufficient training (FDA and industry), rapidly increasing workload associated with the growing complexity and number of submissions, inconsistent data requirements, insufficient guidance for the industry, and poor quality of industry submissions.

To address these issues, CDRH is proposing a set actions centered on three areas of emphasis:

1. Create a culture change toward greater transparency, interaction, collaboration, and the appropriate balancing of benefits and risks
1. Better engagement with industry
1. Improve Interactive Review (informal call to the submitter) to accelerate review time
2. Improve pre-submission meetings to specify consistent and stable submission expectations
2. Greater use of external experts
3. Implementing flexible, risk-based policies that appropriately balance benefits and risks and apply a more patient-centric approach
4. Establishing new ways of doing business that add value
1. Create an innovation pathway (an entirely novel approach) to enable the timely review of ground-breaking technologies
5. Setting clear expectations for CDRH staff
2. Assure predictable and consistent recommendations, decision making, and application of the least burdensome principle
1. Providing adequate management oversight and staffing
2. Enhancing training
3. Improving internal processes
4. Adopting smarter policies and issuing more guidance
5. Developing new communication tools
3. Implement efficient processes and use of resources
1. Making existing processes more efficient
2. Using our resources more effectively
3. Improving our ability to rely on data from outside the U.S. and actions by regulatory bodies of other countries

For regulatory purposes, diagnostics are medical devices.  Therefore, the changes proposed by CDRH will affect the submission and approval of novel diagnostics.  Specifically, the development and approval of diagnostics will most likely benefit from the improved review process with greater predictability and transparency.  The commitment of CDRH to actively interact with the sponsors will most likely provide greater efficiency and reduced review time.  The call for enrolling experts in the relevant fields should streamline the process of defining the requirements for successful submissions.

While these improvements are promising, CDRH makes no secret that a significant number of these solutions will require additional funding.  The ongoing negotiations of the reauthorization of user fees will therefore most likely result in higher cost for the sponsors.  In keeping with this move, CDRH emphasizes the concept of shared responsibilities by stating: “We must fully embrace the paradigm that assuring the safety and effectiveness of devices is everyone’s job and the responsibility resides as much with industry, practitioners and patients as with the Agency”.

The specific aspect of review of approval of companion diagnostics is not specifically addressed in this report.  The sometime chaotic relationship between CDRH and its drug reviewing counterpart CDER would certainly benefit from a similar review.

Thierry Sornasse for Integrated Biomarker Strategy

The Forces Driving the Future of Personalized Medicine

Transport yourself 10 to 15 years from now and try to imagine what the future of personalized medicine will look like.  The vision of every drug prescription decisions being driven by a test aimed at tailoring the treatment to a particular individual is probably utopian.  Rather, I would argue that the realm of personalized medicine will still be limited to the treatment of severe and/or life-threatening diseases that require expensive medications.  Under this premise, what are the forces that will shape the future of personalized medicine?

In my mind, this question can be addressed by considering the field from a supply and demand perspective.  On the supply end, the pharmaceutical and diagnostics industries will remain the main forces driving the future of personalized medicine.  The imperative of improving the return on investment in drug development will dominate the future of the pharmaceutical industry.  With the era of relying mainly on “one-size-fit-all” drugs fading away, the focus will shift towards precision/personalized medicine where drugs are designed to address the need of smaller targeted patient populations.  Hence, the need to develop the tools that will identify the right patient population (for efficacy and/or safety reasons) will constitute a major theme in drug development.  This does not exclude the continuing effort of the pharmaceutical industry to develop and commercialize broadly applicable drugs for the management and/or treatment of conditions for which a personalized approach is not warranted (for cost-benefit and/or clinical utility reasons).  Still on the supply end but with an eye on the demand side, the regulatory authorities will continue to play a major role in the harmonization of the biomarker and companion diagnostic development process.  Beyond the current regulatory framework governing the regulatory approval of drugs and companion diagnostics, the regulators have been working on developing a new process for an integrated development of biomarkers intended to become companion diagnostics (see earlier posts: Harmonization of Biomarker Qualification Regulatory Submissions; Companion In Vitro Diagnostics (IVD) Development).

Probably the most significant force that will shape the future of personalized medicine will be on the demand side, represented by the patients, the medical practitioners, and most importantly the health insurance/payers.  For all three entities, the adoption of a new companion diagnostic will require proof of clinical utility (Ref1, Ref2, & Ref3).  In a nutshell, clinical utility for a molecular diagnostics is the third level of a three-tiered evaluation framework that includes “analytical validity”, “clinical validity/qualification”, and “clinical utility” (Ref2).  Hence, clinical utility encompasses the overall medical impact of a diagnostic.  A diagnostic is considered clinically useful if it provides a real and substantial advantage to the patients, positively alters the practice of medicine, and/or improves the cost / benefit equation for a given treatment.  Although clinical utility is a distinct concept from analytical and clinical validity, it cannot be established without first establishing the latter.  The reciprocal is however not true: establishing analytical and clinical validity does not imply proof of clinical utility.

While the pharmaceutical industry and the regulators are currently focusing most of their efforts on defining and implementing the rules of diagnostics analytical and clinical validation, I would argue that the next decade will be dedicated to the third part of the equation: defining and implementing the rules of diagnostics clinical utility evaluation.

Thierry Sornasse for Integrated Biomarker Strategy

Low Cost Blood Protein Detection System: Of Aptamers, Gold, and Resonance

In the September 1^st issue of Biomedical Optics Express (reference), Zheng and colleagues present a proof of concept study for a novel type of biosensor for the detection of proteins in blood.  Briefly, the team immobilized amine-terminated aptamers – artificial oligonucleotides engineered to bind specific ligands – onto a gold modified surface and used Surface Plasmon Resonance (SPR) to detect the binding of the ligand; in this case thrombin.  This prototype sensor showed good performances (sensitivity, linearity, and reversibility) for the intended ligand (thrombin), in the presence or absence of high levels (400 nM) of BSA, suggesting that this technology could be applied to direct detection of reasonably abundant factors in blood.

Considering the relative inexpensive nature of the manufacturing process of this new biosensor and the relative simplicity of SPR detection, it is tempting to speculate that this technology could solve the issue of cost for current and new blood diagnostics.  Time will tell if the reported performance of this prototype biosensor will be reproduced for other blood proteins.

Thierry Sornasse for Integrated Biomarker Strategy

First approved companion diagnostics for a lung cancer drug: XALKORI (crizotinib) and ALK FISH Test

On August 26^th 2011, Pfizer announced approval by the FDA of XALKORI (crizotinib) – an ALK-specific kinase inhibitor ‑  for the treatment of patients with ALK-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC).  XALKORI was developed and approved in parallel with a molecular companion diagnostic, developed by Abbot Molecular, aimed at detecting the rearrangement of the ALK gene on the 2p23 chromosome by Fluorescent In Situ Hybridization (FISH). 

The parallel approval of this new drug with the companion diagnostic ALK FISH marks the first example of personalized therapy for lung cancer and reinforces the growing trend of personalized medicine in oncology.  Indeed, earlier this month, the FDA approved Zelboraf (vemurafenib) and companion diagnostic for BRAF-mutation positive metastatic melanoma (See: A biomarker finds its drug), adding to the list of cancer treatments that depend on companion diagnostics (See: Personalized cancer medicine review).

Thierry Sornasse for Integrated Biomarker Strategy

Blood-derived disease biomarker of Alzheimer’s disease: tell me what you react to and I’ll tell you who you are

In the August 3 online issue of PLoS One (PLoS One. 2011; 6(8): e23112), Eric Nagele and colleagues report the discovery of a potential new diagnostic biomarker for Alzheimer’s disease (AD) based on the detection of serum autoantibodies specific for a unique set of self-proteins.  This work marks a major step forward in the process of realizing the promises of preventive medicine for this devastating disease.  As I wrote in a previous post, the ability to intervene early in the course of AD is considered to be critical to the success of disease modifying therapies currently under development.  By providing an easily deployable means to screen for individual at risks prior to the onset of clinical manifestation of the disease, this simple blood test has the potential to radically change the disease management practices in AD.

The association of autoantibodies with certain diseases is not new.  Antibodies specific for self-proteins are characteristic of rheumatoid diseases and most cases of multiple sclerosis.  These autoantibodies are generally thought to contribute to the pathobiology of these diseases.  In contrast, the association of autoantibodies with non-immunological diseases is rather intriguing.  It is tempting to speculate that this process could be generalized to other degenerative diseases:  disease states characterized by the release in the body of rare and/or usually sequestered proteins that would be recognized by the immune system as potentially foreign (see principles of immune tolerance).  If this generalization turns out to be valid, one could easily imagine a broad application of autoantibody-based disease diagnostics.  While this hypothesis could potentially open the doors to new applications, it could also constitute a potential obstacle.  If auto-antibodies are broadly associated with degenerative diseases, it might be difficult to distinguish between closely related conditions.  Nagele et al. already addressed part of this potential issue by showing that the subset of autoantibodies specific for AD could distinguish with relative accuracy the sera from AD patients from the sera of patients diagnosed with Parkinson’s disease.  Further analysis of this autoantibody-based biomarker in samples derived from patients at different stages of AD and from patients with different forms of dementia (e.g. vascular dementia, dementia with Lewy bodies) should provide the necessary evidences to qualify this biomarker for practical application.

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