For the FDA, personalised medicine is characterised as providing ‘the right patient with the right drug at the right dose at the right time.’ More broadly, ‘personalised medicine’ is the tailoring of medical treatment to the individual characteristics, needs and preferences of a patient during all stages of care, including prevention, diagnosis, treatment and follow-up.
With regards to drug approval, the FDA recognised that personalised medicine could address one of the unavoidable consequences of approving drugs that were effective for a small portion of the patient population, but would provide no or little benefit, with a high risk of side effects and adverse events, for the balance of the population.
Personalised medicine — by delivering better-targeted therapies — was acknowledged as a possible strategy to improve public health, and reduce waste. The FDA has encouraged the development of diagnostic tests for predictive genetic attributes that could help identify these sub-populations of ‘responders’ in order to target these new therapies. As these tests have no diagnostic value unless developed and reviewed in conjunction with the therapeutic drug, the FDA has worked to provide clear guidance for the development and approval of companion diagnostics, which cut waste by ensuring the right drug is used with the right patient, significantly improving the risk / benefit profile.
On July 31, 2014 the FDA issued ‘Guidance for Industry: In Vitro Companion Diagnostic Devices’, to help companies identify the need for companion diagnostics at an earlier stage in the drug development process and to plan for co-development of the drug and companion diagnostic test. The ultimate goal of the guidance was to stimulate early collaborations that will result in faster access to promising new treatments for patients living with serious and life-threatening diseases. A second guidance to address the requirement necessary for the co-development of companion diagnostics with the targeted therapeutic is eagerly awaited.
But in spite of the very visible efforts, the FDA’s relationship with personalised medicine is more complex than at first appears. In order to understand why, one must first examine the FDA’s role and the role of government in the USA. The FDA’s primary role in the USA is to protect the public health. As such, and as for other protection agencies in the USA, the focus is on protection of the patient, even if that means limiting the choices that are available to those that are proven to provide a benefit that outweighs the risk. It is with this concept that the needs of the patient and the needs of the FDA may diverge.
Whereas, as the Team Consulting survey reveals, the patient may be willing to take the risks associated with choices regarding their medication, the FDA may not feel that the potential risks of these choices on the proven therapeutic benefit of the drug, or potential hazards that may be introduced, are sufficiently balanced by the convenience and user satisfaction benefits that are provided.
Evidence of this dichotomy can even be seen in the area of Companion Diagnostics, where the FDA has already shown great commitment. In the USA, many of the companion diagnostics are developed by laboratories, not manufacturers, and are called Laboratory Developed Tests (LDTs). These LDTs are not regulated by the FDA and not subject to review of clinical data establishing that they are effective, and meet their claims. The FDA has recently published a draft guidance that would bring these tests under their oversight and would require proof to support effectiveness for the test to be legally marketed.
The laboratories argue that they are already regulated and this would impede the availability of these tests to support personalised medicine. The FDA’s position is that speed and availability are outweighed by the possibility that these tests could provide erroneous results and jeopardise the public health.
Another example is in the area of genomic diagnostics, where the FDA has prevented the company 23andMe from marketing their genomic tests because the diagnostic value and patient benefit of the information provided has not been assessed and determined to be adequate by the FDA. In effect, the patient cannot be trusted to use the information and may make the wrong decisions.
Part of this issue is very specific to drug delivery. In the EU, the essential requirements for safety and performance of the delivery function of a separate, or even integrated drug delivery system can be independently established for the ‘device’ portion by the manufacturer (potentially with oversight of a Notified Body), and this assurance or certification is accepted by the EMA as sufficient for approval of the drug or integrated drug product. In the USA, these ‘device’ issues are considered concurrently with the approval of the drug.
The ultimate goal of the guidance was to stimulate early collaborations that will result in faster access to promising new treatments for patients living with serious and life-threatening diseases.
That puts the Center for Drugs (CDER) or Biologics (CBER) as the organisation that must accept both the risks of the drug and the risk of the drug delivery device together for the approval of the system, or combination product.
Although the system is designed to enable device issues to be reviewed and considered by the Center for Devices (CDRH), this does not always happen, and when it does, the opinions or position of CDRH are not always respected and/or followed.
As would be expected of any individual, and is certainly true of the FDA where risk is to be avoided, reviewers when presented with information or concepts with which they may not be familiar or comfortable, will become very conservative. This is a very natural, and not unexpected result. The reviewers in CDER are less likely to be comfortable with the risks or user choices based on user studies, without statistically valid, clinically established proof that these choices do not adversely impact drug efficacy or patient safety. Thus, the burden will fall to the manufacturer to prove that the myriad of combination and/or configurations are all safe and will not impact on the effectiveness of the drug, the safety of the patient or the user’s ability to deliver their dose.
For drug manufacturers, the cost/benefit equation may preclude them from including these options for patients in deference to providing a single, proven safe and effective drug product. This decision may be compounded by a highly litigious US legal system, which has the potential to penalise the manufacturer for poor patient choices.
Although this relationship between the Drug and Biologics Centers and the Device Center may improve over time, it promises to be a slow process. It is clear that the leadership of the FDA is committed to personalised medicine and providing drugs AND devices that will safely and effectively provide medical benefits. However, their focus on protection, sometimes in deference to patient choice, cannot be ignored. In addition, even with the right leadership, the FDA is a very large organisation with an established bureaucracy and any large organisation, like a large vehicle that has enormous inertia, requiring a significant effort and a very long time to change direction (and culture).
As such, I cannot see the FDA resolving its issues around combination products even by 2030, although its relatively quick approval of companion diagnostics does indicate that when the result is a clear ‘win win’ for patients, practitioners and society as a whole then the FDA can act. But the FDA will remain committed primarily to the protection of public health, and may only be capable of implementing incremental change when it comes to “patient choice”. This is something all those working within the personalised medicine space must recognise, and is an issue on which we must all keep a watching brief.
This article was featured in Insight magazine issue 7. To sign-up to Insight, click here.
1. Patient and doctor perspectives, Team Consulting, http://te-am.co/patientreport
Lee Leichter is President of P/L Biomedical and has more than 30 years’ experience in the health care industry with major medical products.