With biomarker deals and diagnostic collaborations becoming a weekly event, the commercial race to provide the next generation of targeted therapies is well underway. But there are many challenges to be overcome in implementing and reimbursing such new and complex technologies.
Speaking at a recent event hosted by the US-based Personalized Medicine Coalition in May, the FDA’s Director, Center for Drug Evaluation and Research, Janet Woodcock, highlighted the changing pace of drug development when she said that around a third of new entities approved by the FDA last year had some type of genotyped biomarker in their marketing application and that anywhere from an eighth to a half of companies’ drug pipelines are targeted therapies. In her keynote address at the event, she said: ‘Personalised medicine has moved from a goal to an emerging reality... The new challenge will be to assist the larger healthcare community in dealing with this medical and scientific transition.’
In her discussion of how the FDA is dealing with the expanding field of personalised medicine, she highlighted some of the many challenges for industry, regulators and the healthcare community. In particular, there is the problem of targeted therapies having much smaller numbers of patients available for trials, which poses difficulties for both the authorities and drug manufacturers.
For example, providing evidence-based assessments as to who should receive the drug, at what dose, and with what expected side-effects won’t be as straightforward as with traditional drug-based clinical trials. ‘Ever-smaller subsets of patients are being identified, and we’re really going to have to put our heads together and figure out how you study these small subsets of diseases,’ said Woodcock.We’re really going to have to put our heads together and figure out how you study these small subsets of diseases
The FDA and drug developers need a new definition of clinical trials that recognises therapies will be targeted at subsets of conventionally defined diseases, she said.
To identify these subsets of patients, pharmaceutical companies may have to work together or work with third parties such as patient advocacy groups to identify them, she said. ‘We’re hoping that independent groups set up these trial networks and standing trials, so that then companies are comfortable coming together through a third party to do development of their drugs.’
The personalised cystic fibrosis drug ivacaftor (Kalydeco), which treats the disease arising from the G551D-CFTR mutation, was developed through such a patient group network, Woodcock suggested.
To achieve evidence-based research on the effectiveness of personalised medicine also requires more specialised data collection, significant biobanking, genotyping and information technology infrastructure to generate sufficient data to gauge the treatment effect and to compute any potential costs and benefits. But this data collection and storage can give rise to consent and privacy issues.
Then there are also major issues of IP for such complex technologies. In June, the US Supreme Court overturned earlier decisions by the US Patent and Trademark Office that had allowed companies to patent human genetic sequences. The Supreme Court ruled unanimously that, as a product of nature human genes cannot be patented. The ruling was a blow for Myriad Genetics, which holds patents on genes that have been linked to breast and ovarian cancer. However, the ruling did allow the patenting of a novel synthetic form of DNA, called cDNA that is used in cancer screening tests, seeing this as having been ‘created’ by Myriad and therefore deserving of patent protection.
The ruling highlights the difficulties in patenting inventions in the personalised medicine field, where much of the science is new and complex. Myriad said ‘We believe the Court appropriately upheld our claims on cDNA and underscored the patent eligibility of our method claims, ensuring strong intellectual property protection for our BRAC Analysis test moving forward.’
Lack of standardisation
Key to the success of personalised medicine are biomarkers and companion diagnostics and in the quest for such entities, laboratories internationally collect, store and study the required proteins in various ways. But there is a lack of standardisation that makes it difficult to compare results accurately from one lab to another and, therefore, limits the number of cancer protein or biomarker tests that are available to the public. In addition to regulating the drugmakers, the regulators need to set new standards to ensure diagnostic test quality.
Earlier this year the FDA highlighted the need to regulate better across the board of diagnostics, saying: ‘There is a category of diagnostics called laboratory-developed tests (LDTs) that are produced in, and offered by laboratories, for use in their own facilities. LDTs are currently marketed without FDA premarket review to determine whether they are safe and effective – whether they are accurate and clinically valid. And that can be a problem.’
Understanding the science
While biomarkers promise the benefit of predicting an individual’s disease risks and could provide earlier diagnosis, there remain many uncertainties. The huge numbers of proteins present, the fact that they are continually moving and undergoing changes and exist in a wide range of concentrations in the body mean that being able to detect them can be difficult. Many tests have problems with false positives and false negatives and all the interactions need to be better understood.
While recent high profile cases – such as that of actress Angelina Jolie, who had a double mastectomy because tests showed she carried a defective gene that greatly increased her risk of cancer – has boosted awareness of such tests, it has done little to highlight the difficulties that face many patients and healthcare providers when biomarker results are not clear cut.
Where once drugs were merely cytotoxic and affected only DNA synthesis or structure, the technology has moved on to include molecules that affect the target in different ways
In addition, the average oncologist needs to understand molecular biology in greater depth than ever before. Where once drugs were merely cytotoxic and affected only DNA synthesis or structure, the technology has moved on to include molecules that affect the target in different ways. For example, molecules may target transmembrane and kinase receptors, intermediate signalling molecules or additional molecules – all of these require some knowledge of how they function to anticipate both the benefit and potential toxicity.
Further down the healthcare chain, the FDA is also considering how to translate prescribing information to providers, who need simple, easy-to-understand instructions. ‘They want directions. They don’t want education. They don’t want to be taught genetics... They just want to know what to do,’ Woodcock said in her address. Therefore the diagnostics that accompany drugs and the information in labels need to be detailed but also easily understood.
In addition, the consumer must be fully equipped to handle direct-to-consumer genetic testing – i.e. tests that provide the consumer with his or her own genetic information, which are now being marketed directly to consumers without involving a doctor in the process. The Cancer Information and Support Network highlights the challenge when it says on its website: ‘Direct-to-consumer genetic tests are not designed to provide a clear-cut “answer” – as if one is pregnant or not pregnant. The information received from genetic tests can be extremely complex.’
The information received from genetic tests can be extremely complex
It concludes that the implementation of personalised medicine requires government support and regulatory oversight, as well as public vetting of ethical issues, emphasising: ‘There is a critical need to educate health professionals. The science of genetics that is traditionally taught in medical schools remains limited, with little or no discussion of complex “omic” information.’
Finally, the problem of reimbursement – how to put the correct value on the new drugs that adequately rewards the industry – is likely to run and run. Big Pharma is collectively spending large amounts on collaborations with biotechs and SMEs that have developed novel biomarkers and diagnostic products, but investers will be slow to back potential drugs that could take nine or 10 years to reach the market, without clear sight of whether they will work, be accepted by the regulators or whether their investment will be adequately rewarded.
