Breaking the code: companion diagnostics
Companion diagnostics are transforming modern medicine by using each patient's genomic information to guide treatment decisions. The benefits become clear in the cancer clinic at the Queen Elizabeth Hospital Birmingham, England.
Visitors to Queen Elizabeth Hospital in Birmingham, England, have a unique opportunity to walk through a historic location known for advances in medicine, and at the same time experience a place where modern medical breakthroughs are being made. The first buildings were built in the 1930s and opened by King George VI and Queen Elizabeth, who is the namesake of the original and new hospitals and would later go on to become the Queen Mother. The new Queen Elizabeth Hospital Birmingham (QEHB) opened in 2012 with a commitment to excellence in medicine.
The hospital’s reputation is built on its rank as the largest renal transplant program in the United Kingdom and also as a national specialist service center for organ transplants. The areas of expertise go beyond organ transplantation, and the staff of QEHB are also known for being at the forefront of advancing the treatment of cancer.
Visitors on the ground floor, where the day clinics are located, are directed to the right locations by a small group of volunteers. British Armed Forces members in uniform pepper the crowds walking through the hallways of this hospital, where about 120,000 patients are treated annually.
What these visitors do not see, however, are the underground offices and laboratories where teams of oncologists and pathologists are hard at work employing the latest molecular technologies and targeted therapies to deliver on the promise of personalized healthcare. Here, pioneering work on these novel, high-tech approaches are quickly becoming the standard care of treatment – and a process that is occurring at many hospitals around the world.
Dr. Stephen Little and Vincent Fert (f.l.t.r) say QIAGEN's expertise is bringing personalized healthcare to reality for patients around the world.
Many of the innovations shaping the daily treatment of patients in Birmingham have their origins about 90 miles away in the outskirts of Manchester, located next to the city’s university complex. In a traditional red-brick building that forms a striking contrast to the glossy, high-tech face of the QEHB, a rapidly growing team of nearly 200 QIAGEN employees work on the development of new companion diagnostics slated to guide treatments with novel drug compounds that will sooner or later find their way into the medical practice in Birmingham and elsewhere.
In one of the conference rooms, a group of QIAGEN managers from around the world gather to discuss the progress of ongoing projects. Leading the meeting is Vincent Fert, a French scientist and entrepreneur who is now as a senior executive leading QIAGEN’s initiatives in Personalized Healthcare. He was a founder of Ipsogen, a global leader in diagnostics for blood cancers that became part of QIAGEN in 2011.
“QIAGEN has demonstrated that we have the right technologies and can develop, obtain regulatory approvals, achieve strong reimbursement levels and also commercialize assays that are bringing the power of Personalized Healthcare to patients and healthcare systems around the world. Our commitment to innovation means that patients and physicians are getting guidance for crucial medical decisions from the precise, reliable information provided by the therascreen portfolio of companion diagnostics,” Fert says.
The 2012 FDA approval of QIAGEN’s therascreen KRAS test kit on the Rotor-Gene Q MDx and its subsequent U.S. launch marked not only a significant milestone for QIAGEN’s business, but also for Personalized Healthcare in general. Only a few months later, approximately 50% of the corresponding testing volume in the U.S. had converted from “laboratory-developed tests” to QIAGEN’s FDA-approved companion diagnostic. And the KRAS launch has provided a model for QIAGEN’s co-development and regulatory submission of other novel drug-diagnostic combinations.
“With the U.S. launch of our KRAS companion diagnostic, QIAGEN has achieved a major milestone on the promise in Personalized Healthcare,” says Fert. “QIAGEN’s team carved out the path to FDA approval for a standardized, highly reliable test paired with an important drug from our pharma industry partner for metastatic colorectal cancer. We took a proactive approach to securing reimbursement from payers based on the value of our companion diagnostic and won market acceptance with rapid conversion to the FDA-approved test.”
Approximately 50% of KRAS testing volume in the U.S. is based on QIAGEN technologies.
Asked the key to QIAGEN’s progress in Personalized Healthcare, Fert says, “We’re successful because we have two sets of customers – the pharmaceutical industry, which needs to target its drugs to succeed, and the diagnostic labs that serve healthcare providers – and our business model and capabilities allow us to meet the needs of both of them. We can translate the needs of one world into the requirements of the other world.”
QIAGEN brings special skills to co-development programs with pharmaceutical R&D. “Cancer is very fragmented,” explains Dr. Little, a pioneer in companion diagnostics and now a senior advisor to QIAGEN on Personalized Healthcare. For every oncology drug in development, researchers investigate various potential diagnostics. Then, he says, the researchers choose the biomarker that will be used to select suitable patients for the drug and that is where QIAGEN comes in. “Our role is to develop a diagnostic test which will allow reliable measurement of the biomarker in clinical samples to allow the selection of patients most likely to benefit from the therapy.”
Dr. Paul Ravetto, a commercially savvy scientist with highly regarded regulatory experience, says the relationship with collaborators is critical. His background is scientific; he developed some of the assays that QIAGEN sells now – “the EGFR assay, our KRAS assay in their earliest forms.” He also has had a lot of external, customer-facing exposure working with Pharma partners. Essentially, he says, the role of project management is two-fold.
“I’m lucky enough to have a technical background, so I know what’s realistic. The way the companion diagnostics business is run is – what’s the critical point on a companion diagnostic timeline?” He knows what is needed – after all, QIAGEN is one of the pioneers in this area. “In terms of companion diagnostics, if you were to look on the FDA website there’s only ever been about 15 companion diagnostics approved and of those, in terms of molecular diagnosis using PCR, there’s only two – of which KRAS is in terms of reach by far the most significant.”
Dr. Ravetto adds, “We are striving with our partners to identify the most appropriate biomarker as early as possible in clinical development. Our role then becomes to develop the companion diagnostic test paired with the drug so that late-stage clinical trials – the last and most expensive trials required before submission – take place with the market-ready version of our test. This provides many benefits, particularly the data to support two important aspects – approval of the drug, and also regulatory approval of the companion diagnostic.”
QIAGEN’s companion diagnostics are aimed at the regulated marketplace – so they must be backed by a strong regulatory team. Of the 150 staffers in Manchester, 50% are in product development, while others such as Dr. Ravetto focus on day-to-day coordination with QIAGEN’s pharmaceutical partners and regulatory bodies in international markets.
Working with the FDA on the KRAS submission was part of a learning process, as this was a new field and it is a complex system. QIAGEN executives participated in many discussions with regulators, exploring and defining frameworks for successful adoption of Personalized Healthcare. In 2011 the FDA produced draft guidance documentation, which shows the difficult path trodden by QIAGEN and others to establish this new market. “I think a lot of what is reflected in the regulatory guidelines is the result of collaboration with mutual respect and a common goal to establish a viable framework to generate the highest possible benefits from pairing medicines with companion diagnostics,” Dr. Ravetto believes.
At the front end of establishing new QIAGEN collaborations and partnerships for the development of companion diagnostics to support novel pharma-therapeutics is the Companion Diagnostics Partnership team. Richard Watts, Vice President of Companion Diagnostics Partnerships, is a dynamic executive, helping partners forge valuable partnership with QIAGEN, such as the comprehensive collaboration agreement he negotiated with Bayer HealthCare in 2012 that focuses on both existing and new biomarkers in QIAGEN’s portfolio.
Richard Watts has a clear understanding about the needs of pharmaceutical companies – and what QIAGEN can deliver – and how to bring this together in effective collaborations.“Our pharmaceutical partners are driven by the science – which must be robust. QIAGEN is unique in having a very wide portfolio of intellectual property and products which meet the requirements of molecular diagnostics,” Mr. Watts says.
“Targeted therapies, guided by the diagnostic, are a very good thing from a health economics perspective, but more importantly from a patient’s perspective. They’re getting the right drugs and they’re living a good quality of life,” Mr. Watts states.
"Targeted therapies, guided by the diagnostic, are a very good thing from a health economics perspective, but more importantly from a patient's perspective."
Richard Watts, VP of Companion Diagnostic Partnerships Americas, QIAGEN
The pharmaceutical industry is bringing personalized healthcare to reality, Dr. Watts has found. “There are many different names for this – some people call it stratified medicine, some say precision medicine, some people say personalized medicine – at the end of the day we’re developing therapies and diagnostics which are enabling us to bring the power of new medicines to patients who can benefit most,” he says.
Current programs at QIAGEN address therapeutic areas that include cancer, autoimmune conditions, and Central Nervous System disorders, involving many new drugs in clinical development.
Asked about the future, Dr. Ravetto says, “We know there’s going to be a desire to have multiple tests for a single patient – so you do a KRAS test, you might do an EGFR test and then there are other less prevalent mutations, which are all related. You’ll be able to do a panel of tests – but they all will be able to develop a picture as to what the best therapy is for the patient.”
Mr. Watts sees the future of companion diagnostics evolving further: “Infectious disease has in fact led the space of companion diagnostic test development, through HIV testing, through other areas as well – but today it’s predominantly oncology. We’re now moving into more complex diseases such as more autoimmune diseases and rheumatoid arthritis, other rheumatology-based diseases, and we’re also expanding into more complex diseases such as Alzheimer’s and Parkinson’s.”
The buzz, however, is about next-generation sequencing (NGS). “This breakthrough technology will be highly complementary to our established molecular testing with real-time PCR, and it will allow us to generate massive amounts of information on a patient. However, more data is not always better since it will be critical to understand the clinical relevance in terms of treatment options,” Mr. Watts says. QIAGEN is preparing to introduce a comprehensive sample-to-result NGS workflow to address the needs of customers for biomedical and clinical applications, including meaningful analysis of the massive amounts of information generated.
"We look into the cells - we extract DNA or even RNA and we look at very specific alterations in genes or levels of expression of genes"
Dr. Philippe Taniere, Consultant Histopathologist, QEHB
Further afield in Birmingham are two long-time colleagues who put companion diagnostics to practical use: Consultant histopathologist Dr. Philippe Taniere and oncologist Dr. Neil Steven at the Queen Elizabeth Hospital Birmingham.
Passionate about his patients and getting to the bottom of cancer, Dr. Steven takes time to explain the complicated cancer process in a way that is easy to understand. “There’s an analogy I would use – breaking ciphers. To some extent, that’s what we’re doing in terms of the way the cells work,” he explains. “You have a very complex system within a cell – it’s quite difficult to pull apart – so if you can find an encoded message, it can give you a handle on how these different bits fit together. You can use that to try and break the cellular code.”
Dr. Taniere heads the University Hospitals Birmingham NHS Foundation Trust’s molecular pathology service integrated in the histopathology department, which is based in the Trust’s QEHB and breaks the code of cancer on a daily basis. The dynamic Frenchman has been in Britain for many years building the formidable molecular pathology unit. The whole team has 30 scientists, technicians, laboratory assistants in the labs and 10 secretaries, who deal with about 30,000 cases a year.
“We look into the cells – we extract DNA or even RNA and we look at very specific alterations in genes or levels of expression of genes,” Dr. Taniere says. Where companies like QIAGEN have been “extremely helpful and supportive, they’ve provided us with kits and equipment, which have been set up to work in what we have in routine practice – in terms of solutions allowing us to process tumor samples and kits targeting the specific alterations which we need.”
Since 2009, his team has done over 100 KRAS tests every month for colorectal cancer patients from the area, from many other hospitals in England and some referrals from abroad. BRAF is a gene that is tested in melanomas, so Dr. Taniere also processes more than 100 BRAF tests a month. “We also test 200 lung cancers for EGFR mutation. So in sum it has already become a big volume of tests that have to be processed, which is very exciting,” he says.
Adoption of companion diagnostics “is extremely exciting and millions are invested. When it comes to diagnostics, it has to be fully validated, it has to be,” Dr. Taniere explains. Along with growing demand for molecular tests, this prompts many laboratories in the space to shift their entire workflows to automated solutions such as QIAGEN’s QIAsymphony RGQ, which not only help to cope with rising test volumes but also ensure a higher comparability of results and minimize the risk of sample mix-ups.
Accordingly, all kits Dr. Taniere and his team use for the diagnosis need to have official validation such as the CE-Mark in Europe or FDA approval in the U.S. He sees the future as technology-driven and constantly evolving, while keeping with accepted standards – a widespread view that is reflected in QIAGEN’s efforts to further expand the menu of validated tests in personalized healthcare and other application areas.
Asked if he believes next-generation sequencing or multiplex testing will become the only way of the future, he replies, “I don’t believe one technique will replace everything – we need to cover all the patients, every type of tumor, every alteration – which makes it more exciting. But we need to have some companies with these wide panels of kits and techniques working and upgraded to follow the needs.”
Additionally, the challenge is to translate the vast amount of molecular information into actionable clinical decisions. “The KRAS test – for example – helps us to identify patients that will benefit from novel targeted treatments. But what do we do with the others?” Dr. Taniere states simply, “We don’t have three other drugs – so currently they go back to classical chemo which is not selective.” The issue is extremely complex. Dr. Taniere concludes with a question, “So with next-generation sequencing, I can test any tumor for everything I can possibly imagine. But what do you do, if the data is not validated and if you don’t have the treatment?”
Another trend he sees is an increasing focus on RNA: “Most of the kits now are assessing DNA alterations, but more and more we need information on the presence of the expression of fusion genes, because there are lots of targeted drugs under validation or already on the market, which are targeting not DNA alterations but chromosomal translocations – the kits we have at the moment don’t do that.”
"It's obvious to us that we can't afford everything under all circumstances, so stratifying medicine becomes increasingly important to healthcare and to our patients."
Dr. Neil Steven, Oncologist, QEHB
On the ground level of the hospital is a waiting room for cancer patients, filled with people sitting patiently, waiting for their appointments with doctors, including Dr. Steven.
Glancing around, the visitors range from the regulars who are prepared, one clutching a book to read, a student trying to learn from her course book and others watching the clock. Reality dawns when a young couple emerges ashen-faced after talking to Dr. Steven, clutching papers and talking earnestly to the staff – who matter-of-factly advise the couple accordingly.
Upstairs is the cancer clinic, which is also run by Dr. Steven. The ward is a circular room with the nursing center in the middle, hospital beds lining the walls and comfy couches well-placed for the visitors returning for follow-up checks. The patients are good-natured and the atmosphere is homelike as the nursing staff is sunny, sympathetic and compassionate. The nurses talk quietly to those being seen to, and sometimes the brightly-colored curtains are drawn close around the beds. But mostly those visiting rest on the large leather chairs.
One of the patients is Allan Robbins, name changed to protect his privacy, suffering from rectal cancer and on Day 6 following surgery. Looking pale yet quietly confident, the older man is resting in his room in the ward, lying on his side and valiantly drinking a cooling cup of tea with a straw.
“I had symptoms and thought ‘It’s just hemorrhoids’ but eventually went to have it checked out,” he admits wryly. “In early June the GP checked me over and the week after that I was here. I had a series of scans, MRI and CT scans and biopsies to decide what the problem was and was referred to the oncologist who put me on a chemo- and radiotherapy course for five weeks. There was then quite a big gap and I recovered from it. I was going out and driving.” His process also included being tested for KRAS to help guide treatment options.
Asked what would make his life easier, Mr. Robbins thinks and replies, “If I had one person in charge of me, that would be nice.” With cancer treatment already heading toward use of multiplex testing and next-generation sequencing, the way of the future could well be to equip each patient’s physician with all of the information needed to evaluate options and select the best possible treatment.
Doctors are beginning to be in position to predict the outcome of treatments, Dr. Steven says. “Essentially we use a predictive marker – if people have KRAS mutations, we do not use these antibodies. If they are not KRAS mutated, then it becomes feasible to use them.” He continues, “It’s built into our clinical algorithms – it’s also built into our funding algorithms – we would not be permitted funding for using these expensive drugs if that’s mutated. Both our reimbursement system and our clinical decision-making are critically dependent on what goes on in our pathology department.”
Dr. Steven adds, “As we move forward with targeted treatments, then having this kind of molecular diagnostics becomes very important, both in terms of personalized medicine for patients and in terms of the way the funding works. It’s obvious to us all that we can’t afford everything under all circumstances, so stratifying medicine becomes increasingly important to healthcare and to our patients.”