If cancer drug prices stay high – or go even higher – what’s the best way of ensuring access for patients? In the final of a three-part series, Donna Chisholm investigates possible solutions.
Adams was diagnosed in July 2013 with chronic lymphocytic leukaemia and later discovered he had a very aggressive form of the disease, known as the “dreaded” 17p deletion. Patients with this genetic mutation have an extremely slim chance of surviving if they’re treated only with the drugs Pharmac funds.
Results from a blood test Adams had in April 2015 were sent in error to a North Shore haematologist he’d been seeing before he moved to a different health board area nine months before. “He rang and said, ‘Your blood isn’t looking that good – I have a clinical trial you might be interested in.”
Each arm of the trial featured a combination of the chemotherapy drug chlorambucil with a new immunotherapy: the monoclonal antibody obinutuzumab or a targeted drug, ibrutinib. Adams was disappointed to be put on the antibody arm of the study because the treatment hasn’t had good results in his type of leukaemia. But patients were told they could switch to ibrutinib – which is funded in Australia, and has given patients significant survival gains – in the event of a relapse.
Adams got slightly better during the trial, but when he relapsed after seven months, luck was again with him. His haematologist, David Simpson, had a new trial underway, using a second generation of ibrutinib, zanubrutinib, developed by the company BeiGene, a biotech with significant operations in China. After two years, Adams is still on the drug and his condition has steadily improved. If he relapses again, he will possibly transfer to a trial of yet another new leukaemia treatment, venetoclax.
Adams, 63, estimates the trials have saved him nearly $300,000 so far – money that would otherwise have come from his life savings, or mortgaging his home.
For Simpson, and other cancer doctors who don’t see drug prices coming down any time soon, clinical trials are increasingly being seen as an important way for public hospital patients to get innovative, expensive new drugs that Pharmac doesn’t pay for, at least until any new health policies kick in.
The Labour-led Government says it intends to introduce an “interim drugs fund”, which would temporarily pay for innovative new medicines while the evidence for effectiveness was still being gathered. Pharmac has warned the plan could blow out the drugs budget by $90 million a year. Health Minister David Clark is also investigating setting up a National Cancer Agency to develop a strategy to address the inequity of what he calls the postcode lottery of cancer care.
Schemes to fast-track innovative drug approval and funding have been controversial overseas, with UK research suggesting overall health outcomes would have been better if the money channelled into Britain’s Cancer Drug Fund had instead gone into the wider National Health Service.
Clark says he’s taking advice on an early-access scheme in the hope that the sorts of problems that have occurred internationally can be avoided, and he’ll be seeking consumer input. “It needs to preserve the best of Pharmac, which is the strong negotiating position they have. It’s not yet clear what the perfect solution is, but it is clear the current Pharmac model is not focused on equity.”
He says although New Zealand spends much less on medicines than other countries for the same benefits, he’s unhappy with some of the delays to innovative therapies. He hopes to have an interim fund launched within this government’s first term. “We’ll never be able to afford all the drugs we want and we need to look carefully at whether we’re getting the best outcomes with the current model.”
None of the oncologists North & South spoke to while researching this series wanted to ditch the Pharmac model, but all thought it could be fine-tuned.
The Cancer Society wants these changes:
- Fixed time frames for Pharmac reviews of new drugs (including a “fast-track” option for special circumstances, such as the situation with melanoma in 2016, where there were no other effective alternatives).
- Involvement of clinicians in the early stages of the approval process (as happens in the UK and Canada).
- Scores from international assessments being assigned to all new drug applications.
- An appeals process that can be used if funding is refused.
- Temporary access for patients needing a drug and who would otherwise die during Pharmac’s review. This should have fixed effectiveness criteria (e.g. three months’ survival gain) and fixed price points that would be acceptable. Access would cease on release of the final Pharmac decision.
- Considering the impact on the whole health system of funding a particular drug.
Ahead of any regulatory changes, clinical trials seem to offer patients the best chance of accessing new therapies quickly. Simpson says global trials are comparing new treatments with drugs regarded as standard care in other countries, but that still aren’t paid for here because New Zealand is so far behind in funding them.
“When patients go on a trial and don’t get the new drug, the ‘control’ arm still offers drugs that are better than what Pharmac will give us.”
He’d like to see public hospitals build their clinical trial capacity. “There’s a groundswell among haematologists and clinicians for this. Hospitals and district health boards don’t seem to have grasped that this is a route to get early access to good drugs.”
District health boards would say they supported research, “but none of them really do”, he says. Most charge departmental overheads to cover the cost of the day stays for infusions, for example, while being blind to the millions of dollars’ worth of free drugs patients receive. In the past, the money drug companies paid for overheads stayed with the hospital department, allowing it to be used for more research. “There are lots of hoops we have to jump through and that means a longer lead time before we can start recruiting patients.”
Regulators, too, keep raising the bar, making the research more arduous. “Trials used to be very simple to do and now it’s incredibly complex with all the time-consuming data collection and data queries you have to do.”
Northern Cancer Network’s chair, oncologist Richard Sullivan, says ramping up clinical trials is becoming a very important way to help patients get new drugs. “I would love to see a real investment in public academic research to enable access to unfunded therapies through clinical trials.” Auckland City Hospital already has a well-established unit running late-phase (efficacy) trials but in September, it opened a new unit for early-phase trials (for safety and dosage) in a joint initiative between the University of Auckland and the Auckland District Health Board. Ultimately, the hospital aims to have around 15–20% of all cancer patients on early- or late-phase clinical trials. Trials can be initiated either by drug companies or by clinicians designing their own research.
Simpson has overseen studies that have involved around 500 patients in the past 20 years. “They’re incredibly important because of this explosion of knowledge on the workings of cancer,” he says. “There are so many drugs that target different pathways – there may be 35 different ones in development, so you can get access to all sorts of versions in various trials.”
New Zealand clinicians have an excellent global reputation for their research, and box above their weight in patient recruitment. He estimates about 90% of patients benefit from a drug they receive in a trial, with 5% being worse off and 5% having a neutral result.
Patients should always ask if their doctor knows of any clinical trials in their types of cancer. In haematology, there’s even a phone app, ClinTrial Refer New Zealand, run by the Haematology Society of Australia and New Zealand, that patients can download to check the location and types of trial. The website CenterWatch.com also lists trials currently underway, but patients should approach their own doctor first.
In smaller centres, however, options for patients may be more limited. As new therapies become more targeted, places such as Christchurch and Dunedin can lack the critical mass of patients to justify having a trial at all, says Professor Bridget Robinson, a Christchurch oncologist who holds a chair in cancer medicine at the University of Otago.
“We’re noticing a big change in the clinical trials available at the moment. In the past, if anyone had early bowel cancer we could put them all in one trial because as far as we knew, the cancers were all the same. Now we know the cancers are not all the same, and there are small groups with particular genetic abnormalities or mutations, which only 3-5% of patients might have, so it’s much harder to get enough people on your site to put into a trial to make it worth the effort.”
The number of trials in Christchurch and Dunedin has remained relatively static, but those that are running now cover fewer patients. “We like to have a portfolio of trials that covers all the common cancers, but we currently are unable to,” she says. “We used to consistently enter 5% of our patients in trials, but we are below that now.”
“It concerns me that in the pharmaceutical market, there is an excessive concentration of intellectual property [IP] in a small number of large companies. I think we do have to think about looking at companies operating out of places like China and India, and other markets that haven’t conventionally been part of Western pharma.”
Weinkove says with the regulatory environment becoming increasingly stringent and risk averse, it’s important that it doesn’t become a barrier to new drug development and introduction.
“We all expect drug safety, and of course it’s important, but if you ask people who are desperate, they may be happy to accept a lower level of regulation in exchange for a lifesaving drug. It’s a concern I have as a clinician that we may end up having to say to patients, ‘You can pay $1 million to get this treatment in the US or $20,000 to go to India and get something similar.’”
He says we should be thinking “outside the box” about regulatory approvals and fostering links with drug companies, perhaps introducing provisional drug registration so a new medicine could be available for a limited period, with formalised reporting of any adverse events, to enable a company to complete the required clinical trials.
“It solves a problem for the drug companies, for the clinicians and most importantly for the patients.”
The Malaghan Institute has teamed up with a Chinese biotech company in a joint venture, Wellington Zhaotai Therapies, that will see Malaghan conduct clinical trials of one of the newest immunotherapies, CAR T-cell therapy. The first CAR T-cell therapy was approved in the US only last August for children with acute lymphoblastic leukaemia.
Weinkove told North & South that the joint venture enabled the institute to work with a third-generation CAR T-cell developed in Guangzhou by Cambridge University-trained scientist Dr Peng Li, in what both sides hope is a win-win deal. China needs to have the treatment developed and clinically trialled in a research laboratory that complies with the stringent, standardised regulations that operate in Western countries; provincial variations in China’s regulatory standards can prove a barrier to their drugs being approved internationally. New Zealand’s pay-off is the Chinese investment in plant and equipment to enable the trial, and a share of benefits should the treatment prove successful.
It’s not as if big pharma is unaware of developments in places such as Asia, however, with a number employing regional “scouts” to help stay abreast of pharmaceutical and technological developments in those countries.
At Merck, Phil Kearney has been director of licensing and business for more than a decade, covering India, Southeast Asia and Australasia, but in that time, he’s assisted in getting just two drugs – both discovered in Australia – into development. He’s proposed “probably 10 times more than that”, which haven’t been taken up, often because they’re inferior to other prospects coming from elsewhere. He’s in touch with many of our leading scientists and universities and says the science here is “really very good; it’s very clever. It runs on the smell of an oily rag. We use a lot of Kiwi clinicians to help us make decisions around drugs.”
But he says the science suffers from a lack of biotech investment. “You win a government grant to do the basic research and some drug development, but the first valley of death the scientists talk about is getting it from the lab with enough money to do the preclinical toxicology tests. When it’s ready to go into patients is when companies like us sit up and take notice.”
Drugs that are at this stage are common in India, and relatively common in Singapore, he says, but it’s “very rare” to find them in Australia and New Zealand. “New Zealand needs a translation grant mechanism, maybe $10 million a year, that scientists could apply for to get the funding to do the preclinical toxicology tests. That might cover 10 drugs – one might work and it could be worth billions.”
One of the scientists whose work is well known to Kearney is immunology researcher Professor Rod Dunbar, director of Auckland University’s Maurice Wilkins Centre for Molecular Biodiscovery. Dunbar says the country has the capability to produce its own immunotherapies. “I’m not suggesting we’d be able to produce an PD-1 inhibitor [such as melanoma drug Keytruda] immediately, but what we may be able to do is have an entry into the biosimilars market, so as all these things come off patent we can produce them. We have a science engine in this country that is capable of producing them to a very high standard, and paired with that we have a fantastic clinical trials structure for testing them in patients.”
New Zealand farms are the source of the bovine serum used to grow the cells that make immunotherapies overseas. “We have this agricultural resource from specialised farms that is all being shipped overseas to make monoclonal antibodies that we have to buy back, so we’ve thought a lot about whether we can put together a nationwide team to start strategising about how we can make our own.”
Scientists at AgResearch’s Ruakura centre in Hamilton have also developed a herd of genetically modified goats, which produce the milk proteins used to make drugs such as Herceptin. “New Zealand has the capability to produce those monoclonal antibodies in a way that has all the advantages of our clean, green image. Yet the project never really took off [locally], because of the issues around genetic modification.” He believes New Zealanders are now sophisticated enough to accept there is a difference between a “massive problem medically” that a transgenic goat can solve, and genetically modified food.
Dunbar laments the lack of any organisation in New Zealand that looks across the health and science sectors for opportunities to protect the country from the future climbing cost of medicines. He’s calling for a new strategic approach within the Ministry of Health that effectively “de-siloes” Pharmac from the groups its decisions affect, from the community to DHBs and surgical services. He says that would allow the impact of a new, effective drug to be more broadly evaluated and properly priced.
The National Health Committee, an independent body established in 2009 to prioritise new and existing health technologies, was quietly disbanded in 2016, leaving a significant gap. “There’s a huge opportunity here to bridge the social, the medical and the scientific and actually work out how New Zealand is going to deal with this, because it’s inevitable that our spending on these types of therapies is going to rise.
“We are a smart country with one of the most agile populations around, in terms of our ability to think through things, and we are early adopters, but in health we don’t seem to be able to come up with modern strategies that address what is going on. Part of the problem is that Pharmac has a closed mandate and they themselves have to go to the government cap in hand for money, so we have ended up in an adversarial rather than strategic position – and that’s a shame.”
Dunbar and his Maurice Wilkins Centre colleague, Distinguished Professor Margaret Brimble, are the scientific founders of biotech start-up SapVax, formed in 2016 in partnership with an American drug development company to bring novel cancer vaccines to clinical trial here. Dunbar says the Americans will pump $7 million into SapVax.
Wellington’s Malaghan Institute and Ferrier Research Institute, where scientists are also developing cancer vaccines – albeit ones that work in different ways – have set up a nearly 100% New Zealand-owned company, Avalia Immunotherapies, to raise investment capital to take the technology to clinical trial.
Avalia’s New York-based CEO, Shivali Gulab, who has a PhD in chemistry and business and science degrees from Victoria University, says about $2 million has already been raised – nearly all from New Zealand – but a further $10 million is required to get one vaccine through phase-one trials and a second ready to enter trials. While phase-one trials are mostly about safety, they can also indicate whether the vaccine is eliciting an immune response in patients.
“Our goal is to get as much investment as possible from New Zealand to get the technology as far forward as possible, but the reality is once we get to a certain stage of clinical development, we need to get international investment.”
She says her New York base is an advantage when talking directly to US investors and potential Big Pharma partners. “We are trying to capture as much value for New Zealand as we can.”
The Malaghan Institute had some success with an early melanoma vaccine, but to an extent those cell-based vaccines have been overtaken by new immunotherapies. Scientists at the Malaghan and Ferrier institutes have extended that earlier work to design cancer vaccines that stimulate the same immune responses without the need to grow cells in the laboratory, and Avalia has been set up to develop these.
The Malaghan’s cancer immuno-therapy programme leader, Professor Ian Hermans, says scientists are working on synthetic “off the shelf” vaccines rather than cell-based personalised products that are more expensive and time-consuming to produce. The type of cancer the vaccines would target hasn’t been determined yet, but he says top of the list would be disease induced by a virus. The first studies in humans could start in a year or so.
The Malaghan and Ferrier teams have already collaborated with Dunbar’s Auckland team on a phase-one clinical trial (evaluating safety) of a melanoma vaccine, and they all continue to work together, along with other immunotherapy researchers brought together by the Maurice Wilkins Centre. Dunbar hopes the vaccines might increase patients’ response rates to other immunotherapies such as the PD-1 inhibitor drugs. “If we can make them work a lot better, it will make the costs of the PD-1s more bearable,” he says.
“In just about every cancer, there will be a combination of a PD-1 inhibitor with something else that is effective that we are going to have to fund. This is curing patients, exactly what civilisation should be doing. We can’t look at it as just another day at the office for Pharmac; it’s a complete revolution.”
But he wonders why so many of them – including ibrutinib – are available in other developed countries, including Australia, but not in New Zealand, given we’re told our economy is the envy of the world. “If we’re such a great little country and we’re leading the world economically, how come we can’t afford the drugs that are on other schedules?”
Although he is still plagued by fatigue – he has to pick a day when he’s feeling relatively energetic to do a simple task such as changing a lightbulb – he’s very aware the trials have saved his life, and how much he owes his haematologist David Simpson and the staff at North Shore Hospital.
Before he was put on the first clinical trial, he remembers his sense of desperation as he faced bankrupting himself to pay for the treatment, but also his gratitude that the new drugs were available. “There is a particular desolation in thinking there is nothing they can do for me. The other desolation is thinking there might be drugs out there and I can’t get hold of them.”
A doctor's lifesaving story
“From my perspective, clinical trials are life-saving and life-changing. As one of those patients, I was extraordinarily grateful. I had no choice, or no chance, unless I went onto a trial. Our vision is that clinical trials become one of the paradigms of treatment. It’s a treatment option and it wasn’t before.”
The centre, which does only phase-one and phase-two clinical trials – assessing safety and dosage – has recruited about 100 patients to six trials evaluating new immunotherapy and chemotherapy drugs in solid tumours and prostate and breast cancers.
So far, the research is on drugs produced by major multinationals and funded by them but ultimately, Watson hopes home-grown innovations can be tested as well. “We have very smart researchers at the University of Auckland who come up with novel, breakthrough therapies. In the past, they’ve all been tested offshore so we’ve lost the intellectual property and associated science very early on. Our vision is to not only make the treatments available to patients, but have the ability to develop them in New Zealand, which from a science and economic perspective will create huge opportunities for the university and New Zealand itself.”
In oncology, later-phase clinical trials that are required to show proof of effectiveness over existing therapies usually cost more than $1 billion, so they’ll always be run offshore, although New Zealand centres can still participate in global studies.
Watson, who was successfully treated from 2004 to 2010 with a forerunner of today’s CTLA-4 drugs (e.g. Yervoy), says that although the drug worked for him, it never made it to market. His surgeon had given him just four months to live when he was admitted to the trial. “There’s no doubt it saved my life.”
This was published in the March 2018 issue of North & South.