Fast-tracking of new drugs

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I'm doctor David Liew, your host for this episode. Today I'm speaking to Dr Paul Kubler, a rheumatologist and clinical pharmacologist at the Royal Brisbane and Women's Hospital and we'll be talking about his upcoming editorial in the August edition of Australian Prescriber on the fast-tracking of new drugs. Paul, welcome to the program.

Thank you very much David for inviting me. It's a pleasure to be here.

It's great to have you here because I mean there have been some recent changes earlier this year to the way that the TGA approve drugs, in particular with the introduction of a provisional approval pathway, it's caused a bit of controversy. So, at heart what's the problem here?

Well, as you might appreciate, many patients and their doctors, particularly if the patient has an unusual or rare condition, desire access to new drugs as soon as possible, but getting fast access to drugs has to be balanced by is the drug effective, does it have an acceptable toxicity, and then there's a third element to that which is a bit more complicated in Australia is how do we make them affordably accessible? So there is a mixture of issues here and I can understand patients and their doctors wanting fast access to a new drug particularly if it's an unusual condition or a rare cancer but that fast access has to be balanced by what is an acceptable toxicity. Is the evidence there that's good enough for its efficacy, and then finally can it be given in a cost-effective manner?

So why fast-track pathways in the first place? How did this start and what were the arguments that have brought about this fast-track pathway?

Well you know the fast-track pathway is not a new concept. If you go back through the literature, It's been present for at least 20 years, 25 years. I think it's become more relevant in the last three to five years because of rapid advances in scientific knowledge have made various unusual or rare conditions which were previously untreatable, that there is an opening up of therapeutics for them. There's also been an increased demand from the public for faster access to treatments and in many countries around the world there's been a sort of political force behind getting faster access to drugs, but there is a number of competing interests here. Obviously pharmaceutical companies would like their new drug to come to market as soon as possible. And then of course you've got the payers, which is in Australia predominantly through the PBS system, trying to make sure that is this drug going to deliver on its promises in terms of efficacy at an acceptable toxicity and at a reasonable price on a population basis? In terms of the history if you go back to the longer data which is, you know, the Europeans have tried fast-tracking pathways in the past, the Canadians’ and the US experience, the whole expedited approval process has been sort of mirrored by I suppose a much higher rate of drug failure when those drugs are followed up post approval and that has sort of coloured the whole mechanism of should we be fast-tracking drugs because in general fast-tracked drugs have twice the rates of subsequent withdrawal or receiving a black box safety warning. So you do need a process of following these drugs over the next four to six years after an expedited approval.

So let's focus in a bit on that. Can you talk us through this process in terms of how it's been up until now a drug company might go about putting up a drug for accelerated approval? What kind of drugs we're talking about here, and then what they get asked to do after that, and how that really plays out in real life?

Well if you look at each sort of area in both the USA and the Europeans, they've all approached it slightly differently. So going back 15–20 years it was really like an expedited drug approval process and the criteria were a little bit opaque. Now a lot of the agencies like the FDA have put more granularity to what drugs are suitable and even the FDA process that's currently in operation has actually four different pathways within the whole expedited process and typically one of the more common ones is it's an orphan disease, there's a lack of therapeutic options. And so within the different pathways under the fast-tracking process there are slightly different criteria for eligibility, I suppose, but the principle is there’s a condition with an unmet therapeutic need and the need is quite high as in there's an associated significant death rate or major mortality. But if you have a look at the most recent FDA data as I've sort of mentioned in the editorial, you know last year there were 46 new molecules that were approved and 40% of them came through the fast-track pathway. But there's actually some of those drugs were not originator drugs so it makes you think well why are we fast-tracking some drugs where there are clearly alternatives in the process.

It's somewhat concerning really to hear that when the accelerated approval is given what kind of conditions are put on those approvals?

Well that was one of the frustrations I had in doing the background research to the article. A lot is said about what is the eligibility criteria. A lot of is also in the published domain about what's the actual pathway. But there's actually a real paucity of publications saying how do we actually follow these drugs post approval? But of course the current regulatory process is usually most drugs will have to provide a periodic safety review typically at a yearly interval and most of that is really done for safety reasons, not to really confirm real-world efficacy. Sometimes like the FDA or the European Medicines Association will mandate like a registry trial post approval which will collect some degree of efficacy data but the primary purpose is safety data. And then one of the problems with a lot of the safety , particularly in the non-registry setting, is it's based on spontaneous reporting of events and of course that's very much dependent on the clinicians and the patients to some extent spontaneously reporting in a voluntary manner, which is, I suppose, a haphazard method for detecting safety events.

Let's talk a bit about efficacy though. These drugs don't necessarily have the same rigor in terms of efficacy, either. They don't have the same level of evidence, do they? What are the kind of burdens that regulatory bodies like the FDA have put on drug companies regarding that?

Well if we're talking specifically about the oncology field often it's a surrogate measure that gives the fast-tracked approval and you often don't have survival data at least initially. It's usually based on some sort of measure of outcome which is not a direct measure of improved survival. It's like something like progression-free survival or something like that or a biochemical end point. So I think it's very important particularly in those oncology trials where you've got a fast-track drug that we do collect post-marketing. What is the difference in terms of the really hard clinical end points of overall survival, improved survival, and then of course we shouldn't forget that quality-of-life measures and patient-reported outcomes are increasingly becoming important because we need to get the patient experience and often there's some degree of patient-reported outcome but it needs to be meticulously collected over the longer term including post-marketing to support that we've got the ongoing benefits that we think are there from surrogate measures in the short term.

Let's take that to the Australian context. So far this pathway’s been largely about oncology drugs.

So, right, usually about half the drugs are related to some oncology indication, about 40 to 50% of them, and then the others seem to be related more to unusual diseases such as an inherited bleeding disorder, you know something where there's a genetic focus which is really sort of an unusual, an uncommon disease for which there is none or very limited treatment options. That probably describes the other half of the indications. And I think the Australian experience is the first drug was only improved through the fast-tracking process in March of this year and that was an anti-cancer drug olaratumab which is a monoclonal antibody for the treatment of solid tumours, mainly soft-tissue sarcomas, so Australia seems to be following the same pattern as what's been seen in the last few years in the US and also in Europe in terms of what's an appropriate drug for a fast-track process. Now going through some of the other indications that were approved in the FDA in the last two to three years obviously there were some hepatitis C drugs which got a fast-tracking. There was a drug for Parkinson's disease. There was a drug for motor neurone disease. So they’re for some difficult-to-treat, debilitating neurological conditions.

We're talking about conditions with relatively small numbers of patients but with therapies with drugs which have got a high price on the ticket. We're talking about six-digits-a-year type of drugs, aren't we?

Yes definitely, I mean most of these drugs would at least be you know $100,000 per year per patient.

So we've got a problem here. We've got dangerous diseases where there aren't necessarily a lot of patients, hard to study, not always direct outcomes that come quickly. These are therapies which cost a lot of money and we’re in a process where we want to give our patients a chance of getting potentially beneficial therapies but at the same time we know that there's unclear efficacy, unclear safety and real potential for financial toxicity to the system to try and hold the PBS together. What should we do about this? This seems like a big problem. What would you do about this?

In my mind I try and break it down into two sort of separate but related issues. I think in terms of the cost-affordability issue, that's a second issue. I think first we can break down to is there the efficacy safety data there to support, you know, it's registration. And we can look at the evidence of efficacy safety and then we can monitor that, if the drug is approved in a post-marketing scenario. And then the question about the affordability both at the individual and at the population level, I think that's a much more difficult discussion but it has to be informed by what is the efficacy outcome we're getting with this new therapy? Is it saving lives? Is it something that is truly life changing for those individuals? And then it has to become more or less a broader public discussion, that is what are we prepared to pay as a community for that outcome?

Even the science bit of it sounds difficult. I guess that puts a spotlight on our post-marketing surveillance, our pharmacovigilance programs in Australia and that puts a lot of pressure on the TGA and on voluntary reporting.

Yes and as you know I think we in Australia, that's one thing that we don't do very well

compared to a lot of overseas bodies. I think that we could do much better with linkage of data particularly between the PBS and MBS datasets. You know, a lot of overseas bodies such as you know the EMA usually have as a part of their registration is that they have to collect a registry data in a meticulous way and I think Australia could do better with its scientific rigor regarding collection of post-marketing information, rather than at the moment we appear to be primarily relying on spontaneous voluntary reporting which, if you go back to the history of Australia, has done very well in picking up unusual events, but it is a far less effective method than I think we can implement going forward.

Well it's certainly a bit of a pressure time for drug regulation and pharmacovigilance in this country and I'm sure we haven't heard the end of this. It's a fascinating area, Paul, and glad we had the chance to chat today. Thanks so much for joining us.

Thank you David.

The views of the hosts and the guests on this podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm David Liew and thanks once again for joining us on the Australian Prescriber podcast.