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Replies to post #189548 on Anavex Life Sciences Corp (AVXL)
04/14/19 4:16 PM
04/14/19 5:22 PM
1.1 Policy Objective
The objective of the Notice of Compliance with Conditions policy is to:
1)provide access to promising new drugs for patients suffering from serious, life-threatening or severely debilitating diseases or conditions for which no drug is presently marketed in Canada or for which a significant increase in efficacy or a significant decrease in risk is demonstrated in relation to an existing drug marketed in Canada;
create mechanisms for the appropriate completion of confirmatory trials to verify the clinical benefit of a drug authorized under this policy; and
2)ensure transparency of the conditions associated with the market authorization.
The benefits of the NOC/c policy are twofold:
It facilitates earlier access to the drug by physicians and patients. The acceptance of promising evidence of clinical effectiveness allows for the filing of an eligible drug submission earlier than normally possible. Should the outcome of the review be positive, the time to approval and market for the drug may be shortened. It should be noted that the time to agreement on the acceptability of the contents of the "Letter of Undertaking" will affect the overall time to market.
It provides the means to effectively monitor, and report on, the safety and efficacy of promising new therapies through enhanced post-market surveillance initiatives.
1.2 Policy Statement
A Notice of Compliance issued under the NOC/c policy may be granted for a drug product with promising clinical benefit, providing that it possesses an acceptable safety profile based on a benefit/risk assessment, and is found to be of high quality.
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1.3 Scope and Application
The Notice of Compliance with Conditions policy applies to:
NDS and SNDSs for a serious, life-threatening or severely debilitating disease or condition for which there is promising evidence of clinical effectiveness based on the available data that the drug has the potential to provide:
1)effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in CanadaFootnote 2; or
a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.
2)ANDS and SANDS in instances where the Canadian Reference Product still holds the NOC/c status.
In all cases, a prerequisite for issuance of an NOC, qualifying under the NOC/c policy, will be the sponsor's written commitment to pursue undertakings acceptable to Health Canada.
As with similar programs in other international jurisdictions, the NOC/c designation applies to the product's specific indication being studied, and not the drug product alone.
04/15/19 6:05 PM
So, three pathways: the standard one at the top, the priority review in the middle, and the provisional pathway at the bottom. Now as I mentioned briefly, the top one is about a year. The second one we've said we'll do it in 150 working days, but as you'll see we're actually doing them much faster than that at the moment. And the provisional approval pathway, which again will be closer to a year. To deal with all these things, we also have an orphan program. And that can apply to each and that makes approval of one of these medicines free of charge to the company. So, that's something to encourage usage and registration of medicines, particularly when it's a rare disease and there's no alternatives and we want to make something available to the Australian public with no impediments. So, I will be concentrating today mainly on priority and provisional.
OK, so during this presentation, we hope that you by the end will be able to describe the priority review and provisional approval pathways for medicines - The new pathways; understand the expected benefits of the priority review and the provisional approval pathway and locate relevant information sources on the TGA website. We can't cover everything today and there's certainly quite a lot that you could use in the future on the TGA website.
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All medicines do have risks. And in fact what we'll be covering a little bit later is how we're managing the risks of a priority and of a provisional medicine versus a standard approval of our medicine. So, it's about benefit and risk and no therapeutic good is risk free. The work of our professional staff is based upon applying our expertise for that decision making. And we ensure that the benefits outweigh the risks associated with the use of medicines. And in this case in particular, we're actually having a slightly increased risk in medicines which have less data or approved with more speed. And we're making that decision based upon greater benefit being perceived to be forthcoming to the population.
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So, what we'll be talking about today is on the left the registered medicines and the fast track pathways. And in fact we've been quite busy with priority reviews so far and becoming busy with provisional approvals, the one on the left. So, just to talk about what those pathways are. There is the standard approval pathway. And we take, we actually have that in legislation that we'll do that in about 255 working days or about a calendar year. Now we have priority approval which is in that second box. And we also have some other aspects as well where we will accept overseas evaluation reports and we'll work with other regulators overseas. And we are in fact, through another initiative, working quite closely with Health Canada. And then the third part that we'll talk about is the provisional medicines, which is based on early data maybe Phase 2 or Phase - maybe a limited Phase 3 for provisional information. And that's a new pathway which we've got at the bottom. So, three pathways: the standard one at the top, the priority review in the middle, and the provisional pathway at the bottom. Now as I mentioned briefly, the top one is about a year. The second one we've said we'll do it in 150 working days, but as you'll see we're actually doing them much faster than that at the moment. And the provisional approval pathway, which again will be closer to a year. To deal with all these things, we also have an orphan program. And that can apply to each and that makes approval of one of these medicines free of charge to the company. So, that's something to encourage usage and registration of medicines, particularly when it's a rare disease and there's no alternatives and we want to make something available to the Australian public with no impediments. So, I will be concentrating today mainly on priority and provisional.
So, if you read a lot of literature you'll hear all sorts of different terms from different regulators. So, if you hear from the FDA, you might hear priority, you might hear accelerated approval, you might say breakthrough designation, you might hear fast track. So, there are four different ones there. And about 65% of medicines go through one of these pathways in the United States. Just to make things more complex, Europe has different terms such as accelerated, conditional approval and exceptional circumstances. In Canada, priority and notice of compliance with conditions. In Japan, they have priority and then they have a special pathway called 'Sakigake' which is to promote sort of the development of Japanese medicines. And then Switzerland has priority procedure with prior notification. So, each one has slightly different names. But I think the general intent of all of them is to make medicines available as soon as possible to the (Australian) public. And certainly in the case of provisional or what they might call accelerated, breakthrough, conditional or Sakigake and other ones, the idea of having the medicine available sooner based upon less data when there is an absolute need to the Australian public. And in fact, as much as we have different terminologies, we actually do have increased concordance with the various jurisdictions.
The provisional approval pathway is something that we implemented as a part of the second batch of legislation. And that was implemented on the 20th of March of this year. So, we again have eligibility criteria different to those in priority. We will have preliminary clinical data. So, we'll have full chemistry and manufacturing. We'll have full toxicology. But it may be that we only have Phase 2 and limited Phase 3 data for provisional. And we'll accept that because we believe that the availability of that medicine outweighs the risk. Our target timeframe is 220 working days. And one of the key things is that it's not provisionally registered ever. It's time limited. There will be a full registration only if we do a subsequent approval after evaluation of confirmatory data. So, the confirmatory safety and efficacy data is required to be put in at a later time by the manufacturer. And these are two of the recommendations of approximately 56 that the Government approved through the MMDR process.
Talking a little bit about how the criteria are different. So, both are for new prescription medicines or indications. In some jurisdictions it's only new prescription medicines. It has to be seriously debilitating or life-threatening condition. And we're quite conscious to say it could be seriously debilitating. So, for instance, one example I've used a number of times is someone who might have relapsing remitting multiple sclerosis. Not immediately life-threatening, but certainly significant impost upon a patient and their carers. A comparison against registered therapeutic goods. So, if certainly if there's a medicine that's of similar quality, safety and efficacy, then they wouldn't be eligible for one of these pathways. It needs to be a major therapeutic advance for these as well. And lastly, in the case of priority, we don't need to know what evidence they're going to bring forward for us in the future because we already have full evidence.
For provisional, we need to see evidence that they're going to produce meaningful data during the provisional registration period so that we can then convert it to a full registration. We will only make a determination for six months or so. And the sponsor is expected to put it in during that time. However, we will potentially give an extension, if the conditions are right to give that extension to allow them to put in the registration.
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So far, provisional has only been open since the 20th of March. And the two medicines that we have so far come through there's one called Pembrolizumab or Keytruda as you may know it, a Merck Sharp & Dohme medicine. And there's two cancer indications available there which I won't go into the specifics for. And olaratumab or Lartruvo which is another cancer medicine put forward by Eli Lilly. So, already these pathways have been well taken up by the industry. And so you will start seeing the priorities. Well, the priorities are starting to come through now. And you'll start seeing the provisional medicines coming through as registrations in 2019. To be more specific for the priority medicines approved, I won't go through all the generic names here. But they are predominantly cancer medicines. You'll see that there's a mixture of new chemical entities, i.e. ones that have never been registered before, and extensions of indications, those medicines which have already got something registered in Australia, but they have an additional usage going through. Now we make this all quite transparent. We put the registrations up on our website. We allow subscriptions to updates. At a later stage and usually within some months, we will put a full AUSPAR up which describes the approval process. And the PI and CMI is always available on the ARTG. I'll also mention that as well as those things, we will have a list of medicines which are determined to be priority even before the registration has been approved. So, that's another link that's available on our website. So, without further ado, I'm going to pass you to Dr Sarah Golding. Now, Sarah is located in Melbourne. So, as much as though you would like to see her, I will just sit back and I'll let her provide audio for the next slides and talk us through a specific case study of a priority pathway medicine that's already come through. So, over to you, Sarah.
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The second pathway I talked about earlier. And this one is one where we haven't had any full registrations yet. We expect the first ones to happen in mid-2019. Just remembering this one only came in later than the other one. This one came in in March of this year whereas the priority came in in July of last year. So, for provisional is where the benefit outweighs the risk. It's where we have a satisfactory clinical trial plan. The initial approval that we will give for a sponsor is two years. And we will extend that in one or two-year increments up to a maximum of six years. So, the sponsor must apply to get that extension and they must provide evidence that they're on track to show that their product can be safely used and that the evidence is being gathered and there are no specific concerns with the medicines. So, we will get the studies that have been conducted to - been designed for the confirmatory studies. And the plan must support the evidence submitted earlier. So, if the company chooses then to research something slightly different it would raise a question mark as to whether that's still appropriate for confirming this medicine. Sometimes it is, sometimes it's not. And we will give that registration up to a maximum of six years.
So, I'm going to talk a little bit about the six-year thing. So, this is something that's specific to Australia and it's something that I think was informed very much by the experience overseas. So, they can apply for full registration before that time as soon as they've gathered their sufficient information. The indication could be narrower or broader than the provisionally registered indication as that further Phase 3 evidence comes and we assess it we can see the benefits in that trial population. And we will make a decision to approve or reject that. So, for instance, the FDA has no time specifications. And I've got some evidence on the FDA the outcomes of that later on. And the other major agency that we look to is the European Medicines Agency. And they have done a report on 10 years of experience there. But they have an equivalent one which is called the conditional medicines approval. So, they have had 30 medicines going through but interestingly they've had none revoked or suspended and generally have been able to convert to full approval within four years. And we hope at least that we'll be getting some things much sooner than the six years based upon that experience.
So, key considerations that you might want to think about and what the evidence is so far. So, there are some interesting articles that have appeared in major journals over this. And one was looking at post market safety events amongst the novel therapeutics approved by the FDA between 2001 and 2010. So, interestingly that 32% of the new active substance applications, those ones that have been approved quickly, had post market safety events. But then they noted that the ones that accelerated had a higher rate of events than the ones that had been approved by the standard pathway.
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. If I haven't answered some of your questions on the way through, we'd be very interested in hearing your questions now. Now these could be questions for myself or Dr Sarah Golding.
OK, there's a good question here. In reality, how will a medicine be revoked if people are using it and getting a response? In fact, that was something that we contemplated. And so we made it very clear that it's a legislative action. It's a legislative commitment that six years is the maximum. We can't do not as an organisation, as an agency to extend beyond six years. And so upfront we are asking to have a lot of clarity on the clinical trial plan and making sure that those that we'll deliver within six years. And if a patient is responding, we have one of those four mechanisms I showed you before and certainly we would do our utmost to work with our sponsors to get it over the line. Having said that, we are still very conscious of the risk and benefit and we want to make sure that everything that's fully registered has got that confirmation. If there is an individual patient who's having benefits, then we would be asking the sponsor to work with us to make that medicine available for patients through one of those schemes.
OK, do you know if provisional approval will allow PBAC submission? Certainly it is a separate process as it is for standard medicines. We as TGA look after the registration of medicines. The Pharmaceutical Benefits Advisory Committee advises government on the suitability of medicines to be reimbursed and after that is the price negotiation. Certainly PBAC is aware of provisional and are working to adapt their pathways to provisional registration medicines. And it's their intention to make expedited approval medicines available. But more details on that I would have to hand you to Pharmaceutical Benefits to answer that question more specifically. Certainly, it's our intention to work with them to make these medicines available and reimburse.
SARAH GOLDING: I might add to your thoughts there Adrian. It's Sarah here. Just to say that you know the decision that TGA is making is a binary one about the benefit-risk balance being positive to the intended usage given the known limitations of the data that's available. Whereas for the reimbursement, it's a decision about qualitative, you know, the size of what something is worth. And that's, you know, that modelling is where really they're experts in that area.
