The Australian Solution to expediting your GMO clinical trial

We also have, and this comes up quite often, an allowance for GMP-like material to be used in early phase clinical trials, so the pilot, phase 1 and up to phase 2.  Now, GMP-like; we expect the quality of the material to be equivalent to GMP, except that you don’t necessarily have to have manufactured in a GMP-certified facility and not necessarily with the same quality oversight as you would expect for GMP.

Now, that’s obviously a great advantage for small biotechs who are really watching their spend.  There are some disadvantages, I guess.  Recently we’ve found that some GMP or CMOs, contract manufacturing organisations, aren’t prepared to release material for clinical trial use unless it’s GMP for liability reasons, and there is the potential, if you’re still quite early on in your manufacturing development that there are changes to your manufacturing process and potentially formulation where you might have some comparability issues later down the track.  So when considering using non-GMP material, there are a number of considerations, and we would highly recommend that you come and talk to one of our CMC specialists before you think about going down that route.

Quite interestingly, with COVID, I know that internationally all COVID programs are expedited in one way or another.  We have four GMOs that are for our SARS-CoV-2 vaccines or for treatment of COVID-19.  We’ve managed to negotiate with the Office of the Gene Technology Regulator, which I’ll talk about in a minute, an expedited process, so instead of 90 working days, we can get the whole process finished and completed in six to 12 weeks, so it’s not holding up the trial in any way.

As I mentioned, the Office of the Gene Technology Regulator, they regulate genetically modified organisms.  They sit under the Department of Health, as does our Therapeutic Goods Administration, which is equivalent to the FDA in Australia, but they don’t work together, so the work that we do with our GMOs with the OGTR is unrelated to any communications that we have with the TGA.

The basis, or the legal instrument, which regulates GMOs in Australia is the Gene Technology Act of 2000 and the associated Regulations of 2001, so with a bit of simple math there you can see that they are almost 20 years old or 20 years old.  Every five years we have like a working committee where we look at the Act and the Regulations to see where with the changes in technology and with things moving so quickly, whether the Act and the Regulations are still suitable for purpose, and I think from every review that I’ve been involved in, we do come up with a lot of really good ideas, and the Act and Regulations haven’t changed for 20 years, but there you go.  I think eventually we will start incorporating some of these new ideas so that they are a bit more flexible around some of these new technologies.

The legislation, the Act and the Regulations; it covers GMOs for clinical trial material, but it also covers all GMOs in Australia, so that includes aquatic and crops as well, so it’s quite broad in its definitions.

Here we have a list of the different classes of GMO dealings.  In Australia we call GMOs a ‘dealing’; I’m not quite sure where that term came from, but there’s five different classes of dealings, and they become more onerous as the risk increases to the environment and to people.  So the first class is excluded and they are not considered to be GMOs at all, and an example would be a naked DNA vaccine.  I’ll talk about IBC in a minute, but it doesn’t require an IBC review and it doesn’t require a licence, so it just goes through as any other investigation or medicinal product.

We then have an exempt category, so these are technically GMOs, but they’re exempt from regulation, so they don’t fall into the Gene Technology Act or Regulations, so for these products, and a good example are the CAR T-cell therapies.  There’s a few of those coming through now.  So they do require, and we do highly recommend that they have an IBC review which will make more sense in a minute, but we don’t need to notify the OGTR about those types of products.

The next is a Notifiable Low-Risk Dealing and they are not applicable at all to the clinical trials.  We do have a few non-clinical trial NLRDs that are coming through and it’s a very straightforward process for our IBC, and we just notify the OGTR.

Now, concerning clinical trials, the most common route for clinical trials is to obtain a Dealings Not Involving Intentional Release licence, and this is where the GMO is unlikely to be released into the environment.  In Australia, probably unlike Canada and the US, there’s no categorical environmental exemption for releasing a small amount of GMO into the environment; we actually have to have evidence that no GMO is going to be released, so that can be either through the type of therapy it is, where it doesn’t shed from the human body so it’s not going to be shed into the environment, or it can be controlled through the design of the clinical study by, for example, decontaminating urine that may have shed some of the GMO during treatment.  These DNIR licences require both IBC review and they also require the OGTR to review them.

The last licences are Dealings Involving Intentional Release, and we’ve done a few of these.  They generally are for products that are going to be commercially available where there is no ability to contain them, so the OGTR perform a risk assessment concerning the particular GMO.  We have had a couple of DIRs for clinical trial where we just haven’t been able to contain them from shedding and they’re actively replicating in the environment once they’re shed.

Now, to the IBC, or the Institutional Biosafety Committee, and as the name suggests, it’s a committee which generally is associated with a particular institution and they generally look after containment, so most of the hospitals have access to an IBC and they consult the IBC about containment issues, like PC2, Physical Containment 2, and also about equipment and those types of things.

At Novotech we have more of a scientific IBC where we’re not associated with any particular institute, which is very advantageous for a lot of companies that come through and they want a centralised review from our IBC which can then go straight through to the OGTR, and then the licence can be distributed amongst one or more clinical trial sites.

So aside from which is a mandatory process when you apply for a licence to the OGTR, you need to have that application vetted by an IBC, so that’s one of the tasks that we perform, as well as giving general advice pertaining to GMOs and how they’ll be classified in Australia.

We also provide scientific advice to help go along with Ethics Committee review if there’s any question as to how it should be regulated, and it sounds like a fairly complex process, but it all is streamlined and in-house, and for our clients it’s something that we kind of perform in the background.

As I mentioned, we do offer a very streamlined process, and there always seems to be a slight bit of conflict of interest here when we present this type of slide, so we have our internal consulting department.  We actually can review licence applications, provide advice, we can also write the applications from scratch.  They then go through, after client review, to our Institutional Biosafety Committee.  I’m chair of that committee, and Dr Hiram Chipperfield also actively works on writing the applications and reviewing them as well.  This isn’t the full Committee; we have another six members.  We have two medical doctors and a molecular biologist, microbiologist and a virologist as well, and then we also have two people from Clin Ops and Quality, which just helps introduce or bring in some of the clinical considerations.

Following IBC review, we then go back to the client with any advice that the other IBC members have put forward that can then be integrated into the application, and then we probably most of the time also act as the applicant on behalf of the client, and there is a reason for that; you need to be accredited in Australia to be able to perform that task, so we all do that and then we manage the whole application from there and also the questions that the OGTR ask during the review.

So here’s just a little snippet just talking about IBCs and also GMO applications in general, and I think this is a really interesting graph.  It shows not only that Novotech, our IBC, came about in 2016, so it just shows the huge growth in the amount of GMO clinical trial applications that need licences over the past few years.  And I must say there has been a slight dip in 2020 for obvious reasons, but we see that now coming up again, especially with a lot of the COVID work coming through.

Just noting that the Novotech IBC is the first national privately owned commercial IBC.  We’ve had 100% approval success rate for all our licence applications, and we’re certainly the most experienced group for GMO clinical trials in Australia.

I think I’ve gone over some of these points as I’ve gone along.  We do offer a central review, so right from having an idea about coming to Australia with a clinical trial that has a GMO as the investigational product.  We can be approached and really streamline that whole process right through to starting the trial and also dovetail some of the post-GMO licence approval activities into some of the regular GCP activities as well.

We’ve found this to be attractive to organisations who, especially when they’re looking at multiple sites, don’t want to submit multiple applications to different IBCs.  It becomes very clunky and can be confusing when you get a number of conflicting questions, and so that’s another benefit of having that centralised review.

We have here that if we’re running the trial, we can also be the licence applicant.  We actually kind of insist that if we hold the GMO licence that we also do run the trial.  We can always transfer the licence to another CRO.  It just becomes extremely clunky trying to maintain compliance to the GMO requirements and also to the general clinical trial requirements, so we’ve found that in the past to work the best.

As I said, we can support the preparation of the application, the review, respond to the questions and then at the other end, once the licence is approved, implement the licence conditions.  And the OGTR have noted that we do have a very high level of preparedness, and I think a lot of that has gone to our post-approval activities where we have experienced auditors who have made sure that the licence conditions are adhered to and put in, and worked with the OGTR to implement a number of processes.

I think just here just to note that our IBC meets on the last Monday of each month, except for December, but with COVID, and we have done it in the past too when there’s been an emergency, we can meet ad hoc as well.

As I mentioned, the TGA and the OGTR; it’s not a sequential process, so here we have just a snapshot of the different timelines for the different types of applications.  Now, because the OGTR is more concerned with environmental exposure, you don’t necessarily have to have your protocol and IB finalised.  It’s good just to have at least a protocol overview at the time of a GMO licence application, so while you’re preparing your protocol and your IB, you can also start with your licence application, and that way the application process isn’t holding up the trial itself.

As I mentioned, there are a number of activities, and this has probably become more relevant over the last year, where the OGTR like to do a pre-audit visit to at least one site if you’ve got multi sites in the country, and it really is based around training, which is an auditor’s favourite thing, making sure the labelling is appropriate and there’s contingency plans in place, and also that the IB has been stored appropriately and other various things which we have checklists and we have auditors and that that go around to help sites be prepared post licence approval.

Here we have some very nice pictures of different organisms and how they’re regulated in Australia, so a viral vaccine that’s been attenuated by chemical mutagenesis because it’s not considered to be a gene technology activity, it’s not a GMO.  As I said, with the somatic cells, they have been modified, they are GMOs, but they’re exempt from regulation.  Most of our products would be oncolytic viruses or similar and they get regulated as GMOs generally as the dealings not including intentional release.  And then we have viral vaccines which are attenuated by using some form of molecular biology, and so because gene technology techniques they use are considered GMOs as well.

Here we have a case study, and this is something that we hope doesn’t happen and this is why we do try and engage early with any clients who want to come to Australia with a cell and gene or a GMO product, so we have had situations where studies have fairly much started, like all the wheels have been put in motion, we’ve got the six to eight week lead-in time and the overseas’ sponsor is expecting the study to start, but the CRO wasn’t aware of the lead-in time for the GMO activities and so then the trial was then completely held up, it couldn’t start, and this is an example where our IBC came in.  I think we worked with the OGTR and made sure that that was approved very smartly so they could get their study underway.  Obviously not an ideal situation and this is why we have our processes in place from the start.

I’m not going to go through all of these different examples, but this particular slide is showing some of our clinical experience in managing GMO studies, so we’ve had quite a number of infectious disease studies, oncology and the interesting gene therapy studies.  As you’ll see, most of them are in the early phase as well, phase 1 and 2, with I think just one or two in phase 3.

Here is a snapshot of the BioDesk services that have been engaged for GMO products; BioDesk being the drug development and the regulatory consulting arm of Novotech, and also encompassing the IBC, and you’ll see that a lot of these examples include IBC support.  Again, infectious disease and oncology are our primary therapeutic areas.

Just to wrap up with the key points, Australia has the practical processes for GMO clinical trials, they are very defined.  Novotech has a very good, close working relationship with the OGTR.  We can provide expert consulting right from the beginning of any company considering coming to Australia with a GMO study and we have, as I’ve mentioned a couple of times, the only independent IBC in Australia which can provide central reviews nationally, and we’ve been accredited since 2006.

Thank you for your attention.