Presentation: Changes to the regulation of compounding glucagon-like peptide-1 receptor agonist (GLP-1 RA) products

Speaker Key:

• NI               Nishi
• RL              Professor Robyn Langham
• UF              Unidentified Female Speaker

00:00:01

NI                   Good evening, and thank you very much to everyone who has joined us today. My name is Nishi, from the TGA’s Regulatory Engagement Branch, and I would like to start today's webinar off with an acknowledgement of country. In the spirit of reconciliation, the Department of Health and Aged Care acknowledges the traditional custodians of country throughout Australia, and their connections to land, sea and community. We pay our respects to their elders, past and present, and extend that respect to all Aboriginal and Torres Strait Islander people today.

                   Now, without further ado, I will pass it on to our speaker of the day, Professor Robyn Langham, who is a Chief Medical Adviser for the Health Products Regulation Group, within the TGA, and is responsible for providing clinical advice and oversight to the delivery, quality and efficiency of policy changes and reforms. Over to you, Robyn.

00:00:51

RL              Thanks very much, Nishi, and welcome, everybody. Thank you very much for your time this evening. As you'll have already heard from Nishi, this webinar will be available to you to access online, so if there's anything that you might miss over the next few minutes, don't worry. You'll be able to catch up in the near future. So, as Nishi’s already acknowledged the traditional owners, I'd like to also join her in acknowledging the traditional owners, and particularly paying my respects to any members of the First Nations community who’d be with us this evening.

                   This, obviously, is the webinar to talk about an update on the TGA's action to restrict the compounding, or the pharmacy compounding, of glucagon-like peptide-1 receptor agonists, so that they're no longer able to be compounded for the community’s use. And we really wanted to talk through what the role of the TGA is, initially, and as well, talk about the regulatory framework for medicines that are approved, versus medicines that are compounded.

                   Then I want to talk about why it is we've taken this decision in compounding, and the public health risks that a large-scale compounding was presenting to the community. We want to talk about how we did it, in terms of the consultation process, and then finish up with the timeframe for change.

00:02:21

                   And lastly, we want to talk about the medicine shortages and our TGA strategy to help with clearly all of the other GLP-1 receptor agonists that are in short supply at the moment. And finally, some information for prescribers, pharmacists and consumers, and the way forward.

                   And as Nishi said, I'm going to go through some of the questions that you've already submitted to us, so that we can cover off on some of those questions. But rest assured, if you have any further questions, there will still be an opportunity for you to send them through to us, so that we can answer any other queries you might have.

                   So, the role of the TGA. Well, the principal role of the TGA is to protect public health and safety by regulating the advertising, the manufacture, the importation, exportation and supply of therapeutic goods in Australia. As a best practice regulator, this regulation includes scheduling, product registration, unapproved product access pathways, as well as quality standards, post-market surveillance, and international collaboration.

                   It really goes a lot far beyond the most well-known aspect of what we do, which is regulating therapeutic goods, and that includes prescription, over-the-counter, complementary medicines, medical devices, biologicals, blood and blood products. Our process to do this is by evaluating these therapeutic goods before they're marketed, and monitoring these products once they're on the market.

00:03:55

                   We also assess the suitability of medicines and devices for export, but we have a very, very strong focus on safety, efficacy, and quality, and we work closely with consumers, health professionals, industry, and our international counterparts. But as I mentioned, we have a broader remit, which includes things such as scheduling, product registration, unapproved product access pathways, and quality standards for these unapproved products, as well as post-market surveillance and international collaboration.

                   I think the TGA seeks to position itself as a contemporary best practice regulator, and this relies on three predominant principles, one of continuous improvement and building trust, of collaboration and engagement, and a risk-based and data-driven approach. We bring these three principles of improvement, collaboration, and a robust evidence base to our regulation of compounding.

                   But it's also important to highlight the regulatory functions for which the TGA is not responsible. I think it's really important to talk about what the TGA does not do. The TGA does not have a role in the regulation of clinical practice or of health professionals, and this clearly sits with AHPRA and the health professional boards, and to a lesser extent, the professional organisations, societies and colleges. The TGA also does not have a direct role in the determination of the cost of any medicines or devices, or any reimbursement arrangements.

                   So, the Therapeutic Goods Act of 1989 provides a national framework for regulating therapeutic products in Australia, to ensure the quality, safety, and efficacy and performance of medicines and medical devices. It sets requirements for entry of products in the Australian Register of Therapeutic Goods, or the ARTG. All therapeutic goods must be entered into the ARTG before they can be supplied in Australia or exported from Australia.

00:06:03

                   There are, however, some special circumstances where individuals can request access to an unregistered product, through their healthcare practitioner, and via certain exemptions.

The TGA has a risk management approach to its regulation. As a clinician, as a patient, aware that all therapeutic goods have some level of risk, and our role is to determine whether the benefits of a product outweigh the known risks.

                   Management of uncertainty is a greater challenge for us. I’m tempted to use a Donald Rumsfeld-ism, but it's the unknown unknowns, and that's the area, really, where we do actively seek stakeholder and expert input, where we have particular areas that we're not aware of or that we need extra input to.

                   The TGA's approach to risk management involves, firstly, identifying, assessing, and evaluating the risks posed by therapeutic goods, as well as applying any measures necessary for treating the risks that are posed. And in some cases, this takes the form of a risk management plan.

                   And as well, we have a very important role in monitoring and reviewing risks over time, so that consumers who are accessing registered goods can be reassured that they are using products that are safe, that are efficacious, and are of high quality. But also that there's an ongoing process that is continuous and renewing, in terms of being able to reassure them of the safety and the performance of those drugs over time.

00:07:54

                   If we talk about how a drug would get registered in Australia and included under the ARTG, I think this is a really nice flowchart of where our work sits. So, for a drug that's being developed, here on the left, in the purple box, the sponsor begins the formulation and development research of a drug, and that includes preclinical studies with sometimes animals or other animal substitutes. And AI is starting to do a little bit of that work, as well.

                   The important thing that most of the consumers are aware of is the role of clinical trials in being able to ensure that drugs actually work. And these clinical trials can start right at the very start, in what we would call a phase one, which is where a drug is given in small and gradually-increasing doses to otherwise healthy people, right through to phase three trials, which is where a drug will be given to large groups of patients with a condition, and that, invariably, there's one group that won't get that active drug but will get a standard of care and a placebo, and another group that does.

                   And it's by doing this sort of evaluation, the science and the evidence, that helps us assess safety and efficacy of a medicine. The TGA evaluation process, once all of this data and all of this evidence being presented to us from clinical trials, from quality, from drug-labelling, involves a process where we're able to review all of those bodies of evidence. And then, when the TGA decides whether there's sufficient data and there are proper safeguards in place for the medicine to receive market authorisation, TGA approval is given.

00:09:48

                   The evaluation process. So, if a new drug is registered for marketing in Australia, prescribers can be assured that it’s safe, quality and efficacy has been evaluated by the TGA, and often with advice from our advisory committee on medicines, which is that other group of experts.

                   The evaluation process relates to premarketing activity, but you can see, in this light green box on the far end of the arrow, that the TGA is also responsible for drugs after they're marketed. And other activities under the control of the TGA includes post-marketing surveillance. It includes adverse drug reaction monitoring. It includes drug and device recalls. It includes laboratory testing by our laboratories here at the TGA. It includes inspection of manufacturing premises. And there are also very strict advertising controls, in Australia, for all registered products.

                   So, you can see, not only from this arrow, but from all of the other processes that happen once a drug is registered in Australia and supplied, that there's a really intensive and complex process of reassuring and ensuring that products are safe and of a high quality for the community. If we switch, though, to a similar picture of what the regulatory framework for a medicine that's going to be compounded is, you can see that this is a lot less complex.

                   So, pharmacy compounding of all applicable medicines under our legislation is intended only for small quantities. It's done at the request of a medical practitioner, for an individual patient, following the presentation of a prescription. And that means, for a prescription-only medicine, the pharmacist has a prescription or an order, and the patient has requested supply of the medicine before the pharmacist compounds the medicine.

00:11:45

                   The formulation. The pharmacist develops the drug formulation in consultation with the prescriber. And the formulation resources, and the professional judgement, and the guidance that is issued by the Pharmacy Board, assists the pharmacist in being able to do this.

                   The pharmacist, as I've mentioned, can compound a medicine for a specific patient on a prescription in the pharmacy, in accordance with the relevant Commonwealth and state and territory legislation, and the relevant practice guidelines and standards that the Pharmacy Board distributes. And that this ultimately results in provision of a compounded product to the single patient.

                   When a compounded medicine is prescribed, compounded and supply, both the prescriber and the pharmacist assume the legal responsibility for providing the patient with a medicine that's effective, that's safe and of good quality. And that's because compounded medicines are not subject to the rigorous assessment for product quality, efficacy, and safety that the TGA normally provides.

                   So that complex arrow and pathway that you saw in the previous slide does not apply to compounded medicines, and that is entirely the responsibility of the pharmacist and the prescriber, in order to be able to do that.

                   It is intended that these drugs meet the clinical need of a particular patient, where a commercially manufactured product is either not suitable or not clinically appropriate. And when compounding medicines, pharmacists must ensure that there is good clinical and pharmaceutical evidence to support the quality, stability, safety, efficacy and rationality of any extemporaneous formulation.

00:13:32

                   The practice of compounding relies on the professional training of the pharmacist, and compliance with professional practice standards and guidelines set by the Pharmacy Board of Australia. Pharmacists must also comply with all legislation relevant to the practice of pharmacy in their jurisdiction.

                   The risk-benefit ratio of using a compounded medicine is considerably altered when compounding occurs on a large scale. And when compounding is performed on a large scale, errors in manufacture may equally adverse many, many patients that are far outweighed by the benefits.

                   So, let's get to the why of the public health risks. We identified, from the magnitude of the compounding that was happening with these particular agents, that there were a number of risks that were identified. The first one was the unknown nature and the safety of the raw ingredients that were being imported and used in manufacture. And as well, there was a complete absence of any regulatory evaluation, and by that, I mean the TGA's regulatory evaluation, or, indeed, of anybody else, for safety and quality.

                   The compounded practices that are outside of the current exemptions that specify manufacture-only on an individual patient basis was also being exceeded by the sorts of practices that we were seeing. And, of course, finally, there was a lack of reporting of any adverse events related to the quality and safety of compounded products, that you would also see with any of the drugs that are evaluated and registered on the ARTG.

00:15:25

                   This is not just a problem that was being seen in Australia. You can see, here, a couple of news headlines and journal headlines from the FDA. This particular one alerting healthcare providers, compounders and patients of dosing errors that were associated with compounded injectable semaglutide products.

                   From the JAMA paper in… I can't see a date there. My apologies. A safety and risk assessment was done, that also highlighted the risk that was associated with this greatly increased use. And below here, the MHRA, which is the regulator in England, also warning of unsafe, fake weight loss pens. Our own work here, in the TGA, was to issue compounding safety information and a warning to consumers, highlighting the unknown nature of these products and the risk to their own health, because they sit outside of a regulatory framework.

                   So how did we move forward with this? Well, we undertook a targeted consultation with peak representative bodies for health professionals, industry and consumers. And as well, just before the consultation, we hosted a roundtable discussion with health regulators of states and jurisdictions, and in clinician regulators, as well. And there was a broad agreement that there was a serious public health risk to the magnitude of the compounding of semaglutide, at that stage.

                   So, as well as the consultation, we also met with a number of individual stakeholders to discuss the matters relating to the compounding of GLP-1 receptor agonists. What we found was the great majority of stakeholders who responded supported the proposed change and the change that we ultimately went on to make through legislative changes. They were citing safety and clinical concerns in relation to the scale, and also the complexity of the manufacture of GLP-1 receptor agonists through pharmacy compounding.

00:17:49

                   Their responses also highlighted that the existing pharmacy board, and state and territory notification and compliance processes for compounding, were not really adequate to address the safety and efficacy concerns, again, unique to this very large-scale compounding of GLP-1 receptor agonists.

                   Several stakeholders also indicated to us that the current regulatory exemptions, as they sit currently in the Therapeutic Goods Act from 1989, have not really kept pace with compounding practices. And so we're working very hard, in this space, to see how we can further improve that.

                   So, when? Well, on 17th June this year, the registration of the new legislation was lodged, schedule five, item six of the Therapeutic Goods Regulations, 1990. And that meant that it outlined the changes for there to be a removal of GLP-1 receptor agonists from the compounding exemptions.

                   What has followed is a period of transition, from 17th June to 30th September. And that's a period of transition that's going to allow for patients to consult their doctors, for doctors to talk to their patients about alternative healthcare plans that will need to be put in place, should they be using the compound, the GLP-1 receptor agonists. And as of October 1st, this year, compounding of GLP-1 receptor agonists will no longer be permitted, and that includes all dosage forms. So that's the timeline.

00:19:38

                   Let me talk a little bit about the medicine shortages and the Therapeutic Goods Act strategy. At the TGA, we take shortages very, very seriously, and we understand, very acutely, the problems that the community experiences when medicines are in shortage.

                   Like anyone in any other regulator in the world, we understand that shortages can occur for many reasons, and sometimes they cannot be avoided. We have a number of regulatory tools that we can use to try and help minimise the effect of shortages, but we work with pharmaceutical companies to help minimise these effects on consumers and healthcare practitioners.

                   While we recognise that shortages cause concern for patients, it's important that alternative treatments accessed during shortages are safe and of good quality. And we do have a medicine shortage report database that's available on the TGA website. We can put all of these links to our website in the chat, and they'll also be available to you after this presentation goes live on the web.

                   These are the tools that we have available to us, but in short, the TGA will continually act to monitor the supply of the registered products, Ozempic, Wegovy, Mounjaro, and Trulicity, and liaise with the supporters of these… Of sponsors of these drugs, pardon me, regarding supply status, and there is up to date information about the shortages of GLP-1 receptor agonist medicines, that are available on the TGA website.

00:21:29

                   The compounding change is unlikely to impact the duration of the current shortages of GLP-1 receptor agonists. However, with the introduction of additional products, supply pressures are expected to gradually ease. Novo Nordisk has advised the TGA that another one of their GLP-1 receptor agonist products, Wegovy, will be available in Australia from early August 2024.

                   Now, Wegovy is specifically indicated for chronic weight management, as an adjunct to reduced-energy diet and increased physical activity when specific criteria are met. It's not known what the impact of the Wegovy launch will have on Ozempic’s ability. Now, while Wegovy contains the same active ingredient as the other Novo Nordisk product, Ozempic, or semaglutide, they have different approved indications and uses, as well as different dosages and devices. And as such, Ozempic and Wegovy are not interchangeable.

                   The TGA recently held a Medicines Shortage Action Group, another one of the tools that we have to help mitigate shortages, to discuss the availability of Wegovy in Australia, and to update the advice around prescribing for these medicines. And that updated advice of the group, to prescribers, is available on our website.

                   Novo Nordisk has advised the TGA that they continue to receive orders of Ozempic but supply will continue to remain unstable throughout the rest of 2024. The sponsor of Trulicity and Mounjaro, Eli Lilly, has advised the TGA that the KwikPen version of Mounjaro will be available from September 2024.

00:23:19

                   As I've said, links to the medicine shortages alert and up-to-date information about the GLP-1 receptor agonist shortages is available on the medicine shortages reports database. And we continue to monitor the supply situation and publish updates as required. And we will give you the links to all of those databases, to make it easier for you to find that information.

                   So, what does this mean for consumers? What are the key points that we'd like to be able to inform you of tonight? Well, the first thing is that compounded GLP-1 receptor agonists are not identical to the TGA-approved medicines. We really encourage you to speak to your doctor regarding your individual situation and how best to manage your ongoing healthcare plans during this transition period.

                   We also want to make you very aware of any online scams that are offering injectable weight loss products. These products are either these online sites or other scams that will result in you not receiving any product and being short of a few dollars at the end. But also, you may actually be receiving product that is fake and also dangerous.

                   The key points for healthcare practitioners. Well, importantly, that compounded medicines containing GLP-1 receptor agonists cannot be prescribed and compounded after 1st October 2024. And again, we encourage you to consult your patients on alternative healthcare plans between now and October 1st. You can keep up to date with TGA GLP-1 receptor agonist product supply updates and the S19A information, via the TGA website, and again, we'd encourage you to report any adverse events.

                   This is the other important bit, the way forward. Our enforcement and compliance team here would like to also share this information with you. And that is that civil and criminal penalties may apply to anyone who's found to have unlawfully manufactured and supplied compounded products containing GLP-1 receptor agonists, from 1st October 2024.

00:25:54

                   Importantly, consumer advertising of compounded products is also unlawful. The TGA is working in partnership with law enforcement, with other health regulators and state and territory colleagues, to address non-compliance. The TGA is dedicating significant resources to investigate these matters and take appropriate enforcement action against anyone found to have breached the law. Importantly, the professional conduct of medical practitioners and pharmacists is regulated by AHPRA and not regulated by the TGA.

                   Consumer advertising of compounded products is also unlawful. And in the last six months, the TGA has issued over 70 infringement notices, totalling over $1 million, to 19 entities, for unlawful advertising of prescription-only medicines, including more than $300,000 of fines in relation to the advertising of weight loss medicines.

                   So, the next steps. I think, importantly, the TGA does want to continue to work with key medical pharmacy and consumer stakeholders, and other health system regulators, to provide guidance in navigating the impact of these changes. The feedback from our stakeholders has noted a need for the regulatory reform of the compounding framework.

                   But I would like to just reassure everyone that we do see the compounding of medicines as a really important part of how the Australian public is able to access their medicines. But in a very, very small section of the community, who are not able to access the registered medicines that may suit them.

00:27:58

                   I'm going to stop here for a little bit and ask for you all to finish the questions from our survey. You can either use the app or use the QR code, and then, once you finish doing that, I'll restart again, and we'll go over some of the questions that were asked in the pre-webinar registration process, that you've asked. So I'll be quiet for a moment.

                   Apologies. There's a button down the bottom that says unmute. Some of the frequently asked questions here. Obviously, we've grouped a few of them where there were like questions. So, the first question was, is this change a reflection on the pharmacy profession? And as I've already said, I really would like to acknowledge the importance of pharmacy compounding clinical practice. And that pharmacy compounding remains fundamental to patient care, to improve treatment outcomes and medication compliance.

                   Pharmacists play an important role in compounding medicines in very specific clinical circumstances. And as mentioned in the presentation, the legislative change to the compounding of GLP-1 receptor agonists was an important regulatory response to mitigate the health and safety risks posed from large-scale compounding of GLP-1 receptor agonist products in Australia.

00:29:48

                   The next question is, what is the consequence for pharmacists found compounding after 1st October? Well, I hope you've picked up in the webinar that the TGA continues to dedicate significant resources to investigate and take appropriate enforcement action against anyone found to have breached the law.

                   You will be breaching the law if GLP-1 receptor agonists are compounded after October 1st. And that there are civil and criminal penalties, under the Therapeutic Goods Act, that may apply to anyone who is found to have unlawfully manufactured and supplied compounded products containing GLP-1 receptor agonists, following the implementation of the compounding changes from 1st October.

                   The next question. Is stockpiling of compounded receptor agonists permitted before 1st October? Well, I have to say that stockpiling of these products is not recommended and is not advised. There are serious health risks in stockpiling any medicine, and these are incredibly magnified when you have sterile compounding medicines, that you're dealing with these sterile compounding medicines.

                   The new Pharmacy Board guidelines that come into effect from 1st October notes that, due to the risks to patient safety associated with compounded, sterile, injectable medicines, as outlined in the Australian Pharmaceutical Formulary and Handbook, the default expiry date of sterile injectable medicines should be 24 hours or less from the time of compounding.

00:31:24

                   And that's when it's stored under the recommended storage conditions for the particular medicine, as a longer expiry date may result in the increased likelihood of microbial growth or contamination by microorganisms and bugs in the compounded medicine, a greater chemical instability of the compounded medicine, which may result in reduced activity of the drug. Or even greater toxicity caused by degradation of products, and also an increased likelihood of dose administration errors that's associated with the compounded medicine.

                   The next question is, can I import GLP-1 receptor agonist products through the personal importation scheme? And the answer is, the compounded medicines, such as compounded semaglutide medicine, could be imported by a patient via the personal importation scheme. But a prescription would be required to allow for this, and would need to be issued by an Australian medical practitioner.

                   Needless to say, though, the TGA does advise caution before importing any unapproved medicines into Australia for personal use, and that includes products subject to global shortages, such as Ozempic. The products the TGA does not regulate may not meet Australian manufacturing quality standards and could contain undisclosed harmful ingredients or be fake.

                   The TGA does not evaluate unapproved medicines for quality, safety or efficacy when imported via the personal importation scheme. And consumers must be prepared to take this risk when importing unapproved products for themselves and their families. The TGA has issued several safety alerts to remind consumers of the potential health risks of using an unapproved therapeutic good.

                   The next question pertains to how the TGA intends to provide access to these medications while they're still in shortage. As I've mentioned, we are working very hard to improve the shortage of the GLP-1 receptor agonists as quickly and effectively as possible. And as part of this, we've been regularly liaising with the sponsors of Ozempic and Mounjaro, Novo Nordisk and Eli Lilly, respectively.

00:33:44

                   It's critical that alternative treatments that are accessed during these situations have met the rigour of the TGA regulatory process, thus ensuring the maintenance of appropriate standards of quality, safety and efficacy of medicines supplied to Australian patients in large quantities. And we can see that the introduction of additional GLP-1 receptor agonist products should ease the supply pressures gradually.

                   The next question is, are there concerns about the longer-term health implications of GLP-1 receptor agonists, and what research is being done to understand their impact? Well, I think, as I've mentioned, the TGA has a very important role in monitoring long-term action, long-term adverse events and reports of any drugs that are registered in Australia. And that we have, also, a role in working with our global counterparts in regulatory medicine, to also understand the evidence and the data that's being produced from around the world.

                   Is there a possibility of reversal of this change in the future? Well, the main reason that this has been done is around public health and safety, and whilst these products were being produced in very large amounts, the answer would be no. The last question. Do you anticipate further changes to the way compounded medicines are regulated? I think the TGA has heard very loudly and very strongly from our stakeholders, and we're listening to the frustrations and the difficulties in the way that the current compounded medicine legislation is working.

00:35:35

                   And we certainly will be examining that legislation, and anticipate that there will be an intensive stakeholder process as part of that, as we move forward. We aim to absolutely be able to supply the Australian public with the very best regulatory oversights of the important goods and products that they access, that they need to access for their health.

So, this is my second-last slide. Please don't write all these down. They're going to be available both in the chat, and they will be available on this slide deck when they become available on our webpage in the coming days.

                   But it basically talks about the specific TGA websites for how to deal with substandard semaglutide vials, the compounding safety information, and what you need to know about compounded weight loss medicine, as well as the medicines shortage information, the webpage on the Ozempic shortage, on the Trulicity shortage, and also the shortage of Mounjaro injections.

                   The last slide is the email that you can use to contact us. If, for some reason, your question has not been answered by the webinar tonight, please feel free to drop us a line at this email. And we will endeavour to answer your question, in order that the entire community understands the reasons for this, and we're able to move forward, and the community is safer for it. I'm going to hand back over to the team now. Wish you all a very good evening.

UF              Thank you very much, Robyn. We will conclude there. We do have a couple more slides there, if I can get access to that. Just reminding you that these slides will be made available on the TGA website, and in the chat, we did have the presentation link to where this will be popped up on the website. We also have the social media slides coming up, where you can stay connected with us and subscribe to these updates through social media, and the links are also made available for you there. Thank you all, again, for joining us this evening, and we appreciate your feedback.

00:38:21